Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CN(C=O)C.O>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:11]=[CH:10]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.01 g, 2.93 mmol) in DMF (10 mL) was added sodium hydride (0.21 g, 5.25 mmol of 60% dispersion on mineral oil). It was stirred for 50 minutes at room temperature then chilled in an ice bath. Ethyl bromoacetate (0.48 mL, 4.3 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The mixture was poured into excess water, acidified with 2N hydrochloric acid, and extracted with diethyl ether. The ethereal extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 5-6% tert-butyl methyl ether in hexane as an eluant. The title compound was obtained as a yellow gum (0.749 g, 59%); 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 7.9-8.1 (m, 3H), 7.8-7.9 (m, 1H, 7.7-7.8 (m, 1H), 7.3-7.5 (m, 4H), 4.95 (s, 2H), 4.2 (q, 2H, J=7.2 Hz), 2.7 (t, 2H, J=7.6 Hz), 1.45-1.65 (m, 2H), 1.0-1.3 (m, 5H), and 0.7 ppm (t, 3H, J=7.6 Hz).
Reaction SMILES: [Br:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Br:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]2[O:19][CH:7]2[CH:6]=1
Reactant: BrC=CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: BrC=CCC1=CC2OC2C=C1
Reaction time: 168 h
Yield: 87.1 %

Procedure:
The mixture of 5.1 g of p-bromoallylbenzene, 8.5 g of m-chloroperbenzoic acid and 200 ml of chloroform was allowed to stand at about 5° C for 7 days. The resulting mixture was washed with 10% sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 4.8 g (yield 85%) of p-bromoallylbenzene oxide.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>>[F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH:37]([CH3:39])[CH3:38])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(OCCCN3CCC[C@H]3C)cnc21
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20), sodium hydride and 2-bromopropane, to give the desired product as a colorless oil (26%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C1(C)C=CC=CC=1.C(O)(=O)C>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CCO[SiH](OCC)OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 92 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane and 56 mg of toluene were placed in a glass reaction tube and 0.002 ml of acetic acid was then added. Then, 0.001 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.39%) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 96.6% and n-octyltriethoxysilane was produced at a yield of 92%.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([CH2:23][OH:24])[CH:17]=[CH:16]3)[CH2:2]1.C(Cl)Cl>>[CH2:5]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:1][CH2:2][CH:3]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([CH:23]=[O:24])[CH:17]=[CH:16]3)[CH2:4]1
Reactant: OCc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Solvent: ClCCl
Product: O=Cc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [6-(Spiro[5.5]undec-3-yloxy)-naphthalen-2-yl]-methanol (150 mg, 0.46 mmol) in methylene chloride (5 mL, 80 mmol) was added Des-Martin periodinane (0.274 g, 0.647 mmol) and the resulting solution was stirred at room temperature for 1 hour. The crude reaction was then passed through a silica gel plug, the filtrate was removed under vacuum to give 6-(spiro[5.5]undecan-3-yloxy)-2-naphthaldehyde as a colorless solid. (0.150 g, 100%). 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.25 (s, 1H), 7.92-7.89 (m, 2H), 7.78 (d, J=8.7 Hz, 1H), 7.24-7.19 (m, 2H), 4.48 (m, 1H), 1.96-1.29 (m, 18H).
Reaction SMILES: C([NH:4][C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[C:8]([C:14]([O:16]C)=[O:15])=[CH:7][C:6]=1[Cl:18])(=O)C.[OH-].[K+].Cl>O>[NH2:4][C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=1[Cl:18]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1c(Cl)cc(C(=O)O)c2c1OCO2
Yield: 96.9 %

Procedure:
Intermediate 21 (18.2 g) was added to a solution of KOH (37.6 g) in water (380 ml). The resulting reaction mixture was stirred and refluxed for 3 hours. The mixture was cooled, acidified with hydrochloric acid, and the resulting precipitate was filtered off, washed with water, suspended in ACN, filtered off, then dried, yielding 14 g (>95%) of 7-amino-6-chloro-1,3-benzodioxole-4-carboxylic acid (intermediate 22).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][NH2:33].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:33][CH2:32][C:23]4[CH:24]=[CH:25][C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: NCc1ccc2ccccc2n1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5ccccc5n4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (150 mg, 0.52 mmol) and quinolin-2-ylmethanamine hydrochloride (206.0 mg, 1.058 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (1 mL, 6 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (30-60% acetonitrile-water [10 mM DEA]) to afford a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]2[CH2:15][CH2:14]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(C2CC2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.90 g (12.6 mmol) 6-bromo-pyridine-2-carboxylic acid ethyl ester in 25 mL toluene was added 3.00 g (29.7 mmol) cyclopropylboronic acid and 5.50 g (25.9 mmol) potassium phosphate followed by 700 mg (0.957 mmol) 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II). The reaction mixture was stirred at 100° C. for 8 h. 1.00 g (9.90 mmol) of cyclopropylboronic acid and 1.50 g (7.07 mmol) of potassium phosphate were added and the mixture was stirred at 100° C. for 5 h. The reaction mixture was filtered through Celite, and washed with DCM and the solvent was evaporated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=4/1→2/1).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])=[O:9].Cl>CO>[OH:15][CH2:14][C:13]1[CH:17]=[CH:18][C:10]([C:8]([O:7][CH3:6])=[O:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Tetrahydrofuran solution of 1.0M borane-tetrahydrofuran complex was added dropwise to tetrahydrofuran solution (45 mL) of 2.25 g of 4-methoxycarbonyl-3-nitrobenzoic acid and stirred at room temperature for 48 hours. Methylalcohol (2 ml) and 1N hydrochloric acid (10 ml) were added thereto and concentrated. After ethyl acetate and water were added, liquid separation was conducted. The organic layer was washed with saturated sodium hydrogen carbonate and dried over sodium sulfate. After removing the solvent, the obtained crude material was purified with silica gel column chromatography to obtain 1.33 g of methyl 4-hydroxymethyl-2-nitrobenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=3)=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.ClCCl.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(OCC)(=O)C>[CH:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=2)[C:6]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=2)=[CH:7]1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cc(-c2cc(F)c(F)c(F)c2)c2ccc(N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2cc(F)c(F)c(F)c2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Method I Combine 6-amino-1-isopropyl-3-(3,4,5-trifluoro-phenyl)-1H-indole (116.6 mg, 0.38 mmol), prepared as described immediately above, dichloromethane (3.0 mL) and pyridine (62 μL, 0.76 mmol) under a nitrogen atmosphere in a 25 mL flask. Cool the reaction to 0° C. and add methane sulfonyl chloride (33 μL, 0.42 mmol). Allow the reaction to warm to RT while stirring for 3 hours. Quench reaction with saturated aqueous sodium bicarbonate (5 mL), dilute with ethyl acetate (10 mL) and separate the layers. Wash the organic layer with water (5 mL), brine (5 mL), dry (Na2SO4) and filter. Concentrate the filtrate and adsorb the crude product onto silica gel. Purify by silica gel chromatography eluting with ethyl acetate in dichloromethane (0-5 v/v %) to give 95.1 mg of the title compound (61%). LRMS (API ES+)=383.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]OCCOC)=[C:7]([O:15][CH3:16])[N:6]=[C:5]([C:17]([F:20])([F:19])[F:18])[C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[ClH:26]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:26][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:17]([F:20])([F:19])[F:18])=[N:6][C:7]=1[O:15][CH3:16]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(OC)c(COCCOC)c1OC
Reactant: Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nc(OC)c(CCl)c1OC
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of 15.5 g (0.0289 mol) of product of Example 26 in 30 ml of CH2Cl2 cooled in a ice water bath was added 12.0 g of titanium tetrachloride. The reaction mixture turned brown with formation of a white precipitate. After stirring at 10°-15° C. for 20 minutes, then at 20° C. for 20 minutes, the reaction mixture was poured into 70 ml of 6N HCl. The CH2Cl2 layer was separated, dried (MgSO4) and concentrated. The residue was kugelrohr distilled at 2 torr (pot temperature 140° C.) to give 9.1 g (97%) of product as a colorless liquid; nD25 1.4738.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:26]=3)[N:21](C(OC(C)(C)C)=O)[CH:20]=2)[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[N:16]=[N:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1cc(-c2cnc3c(c2)c(-c2cn(Cc4ccccc4)nn2)cn3C(=O)OC(C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1cc(-c2cnc3[nH]cc(-c4cn(Cc5ccccc5)nn4)c3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 88 mg (0.63 mmol) of potassium carbonate are added to a solution of 115 mg (0.25 mmol) of tert-butyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-1-carboxylate in 1.3 ml of methanol, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is adsorbed onto kieselguhr and chromatographed on a silica-gel column with dichloromethane/methanol/ammonia water, giving 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine as colourless crystals; ESI 356;
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Br)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[NH:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][N:27]3[CH2:26][CH2:25][CH:24]([N:23]4[C:22]5[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=5[NH:20][C:19]4=[O:18])[CH2:29][CH2:28]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(CBr)Nc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
A mixture of N-(4-cyclohexyl-phenyl)-2-bromoacetamide (50 mg, 0.17 mmol), 4-(2-keto-1-benzimidazolinyl)-piperidine (41 mg, 0.18 mmol), and potassium carbonate (34 mg, 0.25 mmol) in dimethylsulfoxide (2 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated to give a yellow oil. The crude oil was purified on reverse phase silica gel column using 100% acetonitrile to give N-(4-cyclohexyl-phenyl)-2-[4-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)-piperidin-1-yl]-acetamide as a yellow solid (21 mg, 30%): mp 130-132° C. 1H NMR (300 MHz, CDCl3) d 9.28 (s, 1H), 9.05 (s, 1H), 7.53 (d, 2H), 7.22 (d, 2H), 7.11 (m, 4H), 4.33 (m, 1H), 3.22 (s, 2H), 3.12 (d, 2H), 2.40 -2.60 (m, 5H), 1.70-1.90 (m, 7H), 1.20 -1.60 (m, 5H). MS m/z 433 (M+H+).
Reaction SMILES: [C:1]([N:20]1[N:24]=[N:23][C:22]([CH2:25][C:26]([OH:28])=O)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=C[N:31](C(N2C=NC=C2)=O)C=1.NC1C=CC(C(N2CC3(C)CC2CC(C)(C)C3)=O)=CC=1>C1COCC1>[C:1]([N:20]1[N:24]=[N:23][C:22]([CH2:25][C:26]([NH2:31])=[O:28])=[N:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Solvent: C1CCOC1
Product: NC(=O)Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.17 h

Procedure:
To a solution of (2-trityl-2H-tetrazol-5-yl)-acetic acid (0.82 g, 2.20 mmol) in dry THF (50 ml) was added CDI (0.4 g, 2.39 mmol) and the resulting mixture was stirred for 10 min. To this mixture was added (4-amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (0.5 g, 1.84 mmol) and the stirring was continued for 18 hrs. at room temperature. The mixture was evaporated and the residue purified by column chromatography (silica gel) using EtOAc-Heptane (4:1) as eluent. Pure fractions were collected and evaporated to dryness affording 150 mg (13%) of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-2-(2-trityl-2H-tetrazol-5-yl-acetamide which was dissolved in THF (25 ml) followed by addition of 20% aqueous HCl (20 ml). The mixture was stirred for 2 hrs. at room temperature at which time the volatiles were removed in vacuo. The aqueous residue was extracted with EtOAc (2×50 ml), dried (Na2SO4), filtered and evaporated in vacuo affording 30 mg (4%) of the title compound as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][C:14]=2[F:21])=[CH:10][C:9](=[O:22])[N:8]([CH3:23])[CH:7]=1)=[O:5])C.[OH-].[Na+]>CCO>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:11]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:23])[C:9](=[O:22])[CH:10]=2)=[C:14]([F:21])[CH:15]=1)[CH3:20]
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc(CC)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
4-(4-Ethyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (9.20 g, 28.90 mmol) was dissolved in EtOH (100 mL) and treated with NaOH (3.50 g, 86.70 mmol). This mixture was stirred at 90° C. for 2 hours to hydrolyze the ester as in Example 1, alternate Step C to give 4-(4-Ethyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid as a white solid (8.30 g, 98%). 1H NMR [(CD3)2SO, 400 MHz] δ 13.21 (v br s, 1H), 9.41 (s, 1H), 8.49 (s, 1H), 7.35 (dd, J=10.1, 1.9 Hz, 1H), 7.19 (dd, J=8.4, 1.7, 0.8 Hz, 1H), 7.06 (dd, J=8.5 1.9 Hz, 1H), 5.33 (dd, J=0.7 Hz, 1H), 3.37 (s, 3H), 2.57 (q, J=7.2 Hz, 2H). 1.16 (t, J=7.1 Hz, 3H). (APCI+) calcd for C15H15FN2O3 290.29 (M+1), found 291.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22]Cl)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[CH3:24][S-:25].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:25][CH3:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[S-]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCSC
Temperature: 60 °C
Yield: 53.4 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.53 mmol), sodium thiomethoxide (0.48 g, 6.80 mmol), and anhydrous dimethyl formamide (18 mL) under a nitrogen atmosphere. The reaction mixture was heated to 60° C. to give a homogeneous solution that was maintained at 60° C. for 16 hours at which time the starting material was completely consumed. The solution was cooled and then partitioned between chloroform and water. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The combined aqueous layers were extracted with chloroform (1×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark brown oil. The material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide a light yellow solid. The solid was recrystallized from dimethyl formamide and water to give 2-butyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.83 g, 2.42 mmol) as light yellow needles, m.p. 127-130
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][C:22](O)=[O:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.S(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][CH2:22][OH:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Solvent: CSC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OCCC2CCO
Temperature: 0 °C

Procedure:
To a solution of [7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-acetic acid (1.5 g, 4.28 mmol) in THF 40 ml) was added BH3 Me2S (0.41 ml, 4.32 mmol) at 0° C. The mixture was stirred in the ice bath for 30 minutes and then at room temperature overnight. The mixture was quenched with MeOH and the solvent was removed. The residue was dissolved in EtOAc, washed with brine, dried with MgSO4, filtered and concentrated to give 2-[7-(3-Fluoro-benzenesulfonyl)-chroman-4-yl]-ethanol as a clear syrup: 1.35 g; MS: 337.2 (M+H)+, 378.2(M+CH3CN+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21](=[O:26])C(F)(F)F)=[CH:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:30]>CN(C)C=O>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21]([OH:26])=[O:30])=[CH:12]1)=[O:27])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(CCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCn1cc(C(=O)O)c2ccc(Cl)cc21)C(=O)OC(C)(C)C

Procedure:
To a solution of 15.4 g (38.0 mmol) crude {2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-methyl-carbamic acid tert-butyl ester in 380 ml N,N-dimethylformamide were slowly added 11.0 g (228 mmol) sodium hydride (50%, dispersion in oil) followed by 3.40 ml (190 mmol) water at 15-22° C. After stirring for 1 h at room temperature 500 ml water were added slowly. The mixture was washed with two 300-ml portions of tert-butyl methyl ether. The combined organic layers were extracted with 300 ml of a 0.5 M aqueous solution of sodium hydroxide. The combined aqueous layers were acidified to pH 2 with an ice-cold 4 M aqueous solution of hydrochloric acid at 0-5° C. and extracted with two 400-ml portions of ethyl acetate.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([CH3:39])([CH3:38])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]1.[NH2:40][CH2:41][C:42]1[CH:61]=[CH:60][C:45]([C:46]([N:48]([CH3:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)=[O:47])=[CH:44][C:43]=1[CH3:62].CCN(C(C)C)C(C)C>ClCCl>[CH3:62][C:43]1[CH:44]=[C:45]([C:46](=[O:47])[N:48]([CH3:59])[C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:56])([F:57])[F:58])=[CH:51][CH:50]=2)[CH:60]=[CH:61][C:42]=1[CH2:41][NH:40][C:35]([CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][C:26]([CH3:25])([CH3:39])[CH3:38])[CH2:34][CH2:33]1)=[O:37]
Reactant: CC(C)(C)CCN1CCC(C(=O)O)CC1
Reactant: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1CN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1CNC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
PyBroP (188 mg, 0.40 mmol) and 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid (82 mg, 0.38 mmol) were added to a solution of 4-aminomethyl-3,N-dimethyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.3 (100 mg, 0.31 mmol) in dichloromethane (5 ml) and DIEA (0.081 ml, 0.46 mmol). The mixture was stirred at room temperature for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a off-white powder identified as the title compound (22 mg, 14%).