Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27](C=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[C:40](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:40][N:37]6[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: OC1CCNCC1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCC(O)CC5)cn4)sc23)c(F)c1)NC1CC1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a suspension of the aldehyde 47 (0.3 g, 0.669 mmol) in a mixture of DCM (9 mL) and DMF (3 mL) were added 4-hydroxypiperidine (0.135 g, 1.34 mmol) and acetic acid (0.08 mL, 1.34 mmol) at RT. The reaction mixture was stirred for 30 min; NaBH(OAc)3 (0.425 g, 2.00 mmol) was added and the reaction mixture was stirred overnight. More 4-hydroxypiperidine (0.135 g, 1.34 mmol) and NaBH(OAc)3 (0.425 g, 2.00 mmol) were added to the reaction mixture that was stirred at room temperature for 4 hr, then quenched by addition of saturated NaHCO3 solution and extracted with DCM/MeOH. The organic layer was washed with brine and dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel (DCM/MeOH:90/10 to 75/25) then triturated with MeOH to afford title compound 599 (0.17 g, 48% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.56-8.53 (m, 1H), 8.52 (d, J=5.4 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.1 Hz, 1H), 7.85 (dd, J=8.4, 2.4 Hz, 1H), 7.73 (dd, J=13.5, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.24-7.18 (m, 1H), 6.65 (d, J=5.4 Hz, 1H), 6.56 (d, J=2.1 Hz, 1H), 4.58 (d, J=4.2 Hz, 1H), 3.54 (s, 2H), 3.50-3.40 (m, 1H), 2.75-2.65 (m, 2H), 2.60-2.50 (m, 1H), 2.19-2.05 (m, 2H), 1.80-1.65 (m, 2H), 1.50-1.35 (m, 2H), 0.71-0.64 (m, 2H), 0.48-0.40 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[O:3]1.[CH2:9]=[O:10].O>CO.C(Cl)Cl>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH2:9][OH:10])[C:4](=[O:8])[O:3]1
Reactant: C=O
Reactant: Cn1oc(=O)[nH]c1=O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cn1oc(=O)n(CO)c1=O
Reaction time: 8 h

Procedure:
2-Methyl-1,2,4-oxadiazolidin-3,5-dione (2.0 grams; 0.0172 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (2.5 ml of 37% conc.; 0.0344 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. The reaction mixture was stirred overnight. After this time the reaction mixture was stripped of methanol and water to yield an oil. The oil was then dissolved in methylene chloride, and the resulting solution was washed with water. The washed solution was dried over anhydrous magnesium sulfate and stripped of solvent to yield the desired product 2-methyl-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.I[C:17]1[N:18]=[CH:19][N:20]([CH2:22][CH2:23][N:24]([CH2:32][CH2:33][O:34][CH3:35])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]3[N:18]=[CH:19][N:20]([CH2:22][CH2:23][N:24]([CH2:32][CH2:33][O:34][CH3:35])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH:21]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: COCCN(CCn1cnc(I)c1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCCN(CCn1cnc(-c2cc3nccc(Cl)c3s2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (1.39 g, 8.20 mmol) in THF (30 mL) at −15° C. was added n-BuLi (3.28 mL, 8.20 mmol). After 30 min, ZnCl2 (1.12 g, 8.20 mmol) was added at −15° C. and the reaction mixture was allowed to warm to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.126 g, 0.11 mmol) and iodide 249 (2.16 g, 5.47 mmol) in THF (10 mL) was added and the mixture was heated to reflux for 45 min then concentrated. The reaction mixture was diluted with water and ammonium hydroxide and extracted with DCM. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV), to afford the title compound 250 (2.37 g, 5.43 mmol, 99% yield) as light brown solid. MS (m/z): 437.45 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:33])[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I.CO>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:33])[N:18]([CH3:36])[C:19]2[CH:20]=[N:21][C:22]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncccc1Oc1ccc(NC(=O)c2cn(C(=O)OC(C)(C)C)c3ccccc23)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ncccc1Oc1ccc(N(C)C(=O)c2cn(C(=O)OC(C)(C)C)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.7 %

Procedure:
The 1H-indole-3-carboxylic acid[6-(2-methyl-pyridine-3-yloxy)-pyridine-3-yl]-amide (0.2 g, 0.58 mmol) in Example 6 was dissolved in dichloromethane (10 ml), and Boc2O (0.15 g, 0.7 mmol) and triethylamine (0.12 g, 1.16 mmol) were added to the solution. The reaction solution was stirred at room temperature for 2 hours, and then the product was washed, filtered, and dried to obtain tert-butyl-3-(6-(2-methylpyridine-3-yloxy)pyridine-3-ylcarbamoyl)-1H-indole-1-carboxylate (0.27 g, 0.52 mmol). The tert-butyl-3-(6-(2-methylpyridine-3-yloxy)pyridine-3-ylcarbamoyl)-1H-indole-1-carboxylate (0.27 g, 0.52 mmol) was dissolved in THF (10 ml), and NaH (21 mg, 0.54 mmol) and methyl iodide (0.95 g, 0.67 mmol) were added to the solution. The reaction solution was stirred at room temperature for 5 hours, and then the product was washed and filtered to yield tert-butyl-3-(methyl(6-(2-methylpyridine-3-yloxy)pyridine-3-yl)carbamoyl)-1H-indole-1-carboxylate (40 mg, 0.087 mmol) by chromatography (methanol:dichloromethane=1:20).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.C[O:22][C:23](=[O:29])[C@H:24]([CH2:26][CH2:27][CH3:28])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:3][CH2:2]1.[NH2:25][C@H:24]([C:23]([OH:29])=[O:22])[CH2:26][CH2:27][CH3:28]
Reactant: CCC[C@H](N)C(=O)OC
Agent: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 0.62 g N-(Morpholinocarbonyl)-L-phenylalanine-L-norvaline methyl ester in 40 mL methanol and 20 mL water was added 1.2 g potassium carbonate. The resulting mixture was stirred at ambient temperature for 60 h, afterwhich it was concentrated in vacuo to an aqueous solution and washed (3×50 mL) ether. The aqueous phase was acidified with 10 mL 4N hydrochloric acid solution and was extracted (3×25 mL) with methylene chloride. The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 0.46 g crude acid.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13](O)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1csc(Cc2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(Cc2ccccc2)n1

Procedure:
2-Benzyl-4-thiazolecarboxylic acid is converted to the methyl ester and the ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 2-benzyl-4-hydroxymethylthiazole. By the procedure of Example 1 this compound is converted to 4-[(2-aminoethyl)thiomethyl]-2-benzylthiazole. Using this compound as the starting material in the procedure of Example 110 gives N-[2-((2-benzyl-4-thiazolyl)methylthio)ethyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:24].O1CCCC1>O.C(#N)C>[Li+:24].[F:20][C:18]([F:19])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][C:3]([O-:22])=[O:2])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: COC(=O)CCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: O=C([O-])CCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 77.6 %

Procedure:
To 3-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-propionic acid methyl ester (480 mg; 1.52 mmol, prepared in accordance with Example 139) is added lithium hydroxide (72 mg; 3.00 mmol) dissolved in water (6.5 mL). After dilution with tetrahydrofuran (10 mL) the reaction mixture is stirred for 2-4 hours. The mixture is then diluted with acetonitrile until a precipitate is formed. The solid is collected by filtration and dried under high vacuum to deliver the desired compound (364 mg; 1.18 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:7]1[CH:11]=[N:10][N:9]=[C:8]1[CH2:12][CH2:13]O.CS(Cl)(=O)=[O:17].C(N(CC)CC)C>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:12]([C:8]1[O:7][CH:11]=[N:10][N:9]=1)([OH:17])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: OCCc1nnco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)(c1ccccn1)c1nnco1

Procedure:
As per scheme-9, 2-picolinic acid hydrazide (9-a) is reacted with pyruvic acid chloride in the presence of organic base such as triethylamine in dichloromethane at a temperature 0° C. to 5° C. for up to 3 hr. The reaction mixture is further treated with p-toluene sulfonyl chloride and is allowed to stir at ambient temperature for up to 16 hr to provide pyridine-1,3,4-oxadiazole compound 9-b. The compound 9-b, thus obtained, is reacted with reducing agent sodium borohydride in methanol or ethanol at a temperature 35° C. to provide pyridine-1,3,4-oxadiazole ethanol (9-c). The compound 9-c is reacted with methanesulfonylchloride in the presence of triethylamine in dichloromethane at a temperature ranging from 0° C. to 15° C. to provide corresponding methanesulfonyl ester of pyridinyl-1,3,4-oxadiazolyl-ethanol, which is converted to corresponding pyridine-1,3,4-oxadiazolyl ethyl bromide (9-d) by treating sulfonyl ester with lithium bromide in acetone at reflux temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.C(Cl)Cl.Cl[CH2:24][CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>O>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]2[CH2:24][CH2:25][CH2:26][S:27]2(=[O:29])=[O:28])[CH:11]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(Br)cc1N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Temperature: 25 °C

Procedure:
To a mixture of methyl 2-amino-4-bromobenzoate (5 g), triethylamine (5.73 mL), methylene chloride (39 mL) was added 3-chloropropanesulfonyl chloride (3.44 mL) under ice-cooling, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with diluted hydrochloric acid and saturated brine, and the solvent was evaporated. To the residue were added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.9 mL) and DMF (29 mL), and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and saturated brine, and the solvent was evaporated. To the residue was added isopropyl ether, and the precipitated solid was collected by filtration to give the title compound (5.045 g).
Reaction SMILES: [CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([S:17](C)=O)S[C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CCOC(C)=O>[CH3:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:17][C:20]=4[CH:21]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2ncn(Cc3ccc4nc(S(C)=O)sc4c3)c2cc1C
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1C
Temperature: 130 °C
Yield: 46.9 %

Procedure:
A stirred mixture of 6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (150 mg, 0.42 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol (140 mg, 1.2 mmol), DIEA (540 mg, 4.2 mmol) and NMP (2 mL) was heated at 130° C. for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and washed with water (10 mL×2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)-2-((6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (80 mg, 47%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.58 (m, 1H), 7.41 (s, 1H), 7.26-7.31 (m, 2H), 7.14 (m, 1H), 5.40 (s, 2H), 4.71 (d, J=3.0 Hz, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 2.30 (s, 6H), 2.02 (m, 1H), 1.88 (m, 1H), 1.86-1.90 (m, 2H), 1.12-1.27 (m, 4H); LCMS (ESI) m/z 407 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:27][CH2:28][N:29]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:15][CH:14]=3)=[O:13])[CH2:30][CH2:31]2)=[O:25])=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)NCc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(CNS(C)(=O)=O)cc3)CC2)cc1
Yield: 32 %

Procedure:
Using 4-(methanesulfonylaminomethyl)benzoic acid (145 mg) and (4-methylphenyl)(piperidin-4-yl)methanone hydrochloride (152 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (84 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:30]1[CH:31]=[CH:32][C:33]2[N:34]=[CH:35][N:36]=[C:37]([O:40][CH:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[C:38]=2[N:39]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])(=[O:10])=[O:11])=[CH:6][C:5]([C:30]2[CH:31]=[CH:32][C:33]3[N:34]=[CH:35][N:36]=[C:37]([O:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:38]=3[N:39]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(OC4CCOCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.02 g, 0.075 mmol) (Intermediate 3), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.032 g, 0.075 mmol), sodium bicarbonate (0.151 ml, 0.151 mmol) and PdCl2(dppf)-CH2Cl2Adduct (6.15 mg, 7.53 μmol) in dioxane (0.376 ml) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=2:1) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.02 g, 50%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=O)=[CH:19][CH:18]=1)#[N:11].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:33]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:33]=[C:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]#[N:11])=[CH:22][CH:21]=1)[C:24]2=[O:26]
Reactant: CN(C)C=O
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: N#CCCCCOc1ccc(CC(=O)O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: N#CCCCCOc1ccc(-c2coc3cc(O)c(Cl)cc3c2=O)cc1
Yield: 66.2 %

Procedure:
This compounds was synthesised in the same manner as described in Section 1.1.4.1. 4-Chlororesorcinol (0.37 g, 2.58 mmol), [[4-(4-Cyano-butoxy)-phenyl]-acetic acid (0.6 g, 2.28 mmol), BF3Et2O (5 ml), PCl5 (0.81 g, 3.89 mmol), DMF (8 ml and 12 ml). The precipitate formed was filtered and re-crystallized from methanol to give 5-[4-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-pentanenitrile as a white solid (0.63 g, 66.2%); Rf 0.65 ethyl acetate/hexane (80/20)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CCOC(=O)CC(=O)Cc1cccc(Cl)c1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-(3-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione according to the procedure for the preparation of Example 162, part A.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:19][CH2:20][OH:21])[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH2:19][CH2:20][O:21][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reaction time: 2 h

Procedure:
Combine 1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.15 g, 0.3 mmol) and dichloromethane (5 mL). Cool in an ice bath. Add N,N,-diisopropylethylamine (0.12 mL, 86.5 mg, 0.67 mmol), and methanesulfonyl chloride (0.035 mL, 52 mg, 0.46 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with aqueous 1 M hydrochloric acid solution, water, and then a saturated aqueous solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.23 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si](C)(C)C(C)(C)C(C)C)[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH2:33])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1.[F-].[NH4+]>CO>[CH3:1][O:2][C:3](=[O:34])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH2:33])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1
Reactant: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1c(C)c(OC)cc(O)c1CSC[C@H](N)c1nc(C)no1

Procedure:
(R)-2-[2-Amino-2-(3-methyl-1,2,4 -oxadiazol-5-yl)-ethylsulfanylmethyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methyl-benzoic acid methyl ester was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl -methyl]-3-hydroxy-5-methoxy-6-methyl-benzoic acid methyl ester as an amorphous foam.
Reaction SMILES: C(OC(N1C(C(=O)NC2C=C(Br)C=CC=2N)CC2(CC2)C1)=O)C1C=CC=CC=1.[CH2:29]([O:36][C:37]([N:39]1[CH:45]([C:46](=[O:56])[NH:47][C:48]2[CH:53]=[CH:52][C:51]([Br:54])=[CH:50][C:49]=2[NH2:55])[CH2:44][C:41]2(CC2)[CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(N1[C@H](C(O)=O)CC2([O:73][CH2:72][CH2:71][O:70]2)C1)=O)C1C=CC=CC=1>>[NH2:55][C:49]1[CH:50]=[C:51]([Br:54])[CH:52]=[CH:53][C:48]=1[NH:47][C:46]([C@@H:45]1[CH2:44][C:41]2([O:73][CH2:72][CH2:71][O:70]2)[CH2:40][N:39]1[C:37]([O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:38])=[O:56]
Reactant: O=C(O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCO2
Reactant: Nc1cc(Br)ccc1NC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Agent: Nc1ccc(Br)cc1NC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Product: Nc1cc(Br)ccc1NC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCO2

Procedure:
Title compound was prepared in quantitative yield according to the method employed to make 6-(2-Amino-5-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester and 6-(2-Amino-4-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester, substituting (S)-5-(benzyloxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid with (S)-7-(benzyloxycarbonyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylic acid (357 mg, 99%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:26])=[CH:20]4)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:27][CH3:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:28][O:27][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)[N:13]=[CH:12][N:11]=[C:10]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[CH:20]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCCl
Reactant: CN1CCNCC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCN(C)CC1
Yield: 32 %

Procedure:
A solution of 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (150 mg, 0.38 mmol), (prepared as described in Example 73), in 1-methylpiperazine (2 ml) was heated at 100° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and aqueous 5% sodium hydrogen carbonate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on an isolute column eluting with methanol/ethyl acetate/methylene chloride (1/4/5 followed by 1/9/0) and 3M ammonia in methanol/methanol/methylene chloride (5/10/80). After removal of the solvent under vacuum, the solid was dissolved in the minimum of methylene chloride and ether/petroleum ether was added. The precipitate was collected by filtration, and dried under vacuum to give 6-methoxy-4(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline (55 mg, 32%).