Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:29]([CH2:28][C@H:25]2[CH2:24][CH2:23][C:22]3[S:21][C:20]4[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]5[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]5)[C:27]=4[C:26]2=3)=[O:30])=[N:38][CH:39]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Reactant: Nc1ccc(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Yield: 83.7 %

Procedure:
A solution of 35.1 (200 mg, 0.43 mmol, 1.00 equiv), 5-fluoropyridin-2-amine (55 mg, 0.49 mmol, 1.13 equiv), HATU (200 mg) and DIPEA (170 mg) in distilled DMF (8 mL) was stirred at room temperature under nitrogen for 2 h. The reaction was then quenched with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) to give tert-butyl N-(4-[[(3R)-3-[[(5-fluoropyridin-2-yl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (36.1, 200 mg, 83%) as a yellow oil. MS: m/z 556 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:7][C:6]=2[CH:25]=1.[H-].[Na+].[CH3:28][O:29][CH2:30]Br>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:28][O:29][CH3:30])[C:10](=[O:12])[CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:25]=1
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)C(C(=O)OC)C(c2ccc(OC)cc2)Cc2cc(Cl)ccc21
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (270 mg; 0.75 mmole; see Example 1C) in dimethylformamide (10 ml), cooled at 0°-5° C. in an ice-water bath, was added 50% sodium hydride (72 mg; 1.5 mmole). After stirring at 0°-5° C. for 15 minutes, methoxymethylbromide (240 μ; 3 mmole) was added dropwise. The reaction mixture was allowed to stir at 0°-5° C. for two additional hours. The excess sodium hydride was destroyed by the addition of water, and the resulting mixture was extracted with ether. The aqueous layer was extracted with ether (three times) and the combined organic layers were dried (magnesium sulfate) and concentrated. The crude residue was flash chromatographed (silica gel/5-20% ethyl acetate:hexane) yielding 233 mg of the title compound as an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCl>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: C1=C(CCc2ccco2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: c1coc(CCC2CCNCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A cooled (0° C.) solution of 1-benzyl-4-(2-[furan-2-yl]ethyl)-1,2,3,6-tetrahydropyridine (1.8 g, 6.8 mmol) in anhydrous dichloromethane (20 ml) was treated with 1-chloroethylchloroformate (0.95 ml, 8.8 mmol) dropwise. The mixture was stirred for 1 hr at 0° C. The solvent was evaporated and the residue dissolved in methanol (60 ml). This solution was heated at reflux for one hour whereupon the solvent was evaporated. The residue was partitioned between dichloromethane and saturated aqueous potassium carbonate solution. The organic phase was separated, dried (Na2 SO4) and evaporated to give the title compound (867 mg, 72%) as a colourless oil; δH (DMSO-d6) 1.84-1.96 (2H, m, tetrahydropyridinyl CH2), 2.16-2.30 (2H, m, CH2), 2.64-2.80 (4H, m, tetrahydropyridinyl CH2 and CH2), 3.06-3.10 (2H, m, tetrahydropyridinyl CH2), 5.40-5.46 (1H, m, tetrahydropyridinyl 5-H), 6.06-6.12 (1H, m, furanyl H), 6.32-6.38 (1H, m, furanyl H), and 7.48-7.56 (1H, m, furanyl H).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]2[O:20][CH2:19][O:18][C:17]=12)[CH:8]=[C:9]([CH2:12][O:13][CH3:14])[C:10]#[N:11])[CH3:3].[CH3:21][OH:22]>>[CH3:14][O:13][CH:12]([O:22][CH3:21])[CH:9]([C:10]#[N:11])[CH2:8][C:7]1[CH:15]=[C:16]2[O:20][CH2:19][O:18][C:17]2=[C:5]([O:4][CH2:2][CH3:3])[CH:6]=1
Reactant: CO
Reactant: CCOc1cc(C=C(C#N)COC)cc2c1OCO2
Agent: [Na]
Product: CCOc1cc(CC(C#N)C(OC)OC)cc2c1OCO2

Procedure:
To 6.6 g. sodium dissolved in 96 ml. of methanol, 37.5 g. of 3-ethoxy-4,5-methylenedioxy-α-methoxymethylcinnamonitrile were added. The resulting mixture was refluxed for 24 hours. The solution was poured into 400 ml. water and was extracted with methylenechloride. Upon evaporation of the solvent, the product, 3-ethoxy-4,5-methylenedioxy-α-cyanodihydrocinnamaldehyde dimethylacetal, was vacuum distilled and had a b.p. of 191°/0.4 mmHg., nD23 = 1.5340.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([O:20][CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2cc(Cl)ccc2C#N)ccc1C=O
Yield: 82.9 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.60 g, 3.9 mmol), 4-hydroxy-2-methoxybenzaldehyde (0.59 g, 3.9 mmol) and cesium carbonate (1.26 g, 3.9 mmol) were heated with stirring in dry DMF (4 ml) at 50° C. for 21 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, 10% aqueous sodium carbonate (2×), water (2×), brine, and dried over magnesium sulphate. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(4-formyl-3-methoxy-phenoxy)-benzonitrile (0.93 g, 83%) as an orange solid.
Reaction SMILES: [SH2:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1>CO>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[S:1])[NH2:10])=[CH:4][CH:3]=1
Reactant: S
Reactant: N#CCc1ccncc1
Solvent: CO
Product: NC(=S)Cc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
Hydrogen sulfide was passed through a solution of 2-(pyridin-4-yl)acetonitrile (2.5 g) in 30% strength ammoniacal methanol (12 ml) at 0° C. for 30 minutes. The resulting reaction mixture was stirred at 25° C. for 16 hours. The solid which had precipitated was filtered out, washed with ether and dried. The desired product was obtained in a yield of 76%.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[CH2:20]O.C(N(CC)C(C)C)(C)C.[CH3:37][O:38][C:39](=[O:62])[C@H:40]([CH2:49][C:50]1[N:54]=[CH:53][N:52](C(OC(C)(C)C)=O)[CH:51]=1)[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].P([O-])([O-])([O-])=O>C(Cl)Cl>[CH3:37][O:38][C:39](=[O:62])[C@H:40]([CH2:49][C:50]1[N:54]([CH2:20][C:19]2[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:17]([CH3:16])[CH:18]=2)[CH:53]=[N:52][CH:51]=1)[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cncn1Cc1ccc([N+](=O)[O-])c(C)c1)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
Trifluoromethanesulfonic anhydride (10.00 g, 0.0354 mol) and dry methylene chloride (60 ml) were placed into a 500 ml separable flask having its interior atmosphere replaced with well dried nitrogen gas, and cooled to -70° C. Then a solution of 3-methyl-4-nitrobenzyl alcohol (5.34 g, 0.0325 mol) and N,N-diisopropylethylamine (6.2 ml, 0.0356 mol) in dry methylene chloride (40 ml) was added dropwise over a period of 15 minutes, followed by stirring for 30 minutes, after which a solution of N,1-bis-t-butoxycarbonyl-L-histidine methyl ester (XI-2) (10.00 g, 0.0271 mol) in dry methylene chloride (40 ml) was further added dropwise over a period of 20 minutes. Thereafter, the reaction flask was taken out of the cooling bath and the mixture was stirred at room temperature for 6 hours. The reaction mixture during rapid stirring was poured into a 0.2M phosphate buffer solution (about 400 ml) to separate the methylene chloride layer, and the residue was washed with a 0.2M phosphate buffer solution (about 400 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an orange-colored oily material (12.07 g). This crude oily material was purified by silica gel column chromatography (LiChroprep Si60, 300 g, chloroform/methanol=30/1) to obtain the objective compound (IX-2) (4.45 g; yield: 39.3%) as a light-yellow oily material.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:34])[C@@H:16]([NH:20][C:21](=[O:33])[C@@H:22]([N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])[CH3:23])[CH:17]([CH3:19])[CH3:18])=[O:5])C.[OH-].[Li+]>C1COCC1.O.CO>[C:29]([O:28][C:26]([N:24]([CH3:25])[C@@H:22]([CH3:23])[C:21]([NH:20][C@@H:16]([CH:17]([CH3:18])[CH3:19])[C:15]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][C@H:6]1[C:4]([OH:5])=[O:3])=[O:34])=[O:33])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 97.9 %

Procedure:
To a solution of (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.93 g, 6.16 mmol) in THF/water/methanol (3:1:1; 60 mL) was added 1 M aqueous lithium hydroxide (18.5 mL, 18.5 mmol). The reaction mixture was stirred at 23° C. for 2.5 h and then concentrated in vacuo. The residue was diluted with water and acidified with 6 M and then 1 M aqueous HCl to pH˜2. The mixture was extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuo to give (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-indole-2-carboxylic acid (2.70 g) as an off-white foam, m/z=470 (M+Na).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH2:35][CH2:36][S:37][CH3:38])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:48])C=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:34][CH2:35][CH2:36][S:37]([CH3:38])=[O:48])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCSC)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
180 mg 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-(methylsulfanyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (0.326 mmol, 1.0 eq.) were dissolved in 1.7 mL chloroform and cooled to 0° C. 80.3 mg 3-chlorobenzenecarboperoxoic acid and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with DCM and a solution of sodium thiosulfate (10% in water) was added and stirred for 5 minutes. The layers were separated and the aqueous layer was washed with DCM twice. The combined organic layers were washed with saturated sodium hydrogencarbonate solution, was dried over a silicon filter and concentrated in vacuo. The crude product was purified by flash chromatography to provide 136 mg of the analytically pure target compound as a racemate.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([SH:25])=[N:22][C:21]=2[CH:26]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:28])([F:27])[F:15])=[CH:26][C:21]=3[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Product: O=C(CSc1nc2cc(C(F)(F)F)ccc2s1)N1CCCc2ccccc21
Yield: 80 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 5-(trifluoromethyl)benzo[d]thiazole-2-thiol as the nucleophile to yield 23 as a white solid (80%): MS m/z: 409 (M+H)+. Anal. Calcd. For, C19H15F3N2OS2: C, 55.87; H, 3.70; N, 6.86; S, 15.70; F, 13.95. Found: C, 55.79; H, 3.71; N, 6.92; S, 15.67; F, 14.07.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].N1CCOCC1.C(O)(C(F)(F)F)=O>CO.ClCCl>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][C:26]2([NH:6][C:4](=[O:5])[C:3]3[CH:7]=[C:8]([C:11]4[NH:15][N:14]=[N:13][N:12]=4)[CH:9]=[CH:10][C:2]=3[O:1]2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: NC(=O)c1cc(-c2nnn[nH]2)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(-c3nnn[nH]3)ccc1O2
Yield: 21.6 %

Procedure:
A mixture of 75 mg (0.37 mmol) of 2-hydroxy-5-(1H-tetrazol-5-yl)benzamide, 110 mg (0.55 mmol) of 1-Boc-4-piperidone, and 71 μL of morpholine in 8 mL of MeOH is refluxed for 72 hr. The MeOH is removed by rotoevapoation and the residue is purified by preparative TLC to give 29 mg (0.08 mmol, 15% yield) of 1′-(tert-butyloxycarbonyl)-6-(1H-tetrazol-5-yl)spiro[1,3-benzoxazine-2,4′-piperidine]-4(3H)-one which on treatment with 40% TFA in dichloromethane at room temperature for 3 hr. gives the TFA salt of 6-(1H-tetrazol-5-yl)spiro[1,3-benzoxazine-2,4′-piperidine]-4(3H)-one in quantitative yield.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:35][CH2:34][CH2:33]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:35][CH2:34][CH2:33]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from trans-4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A173) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[C:11]([OH:13])=[O:12].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.O.[Cl-].[Zn+2].[Cl-]>[I:14][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4]2
Reactant: O=I(=O)Cl
Reactant: O=C(O)[C@H]1CCc2ccccc2O1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)[C@H]1CCc2cc(I)ccc2O1

Procedure:
(2R)-3,4-Dihydro-2H-chromene-2-carboxylic acid (WO 99/32476) (26.7 g, 150 mmol), benzyltrimethyl-ammonium dichloroiodate (50.1 g, 144 mmol) and zinc chloride (25.3 g, 186 mmol) were stirred in glacial acetic acid (500 mL) under argon at room temperature for 18 hours. The solid was removed by vacuum filtration and then washed with acetic acid (100 mL). The filtrate was concentrated in vacuo to obtain a solid which was slurried in water (300 mL). The crude product was obtained as a pink solid after vacuum filtration and dried (38.3 g, 84%): 1H NMR (DMSO-d6) δ1.95-2.10 (m, 1H), 2.60 (m, 1H), 2.70-2.80 (m, 1H), 4.79 (dd, J=6.0, 3.9 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H). CI-MS m/z 305 (M+H+). The crude was used for next step directly.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:1][C:2]1[N:7]=[C:6]([OH:13])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(O)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A 3-necked roundbottom flask was charged with a solution of 6-methyl-5-nitropyridin-2-amine (20 g, 130.72 mmol) in water (330 ml). To the mixture was added sulfuric acid (23.6 ml). The mixtir was cooled to 0° C. and a solution of sodium nitrite (12.0 g, 173.91 mmol) in water (30 ml) was added dropwise. The resulting solution was allowed to react, with stirring, for 20 at 0° C. and then allowed to warm to room temperature and stirred for an additional one hour. The resulting slurry was filtered and the solids collected to afford the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[BH4-].[Na+].C(O)C.C(O)(=O)C>O>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCC(=O)CCCCCNc1ccc(C(=O)OCC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCC(O)CCCCCNc1ccc(C(=O)OCC)cc1

Procedure:
A suspension of 10 g. of ethyl 4-(6-oxohexadecylamino)benzoate and 2.8 g. of sodium borohydride in 250 ml. of ethanol is stirred at ambient temperature for 3 hours, acidified with glacial acetic acid, and poured into water. The solid is collected by filtration, dried, and recrystallized from hexane to yield the product as a white solid. Alkaline hydrolysis of this ester by the method of Example 10 affords 4-(6-hydroxyhexadecylamino)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:26]2[CH2:27][CH2:28][N:23]([C:15]3[CH:16]=[CH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[CH:19][C:14]=3[CH:11]3[CH2:13][CH2:12]3)[CH2:24][CH2:25]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: O=C(c1ccc(Br)nc1)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 100 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)piperazine (3 g), di-tert-butyl dicarbonate (3.23 g), triethylamine (5.5 mL) and methanol (30 mL) was stirred at room temperature for 5 hr. Water and ethyl acetate were added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(2,4-dichlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g). To a solution of 4-(2,4-dichlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g) in tetrahydrofuran (15 mL) were added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (809 mg), palladium acetate (442 mg), tripotassium phosphate (11 g) and cyclopropylboronic acid (2.54 g), and the mixture was refluxed for 7 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(2,4-dicyclopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g). 4-(2,4-Dicyclopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g) was dissolved in dichloromethane (20 mL), 4N hydrogen chloride/dioxane (10 mL) was added, and the mixture was stirred at room temperature for 3.5 hr. Diethyl ether (100 mL) was added, and the precipitate was collected by filtration. To the obtained precipitate were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(2,4-dicyclopropylphenyl)piperazine (1.6 g). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (237 mg) and 1-(2,4-dicyclopropylphenyl)piperazine (300 mg), the title compound (500 mg) was obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[S:40][CH:41]=[C:42]([C:44]([NH:46][CH:47]2[CH2:49][CH2:48]2)=[O:45])[N:43]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:47]1([NH:46][C:44]([C:42]2[N:43]=[C:39]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:9][N:8]=5)[CH:11]=4)[NH:15][CH:14]=3)[S:40][CH:41]=2)=[O:45])[CH2:48][CH2:49]1
Reactant: O=C(NC1CC1)c1csc(Br)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4nc(C(=O)NC5CC5)cs4)c3c2)o1
Yield: 29.9 %

Procedure:
The title compound (34 mg, 30% yield) as a yellow crystalline solid was prepared according to Example 275, using N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (145 mg, 0.278 mmol), 2-bromo-N-cyclopropylthiazole-4-carboxamide (75 mg, 0.305 mmol), and Pd(PPh3)4 (Strem Chemicals, 16 mg) as the starting materials and reagent. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (1H, br.), 8.57 (1H, s), 8.29 (2H, m), 8.15 (1H, s), 7.74 (1H, d, J=7.4 Hz), 7.65 (2H, d, J=8.6 Hz), 3.77 (1H, m), 2.90 (1H, m), 1.25 (6H, d, J=6.1 Hz), 0.75 (2H, m.), 0.69 (2H, m). MS (ESI, pos. ion) m/z 409.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(Br)cc1)c1ccccc1F)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-3-(2-fluoro-phenyl)-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless solid, MS (ESI+): m/z=400.0 [M+H]+.