Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]2[C:20]([C:21](=[O:23])[CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].O.OS([O-])(=O)=O.[K+]>S(=O)(=O)(O)O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:22]=[C:21]([OH:23])[C:20]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[CH:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C#Cc2ncccc2C(C)=O)cc(OC)c1OC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: COc1cc(-c2cc(O)c3cccnc3c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
90 mg 1-(2-(3,4,5-trimethoxyphenylethynyl)pyridin-3-yl)ethanone were suspended in 750 μL 1N sulfuric acid and 4 mg mercuric chloride and stirred for 1 h 45 minutes at 60° C. Then 2 mL of NaOH was added and the mixture stirred for additional 1 h at 25° C. Water was added and a neutral pH was adjusted with KHSO4 solution. The precipitate was filtered off and washed with water and dried to yield 80 mg 7-(3,4,5-trimethoxyphenyl)quinolin-5-ol 6.2 as solid. Analysis: HPLC-MS: Rt=1.18 min (method D), M+H=330.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=1/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([O:6][CH3:7])=[O:5].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]([C:11]1[S:12][C:8](/[C:3](=[CH:2]\[O:1][CH3:26])/[C:4]([O:6][CH3:7])=[O:5])=[C:9]([CH:16]=[CH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:10]=1)([CH3:15])[CH3:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(=CO)c1sc(C(C)C)nc1/C=C/c1ccccc1
Agent: CO/C=C(/C(=O)OC)c1sc(C(C)C)nc1/C=C/c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CO/C=C(/C(=O)OC)c1sc(C(C)C)nc1C=Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The product of Step G was dissolved in 20 ml of acetone and then 3 ml of methyl iodide and 4 g of potassium carbonate were added. The mixture was stirred for 16 hours at 20° C. After bringing the mixture to dryness, the residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (8-2) to obtain 1.3 g of the desired product. Thin layer chromatography; Rf=0.20 [eluant: hexane-ethyl acetate (8-2)].
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:14])[CH2:3]1
Reactant: CN1CC(=O)Nc2ccccc2C1=O
Reactant: O=[N+]([O-])O
Product: CN1CC(=O)Nc2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
300 ml of 89 percent nitric acid are treated portionwise at room temperature over a period of 35 minutes with 94.5 g (496.8 mmol) of 3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione. The mixture is stirred at room temperature for 18 hours and poured into 3.5 l of ice-water. The precipitated material is filtered off under suction, washed with water and dried at 70° in vacuo. There is obtained 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 252°-253°.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C@@H:7]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:27][CH:26]=1.[O-]CC.[Na+].O.[OH-].[Li+].C(O)(=O)C>C(O)C.O>[O:1]=[C:2]1[O:6][C@H:5]([C@@H:7]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH:3]1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: BrCc1ccc(-c2ccccn2)cc1
Agent: CC[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccn3)cc2)C(=O)O1
Temperature: 3 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
450 g of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate was treated with 1.1 equivalents of diethyl malonate and 1.05 equivalents of sodium ethoxide in 1200 mL of ethanol at 5° C. for 0.5 hr, then at 25° C. for 5 hrs. The reaction mixture was quenched with acetic acid till the pH of the mixture was about 6. The reaction mixture was extracted with ethyl acetate (4 L) and the isolated organic phase was washed sequentially with 25% brine (4 L), 5% NaHCO3 (5L), and 25% brine (4 L), dried over NaSO4, filtered, concentrated and chased with 2 L of methyl tert-butyl ether to dryness. The oil was dissolved in 950 mL of methyl tert-butyl ether and warmed to 45° C., added heptane (4L) and cooled to −5° C. The solid was isolated by filtration to provide tert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate. A mixture of the tert-butyl (1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate (400 g, 1.028 mol), the product of Example 111-7 (321 g, 1.08 mol, 1.05 equivalents) in absolute ethanol (3.35 L) was cooled to 5° C. was treated with a solution of sodium ethoxide (77.5 g sodium ethoxide in 0.65 L of absolute ethanol, 1.05 equivalents) over 1 hour. The reaction mixture was stirred at 3° C. for 3 hours. Lithium hydroxide monohydrate (215.6 g, 5.138 mol, 5 equivalents) was added all at once and the temperature rose to 10° C. The mixture was stirred at 10° C. for 2 hours, treated with acetic acid (308.6 gm, 5.138 mol, 5 eq) and stirred at 60° C. for 17 hours. The reaction mixture was treated with distilled water (4 L) over 20 minutes while maintaining the internal temperature >55° C. The slurry was cooled slowly to 14° C. over 2.5 hours, filtered, washed with 1:1 ethanol:water (total volume=2 L), heptanes (2 L) and dried at 55° C. vacuum oven under N2 for 40 hours to give the title compound (451.9 g, 91% yield). 1H NMR (CDCl3): δ 8.65(m, 1H), 7.90(m, 2H), 7.65-7.75 (m, 2H), 7.17-7.30(m, 8H), 4.63(m, 1H), 4.32(m, 1H), 3.95(m, 1H), 3.32(m, 1H), 2.7-3.0(m, 4H), 2.10 (m, 1H), 1.74(m, 1H), 1.36 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:31][CH2:32][C:33]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=2[F:40])[C:5]2[N:6]([C:8]([C:12]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:31][CH2:32][C:33]2[C:34]([F:40])=[CH:35][CH:36]=[CH:37][C:38]=2[F:39])[C:5]2[N:6]([C:8]([C:12]([NH:14][CH:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16]3)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)NC1CN(C(=O)OC(C)(C)C)c2ccccc21
Agent: Cl
Solvent: CCOCC
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)NC1CNc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
141 mg of rac-tert-butyl 3-[({6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]indolin-1-carboxylate (Example 104A, 0.25 mmol) were dissolved in 1.2 ml of diethyl ether, 1.24 ml of a 2 M solution of hydrochloric acid in diethyl ether (2.48 mmol) were added and the mixture was stirred at RT overnight. 1.24 ml of a 2 M solution of hydrochloric acid in diethyl ether (2.48 mmol) were then added, and the mixture was stirred at RT for 3 d. 1.24 ml of a 2 M solution of hydrochloric acid in diethyl ether (2.48 mmol) were then added a little at a time and the mixture was stirred under reflux for 4 h (with additional diethyl ether and hydrochloric acid in diethyl ether being added a little at a time!). The precipitate was filtered off and washed thoroughly with diethyl ether, and ethyl acetate and saturated aqueous sodium bicarbonate solution were then added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered, and the filtrate was concentrated and lyophilized. This gave 93 mg of the title compound (80% of theory).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@H:14]1[CH2:28][O:27][C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:26])[CH:22]=[CH:23][O:24][C:25]=3[C:16]=2[O:15]1.O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[CH2:28][O:27][C:17]3[CH:18]=[CH:19][C:20]4[C:21](=[O:26])[CH:22]=[CH:23][O:24][C:25]=4[C:16]=3[O:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1ccoc2c3c(ccc12)OC[C@H](CO)O3
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(=O)ccoc4c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Toluenesulfonyl chloride (0.60 g, 3.15 mmole) was added to solution of (2S)-2-(hydroxymethyl)-2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-one (0.41 g, 1.75 mmole) in 50 mL of pyridine. The solution was stirred at room temperature overnight under nitrogen. Water was added to quench the excess tosyl chloride and the solvent was removed in vacuum and replaced with methylene chloride. The solution was washed with 2N aqueous HCl, with saturated aqueous sodium bicarbonate, and with saturated brine, and dried over magnesium sulfate. Filtration, evaporation in vacuum and column chromatography on silica gel with 3% methanol/methylene chloride as eluant gave 0.36 g (54%) of the (R)-enantiomer of the title compound as a yellow solid, m.p. 190-191° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][N:5]([C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])[C:6](Cl)=[O:7].O>O1CCCC1>[CH2:1]([NH:3][C:6]([N:5]([CH3:4])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])=[O:7])[CH3:2]
Reactant: CCN
Reactant: CN(C(=O)Cl)C(=O)Nc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 80 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, 9.0 g (0.2 mol) of ethylamine was dissolved, and under cooling below 0° C. with stirring, a solution prepared by dissolving 21.3 g (0.1 mol) of 2-methyl-4-phenylallophanoyl chloride into 50 ml of anhydrous tetrahydrofuran was added by drop-wise. The reaction was continued at a room temperature for 1 hour, the solvent was then removed by distillation under a reduced pressure. To the residue thus obtained was added water and the precipitate thus formed was separated by filtration and dried, and recrystallized from ether-petroleum ether to obtain 17.7 g (yield 80%) of 1-ethyl-3-methyl-5-phenylbiuret having a melting point of 80.5°-81.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(O)CCC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1
Reactant: Fc1ccc(F)c([C@H]2CCCN2)c1
Reactant: Clc1ccn2nccc2n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc(F)c([C@H]2CCCN2c2ccn3nccc3n2)c1
Temperature: 160 °C
Yield: 68 %

Procedure:
In a pressure reaction tube was added 5-chloropyrazolo[1,5-a]pyrimidine (4.2 g, 27 mmol), (R)-2-(2,5-difluorophenyl)pyrrolidine (Preparation A; 5.3 g, 29 mmol), anhydrous n-butanol (5 ml, 55 mmol), and DIEA (9.5 ml, 55 mmol). The yellowish suspension was sealed and heated in an oil bath (160° C.) overnight. The reaction was cooled to ambient temperature, diluted with EtOAc (250 mL), and filtered, rinsing the solid with EtOAc. The filtrate (330 mL) was washed with water (2×150 mL), brine (100 mL), concentrated, and purified by silica chromatography, eluting with 2:1 EtOAc/hexanes to give the product as a bright yellowish solid (5.6 g, 68% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:47][S:44]([NH:43][C:41]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]([C:25]1[CH:24]=[C:23]([NH:22][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH:28]=[CH:27][CH:26]=1)[C:38]([CH3:40])([CH3:39])[CH2:37]2)=[O:42])(=[O:45])=[O:46]
Reactant: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N)c1
Reactant: O=C(O)c1cnccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
A solution of pyrazine-2-carboxylic acid (42 mg, 0.34 mmol) and 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h. Then a solution of N-[2-(3-Amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (130 mg, 0.34 mmol) in N,N-dimethylformamide (1 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded pyrazine-2-carboxylic acid [3-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (12 mg, 7%) as a white solid: LC/MS m/e calcd for C24H25N5O4S (M+H)+: 480.56, observed: 480.2.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[N:10][CH:11]=1)[CH3:5])=[N+]=[N-]>[Pd].C(OCC)(=O)C>[CH3:12][C:9]1[N:10]=[CH:11][C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][N:8]=1
Reactant: Cc1ncc(C(C)N=[N+]=[N-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ncc(C(C)N)cn1
Reaction time: 8 h

Procedure:
A mixture of 5-(1-azidoethyl)-2-methylpyrimidine (2.20 g, 12.8 mmol), ethyl acetate (170 mL), and 10% palladium on carbon (1.32 g) was stirred under hydrogen (1 atm) overnight. The mixture was filtered and concentrated. The residue was purified by silica gel column (0-50% MeOH/EtOAc with 10% Et3N) to afford a colorless oil. 1H NMR (300 MHz, CD3OD): 8.71 (s, 2H), 4.12 (q, 1H, J=6.6 Hz), 2.67 (s, 3H), 1.44 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][C:7]([Si:10]([CH3:20])([CH3:19])[O:11][CH2:12][CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)([CH3:9])[CH3:8].[CH2:21]1[O:23][CH2:22]1.[NH4+].[Cl-]>C1COCC1>[CH3:9][C:7]([Si:10]([CH3:19])([CH3:20])[O:11][CH2:12][CH2:13][C:14]1[O:15][C:16]([CH2:21][CH2:22][OH:23])=[CH:17][CH:18]=1)([CH3:6])[CH3:8]
Reactant: C1CO1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccco1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
t-BuLi (1.2 M in pentane, 10 mL, 16.99 mmol) was added to a stirred solution of 255B (3.49 g, 15.44 mmol) in 13 mL of THF at −78° C. dropwise. The mixture was stirred for an additional 4 h at 0° C. Ethylene oxide (1.05 mL) was added at −78° C. to the reaction solution. The mixture was warmed to rt and stirred overnight. Aqueous sat. NH4Cl was added and most of the THF was removed under reduced pressure. The mixture was extracted with ether (3×) and the combined organic layers were washed with water (1×) and brine (1×) and dried over Na2SO4. Purification by flash chromatography on silica gel eluting with 5% EtOAc/95% CH2Cl2 gave 2.8 g (10.4 mmol, 67%) of compound 255C as a yellow oil.
Reaction SMILES: N1CC[C@H](/C=C/C2C=NC=NC=2)C1.[OH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([O:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: C(=C/[C@H]1CCNC1)\c1cncnc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1

Procedure:
One aspect of the present invention includes the method for the stereospecific synthesis of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine (11) outlined in Scheme 1. Commercially available tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (compound 1) is treated with methanesulfonyl chloride to give tert-butyl (R)-3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (compound 2), which then is reacted with diethylmalonate and a suitable base (e.g., potassium tert-butoxide or sodium ethoxide) to give diethyl (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)malonate (compound 3) with inverted stereochemistry around the chiral carbon.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:15]=1[C:16]([O:18][CH3:19])=[O:17].[C:25](=[O:27])=[O:26]>O1CCCC1>[Cl:13][C:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([Cl:24])[CH:21]=[CH:22][C:23]=1[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1c(Cl)cccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc(C(=O)O)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (22 ml) in dry tetrahydrofuran (160 ml) cooled to 0° C. under an inert atmosphere was added n-butyl lithium (2.5M, 67 ml) dropwise. The solution was stirred for 30 minutes at 0° C., then added to a solution of methyl 2,6-dichlorobenzoate (26.62 g) in dry tetrahydrofuran (160 ml) cooled to -78° C. under an inert atmosphere. After 1.5 hours at this temperature the mixture was poured onto excess solid carbon dioxide and left to stand overnight. The solvent was evaporated in vacuo and the residue acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate, dried over anhydrous magnesium sulphate and evaporated in vacuo to yield 2,4-dichloro-3-methoxycarbonylbenzoic acid (32.37 g) as a solid, NMR (DMSO D6) δ3.93 (3H,s), 7.70 (1H, d), 7.91 (1H,d).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9][CH3:10].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:10][CH:9]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=C(c1ccccc1)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1C(=CCBr)c1ccccc1
Yield: 75.3 %

Procedure:
TLC: rf=0.50 (SiO2; n-heptane/THF=7:3). 1-(2-Methylphenyl)-1-phenyl-1-propanol (10.4 g, 46 mmol) was dissolved into isopropanol (100 ml) and a 4 N sulphuric acid solution (50 ml) was added. The reaction mixture was heated at reflux temperature for 18 h and cooled to room temperature. Water (300 ml) was added and the mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts was washed with a diluted sodium bicarbonate solution, dried (Na2SO4) and the solvent evaporated in vacuo to give 9.0 g (91%) of 1-(2-methylphenyl)-1-phenyl-1-propene. To a solution of 1-(2-methylphenyl)-1-phenyl-1-propene (9.0 g, 43 mmol) in carbon-tetrachloride (40 ml), N-bromosuccinimide (7.7 g, 43 mmol) and benzoylperoxide (0.1 g) were added. The reaction mixture was heated at reflux temperature for 18 h. The cooled reaction mixture was filtered through silica gel and the solvent evaporated in vacuo to give 9.3 g (76 %) of 3-bromo-1 (2-methylphenyl)-1-phenyl-1-propene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37].[H-].[Na+].O>O1CCCC1.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:34])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NS(C)(=O)=O)c3ccccn3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (4.5 mmol) of 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)amide and 0.73 g (4.7 mmol) of carbonylduimidazole were dissolved in 80 mL of tetrahydrofuran and 5 mL of dimethylformamide and stirred for 30 minutes at ambient temperature and for 2 hours at 90° C. In parallel, 0.55 g (5.8 mmol) of methanesulfonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 mL of dimethylformamide and stirred for 2 hours at ambient temperature. Then this suspension was added at ambient temperature to the tetrahydrofuran solution. After 12 hours at ambient temperature, 50 mL of water were added and the pH value was adjusted to 6.8. The solution was extracted 4× with methylene chloride, the combined organic phases were dried over sodium sulfate and evaporated down. The crude product was chromatographed on silica gel (methylene chloride/ethanol (40:1)). The desired fractions were combined and evaporated down. Yield: 1.05 g (44% of theory), C26H25N7O4S (531.6); Rf value: 0.72 (silica gel; dichloromethane/methanol=9:1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH2:32]([N:34](CC)CC)C>CN(C)C=O.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][NH:17][C:4]2[N:3]=[C:2]([C:32]#[N:34])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCN(CC)CC
Reactant: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 40.8 %

Procedure:
A solution of 2-chloro-N-(2,2-diphenylethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (Preparation 2) (1.0 g, 2.31 mmol), zinc cyanide (0.162 g, 1.38 mmol), triethylamine (0.28 g, 2.77 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.133 g, 0.12 mmol) in N,N-dimethylformamide (3 ml) was heated under a nitrogen atmosphere at 100° C. for 6 hours. The reaction mixture was allowed to cool and partitioned between ethyl acetate (100 ml) and 2 M sodium hydroxide solution (100 ml). The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The resulting 1:1 mixture of 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile and 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (Preparation 8) were separated by column chromatography on silica gel eluting with a gradient system of ethyl acetate:hexane (40:60 by volume) gradually changing to ethyl acetate:hexane (60:40 by volume) to give the title compound as a white solid (0.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.CC#N.N1C=CC=CC=1.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:9][O:8][C:4]1[N:3]=[C:2]([NH:1][C:26](=[O:27])[O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COc1cncc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cncc(NC(=O)Oc2ccccc2)n1
Reaction time: 18 h

Procedure:
2-Amino-6-methoxy-pyrazine (1.00 g, 8 mmol) was dissolved in a mix of 1:2 THF:MeCN (30 mL), cooled to 0° C., and treated with pyridine (0.664 g, 8.3 mmol) followed by the dropwise addition of phenylchloroformate (1.3 g, 8.3 mmol) in THF (10 mL). After stirring for 18 h, the resulting white solid was collected by filtration (1.3 g, 68%) and was used without further purification.