Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].O>CC(C)=O.CN(C)C1C=CN=CC=1>[CH3:39][C:38]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)=[O:40]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
2-(Tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (3.0 g) prepared by example 2 was dissolved in acetone (10.0 mL) and the solution was cooled to 0° C. Triethylamine (1.02 g) was then added dropwise followed by adding 4-dimethylaminopyridine (DMAP) (0.025 g) and the mixture was stirred for 10 minutes at the same temperature. Acetic anhydride (0.83 g) in acetone was then added and the reaction was monitored by Thin Layer Chromatography (TLC) (petroleum ether/ethyl acetate=10/1 or 5/1). After the reaction was completed, cold water (7.5 mL) was then added to the reaction mixture. After the reaction mixture was stirred for 15 minutes, the reaction mixture was cooled to −5° C. and further stirred for 3 hours. Solid precipitate was collected by filtration followed by washing with a mixture of pre-cooled acetone/water (1:1 v/v) (10 ml). The obtained prasugrel free base was dried under vacuum at 50° C. for 24 hours. The yield was 85%.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([S:15][CH2:16][C:17](O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:17]=1[CH2:16][S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CSc1ccccc1
Reactant: Nc1ccccc1N
Agent: Cl
Product: c1ccc(SCc2nc3ccccc3[nH]2)cc1
Yield: 68.8 %

Procedure:
A 100 mL flask fitted with a stir-bar and condenser was charged with 1,2-phenylenediamine (2.88 g, 26.6 mmol), (phenylthio)acetic acid (4.00 g, 26.6 mmol), and 4M HCl (40 mL). The resultant suspension was heated in a 130° C. bath 48 hr. The mixture was cooled and concentrated in vacuo to a brown syrup. The syrup was taken up in EtOAc (100 mL) and washed with saturated NaHCO3 (2×75 mL) and brine (50 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a tan solid. The crude solid was triturated with hexanes:EtOAc 6:1 (50 mL), filtered, pressed with rubber dam, and rinsed with hexanes:EtOAc 4:1 (2×10 mL). The material was dried to give 4.4 g of 68 as a tan solid (77%). 1H NMR (300 MHz, CDCl3): δ 11.7 (bs, 1H), 7.7-7.4 (m, 2H), 7.4-6.9 (m, 7H), 4.4 (s, 2H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with retention time of 4.0 min.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C@@H:13]12[C:22](=[O:23])[O:21][C:19](=[O:20])[C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2>CN(C1C=CN=CC=1)C.C1COCC1>[C:22]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]([OH:1])=[O:20])([OH:21])=[O:23].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: C1CCOC1
Product: O=C(O)C1CCCCC1C(=O)O
Temperature: 25 °C

Procedure:
To a mixture of 20.0 g of D-glucose, 3.4 g of 4-(N,N-dimethylamino)pyridine, 68.0 g of TEA and 440 g of THF, a solution of 86.0 g of cis-1,2-cyclohexanedicarboxylic anhydride and 88 g of THF was added with stirring at room temperature, then the added mixture was stirred for 3 days. After the stirring, the solvent was removed from the resulting mixture under reduced pressure. To the concentrate, 600 g of chloroform and 300 g of ion-exchanged water was added, and was neutralized with hydrochloric acid. The neutralized organic layer was separated, washed with ion-exchanged water, and dried with anhydrous magnesium sulfate. Then the solvent was removed from the dried organic layer to obtain 160.1 g of crude pentakis-D-glucose (2-carboxycyclohexyl)carboxylate (abbreviated to “GLUCHA”).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[C:7]([Cl:13])[N:6]=1>C1COCC1>[Cl:13][C:7]1[C:8]([Cl:12])=[C:9]([O:2][CH3:1])[N:10]=[C:5]([CH3:4])[N:6]=1
Reactant: Cc1nc(Cl)c(Cl)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc(Cl)c1Cl
Temperature: 5 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
1.37 g of sodium methoxide are added to a solution of 5 g of 2-methyl-4,5,6-trichloropyrimidine in 41 ml of THF cooled to 5° C. in an ice bath. The ice bath is removed. The suspension is stirred at ambient temperature for 18 hours. The reaction medium is cooled to 5° C. in an ice bath. 20 ml of water and 100 ml of ethyl acetate are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure so as to give 4.73 g of 4,5-dichloro-6-methoxy-2-methylpyrimidine in the form of a colorless oil which crystallizes, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:38][Si:39]([CH3:46])([CH3:45])[CH2:40][CH2:41][O:42][CH2:43]Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:43][O:42][CH2:41][CH2:40][Si:39]([CH3:46])([CH3:45])[CH3:38])[C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(OCc4ccccc4)cc3)nc2n(CCC)c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(-c3ccc(OCc4ccccc4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (1.2 g, 2.9 mmol) and potassium carbonate (1.19 g, 8.6 mmol), were taken in DMF (15 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (1.52 ml, 8.6 mmol) was added drop wise at 0° C. and mixture was stirred at room temperature for 20 hours. The mixture was cooled to 10° C. and diluted with water, extracted with ethyl acetate. The organic layer was washed with saturated brine solution and dried over Na2SO4. Solvent was removed and residue obtained was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (1.12 g, 71%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:27][C:28]1[O:32][C:31]([CH3:33])=[N:30][CH:29]=1>CN(C)C=O>[CH3:33][C:31]1[O:32][C:28]([CH2:27][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:29][N:30]=1
Reactant: Cc1ncc(CBr)o1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 26 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole in 282 parts of N,N-dimethylformamide there were added 4.8 parts of a dispersion of sodium hydride in mineral oil (50%) under a nitrogen atmosphere. After stirring for 1 hour, there was added portionwise a solution of 15 parts of 5-(bromomethyl)-2-methyloxazole in 47 parts of N,N-dimethylformamide, while cooling in an ice-bath (<20° C.). The whole was stirred for 18 hours and allowed to warm to room temperature. The oily layer was separated and discarded. The N,N-dimethylformamide layer was poured into water and the whole was extracted with 4-methyl-2-pentanone (3×). The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was successively crystallized from 2,2'-oxybispropane and acetonitrile, yielding 14.31 parts (42.0%) of 1-[(2-methyl-5-oxazolyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole; mp. 108.6° C. (comp. 1).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C:7](=[CH:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21]>C(OCC)(=O)C.[Pd]>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)=[C:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC=C1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@]12CCC(=O)C[C@@H]1CCC1=C3CC[C@H](O)[C@@]3(C)CC[C@@H]12

Procedure:
A solution of 5α-androst-7-ene-3-one-17β-ol in ethyl acetate is hydrogenated at room temperature and 1 atmosphere over 10% palladium on carbon for 8 hours. Filtration to remove the catalyst and concentration affords 5α-androst-8(14)-ene-3-one-17β-ol.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1([CH3:21])[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:10]=2[CH2:9][N:8]([CH3:20])[CH2:7]1)[CH:4]=[CH2:5].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[CH2:25]>CN(C=O)C>[CH2:3]([C:6]1([CH3:21])[C:11]2[N:12]([CH2:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH2:23])[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:10]=2[CH2:9][N:8]([CH3:20])[CH2:7]1)[CH:4]=[CH2:5]
Reactant: C=C(CBr)c1ccc(F)cc1
Reactant: C=CCC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C)CN(C)Cc2c1n(CC(=C)c1ccc(F)cc1)c1ccc(C)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
To a stirred suspension of sodium hydride (0.236 g, 5.9 mmol) in dry DMF (5 mL) at 0° C. was added 4-allyl-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 3.937 mol, in dry DMF 2 mL). After addition was complete, reaction mixture was stirred at 0° C. for an additional 10 min. 1-(1-Bromomethyl-vinyl)-4-fluoro-benzene (1.09 g, 5.118 mmol) in dry DMF (3 mL) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with ice-water and extracted with EtOAc (2×50 mL). The organic layer was repeatedly washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by chromatography on neutral aluminum oxide (eluting with EtOAc:Hexanes, 1:99) to obtain 700 mg of 4-allyl-5-[2-(4-fluoro-phenyl)-allyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(C(=O)OC)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A solution of methyl 4-hydroxy-3-propylbenzoate (7.00 g, 36.0 mmol), benzyl bromide (11.48 g, 0.15 mol), and potassium carbonate (20.73 g, 0.15 mol) in N,N-dimethylformamide (20 mL) was heated and stirred at 80° C. for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (10.25 g, yield 100%) was obtained as a pale yellow oil.
Reaction SMILES: N1(N)C2C(=NC=CC=2)C=[CH:2]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([NH:22][C:23]([C:25]1[CH:26]=[N:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:29][CH:30]=1)=[O:24])[CH:17]=[CH:16]2>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([NH:22][C:23]([C:25]1[C:26]([CH3:2])=[N:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:29][CH:30]=1)=[O:24])[CH:17]=[CH:16]2
Reactant: COc1ccc2c(ccn2NC(=O)c2cnc(-c3ccccn3)nc2)c1
Reactant: Nn1ccc2ncccc21
Product: COc1ccc2c(ccn2NC(=O)c2cnc(-c3ccccn3)nc2C)c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Following procedures similar to those of Example 127, but substituting 5-methoxy-indol-1-ylamine for pyrrolo[3,2-b]pyridine-1-ylamine, and the reaction is stirred at 150° C. for 1 h, there is prepared 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-methoxy-indol-1-yl)-amide (22%) as a solid. MS: 360 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.88 (s, 3H), 3.84 (s, 3H), 6.50 (d, H) 6.90 (m, H), 7.13 (d, H), 7.25-7.34 (m, 2H), 7.60 (m, H), 8.05 (m, H), 8.65 (d, H), 8.79 (d, H), 9.20 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([S:5](Cl)=[O:6])([CH3:4])[CH3:3].Cl.[NH2:9][C:10]([CH3:14])([CH3:13])[C:11]#[N:12].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([C:10]([NH:9][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([CH3:14])[CH3:13])#[N:12]
Reactant: CC(C)(N)C#N
Reactant: CC(C)(C)S(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C#N)NS(=O)C(C)(C)C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
2-methylpropane-2-sulfinic chloride (1.28 g, 9.12 mmol) was added to a stirring solution of 2-amino-2-methylpropanenitrile hydrochloride (1.0 g, 8.3 mmol) in DCM (21 ml) and N-ethyl-N-isopropylpropan-2-amine (3.04 ml, 17.4 mmol) at rt. DMAP (10 mg, 0.083 mmol) was added and the reaction was allowed to stir 1 h. The mixture was then diluted with dichloromethane and washed with sat NH4Cl aq, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product N-(2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide (1.45 g, 7.71 mmol, 93% yield) consistent by LCMS and NMR. LC-MS retention time: 2.15 min; m/z (MH+): 189. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.76 (s, 3H), 1.69 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:7]=[CH:8][N:9]=1.[H-].[Na+].Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[O:28][CH:29]=1>>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1/[CH:31]=[CH:30]/[C:27]1[O:28][CH:29]=[C:25]([CH2:24][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:6]3[CH:7]=[CH:8][N:9]=[C:5]3[CH2:4][CH2:3][S:2][CH3:1])=[CH:15][CH:16]=2)[N:26]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: CSCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CSCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Yield: 92.6 %

Procedure:
Using 4-[4-[4-[2-[2-(methylsulfanyl)ethyl]-1H-imidazol-1-yl]butyl]phenol (500 mg), 65% sodium hydride (69.8 mg) and 4-chloromethyl-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (483 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (812 mg) as a colorless amorphous form.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)[C:17](O)=[O:18].C1N2CN3CN(C2)CN1C3.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:6][C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH:17]=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1CC1CCCC1
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(C=O)cc1CC1CCCC1
Temperature: 100 °C
Yield: 55.7 %

Procedure:
To a stirred mixture of 1-cyclopentylmethyl-2-methoxybenzene (383 mmol, 72.7 g) in trifluoroacetic acid (3.83 mol, 435 g; 294 mL) was added hexamine (766 mmol, 107 g) in one portion at room temperature, resulting in an exothermic reaction. After the exotherm had subsided, the reaction mixture was heated to 100° C. for 18 hours and cooled to room temperature. The heterogenous mixture was diluted with CH2Cl2 (800 mL) and the resulting homogenous solution was cooled to 0° C. and neutralized to pH 7 by the dropwise addition of 2.5N NaOH (~1L). The layers were separated, the aqueous phase extracted with CH2Cl2 (1×600 mL), dried (Na2SO4), and concentrated in vacuo to afford a viscous oil. Purification by filtration through a plug of SiO2 (gradient elution: 1) hexane, 2) 36:1 hexane/EtOAc, 3) 18:1 hexane/EtOAc, 4) 12:1 hexane/EtOAc, 5) 8:1 hexane/EtOAc) afforded the title compound as a light yellow oil (46.6 g, 56%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=2)[N:5]=[C:4]2[CH2:18][N:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH:26]=3)[C:20](=[O:21])[C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH2:38](OB(OCC)OCC)[CH3:39].C1COCC1>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:18][N:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][C:28]([F:31])([F:30])[F:29])[CH:26]=4)[C:20](=[O:21])[C:3]3=[C:2]([CH2:38][CH3:39])[CH:7]=2)[CH:9]=[N:10][C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2cc(Cl)c3c(n2)CN(c2cnn(CC(F)(F)F)c2)C3=O)cnc1OC
Reactant: CCOB(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(-c2cnc(OC)c(OC)c2)nc2c1C(=O)N(c1cnn(CC(F)(F)F)c1)C2
Temperature: 80 °C

Procedure:
As shown in step 10-iii Scheme 10, 4-Chloro-2-(5,6-dimethoxypyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 82, 75 mg, 0.165 mmol and a degassed solution of 2M aqueous sodium carbonate (826 uL, 1.65 mmol] were suspended in 10 mL of toluene. The reaction mixture was purged with nitrogen for 5 minutes and tetrakistriphenylphosphine palladium(0) (38 mg, 0.033 mmol] was added, followed by the addition of 2 M triethylborate solution in THF (992 μL, 1.0 mmol). The reaction vessel was sealed and heated for 14 hours at 80° C. The reaction mixture was cooled and the volatiles removed under reduced pressure. The residue was dissolved in EtOAc/DCM 1:1 and filtered. The filtrate was concentrated under reduced pressure. The product was purified by preparative thin layer chromatography produced 2-(5,6-dimethoxypyridin-3-yl)-4-ethyl-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 182, 1.1 mg): ESMS (M+1) 448.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][C:52](O)=[O:53].CCN(C(C)C)C(C)C>O.CN(C)C=O>[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][C:52]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:53]
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2-chlorophenylacetic acid (63.8 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-{1-[(2-chlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (85.3 mg) as a pink solid. LC/MS (ES) m/z=420.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (t, J=8.34 Hz, 2H) 4.02 (s, 2H) 4.32 (t, J=8.46 Hz, 2H) 5.43 (br. s., 2H) 7.23 (d, J=8.08 Hz, 1H) 7.26 (d, J=5.56 Hz, 1H) 7.31-7.37 (m, 3H) 7.39-7.44 (m, 2H) 7.45-7.51 (m, 1H) 7.83 (d, J=5.56 Hz, 1H) 8.11 (d, J=8.08 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:24](O)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:24]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (257 μl) was condensed with Boc-p-chloro-L-phenylalanine (800 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-(Boc-p-chloro-L-phenylalanyl)morpholine (913 mg) as a colorless oily product (yield 93%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (238 mg) as obtained in Reference Example 8 to yield the title compound (compound 67; mg) as a white powder (yield 58%).