Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7]1)C.CO.[OH-].[Na+]>O1CCCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8][C:9]=3[C:17]=2[CH:16]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1CCc2c1[nH]c1ccc(F)cc21
Reaction time: 2.5 h

Procedure:
To a solution of 1.24 g of the ester from Step 1 in 14 mL of tetrahydrofuran (THF) at room temperature, 7 mL of MeOH followed by 7 mL of 2N NaOH were added. After 2.5 h, the reaction mixture was poured into a separatory funnel containing ethyl acetaqte (EtOAc)/1N HCl. The phases were separated and the acidic phase was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness to yield 1.08 g of a crude and unstable waxy brown oil that was used as such in the next step (>90% purity).
Reaction SMILES: CN.[ClH:3].[S:4]1(=[O:11])(=[O:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5]1.S1(=O)(=O)CC=C[CH2:13]1>>[ClH:3].[CH3:13][NH:9][CH:6]1[CH2:7][CH2:8][S:4](=[O:11])(=[O:10])[CH2:5]1
Reactant: O=S1(=O)CC=CC1
Reactant: NC1CCS(=O)(=O)C1
Agent: CN
Agent: Cl
Product: CNC1CCS(=O)(=O)C1
Yield: 82.2 %

Procedure:
The procedure of Example 1 was repeated substituting 50 percent aqueous monomethylamine (174 ml.) for the ammonium hydroxide of Example 1. Sixty-four and seven-tenths grams of a white crystalline solid was obtained for a yield of 82.2 percent of theory based upon the 2,5-dihydrothiophene 1,1-dioxide. The solid sublimes over 180° C. and metls between 205° and 210° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Fc1ccc2cccc(CBr)c2c1
Reactant: CCOC(=O)c1cc2c(OC)cccc2[nH]1
Product: CCOC(=O)c1cc2c(OC)cccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, 4-methoxy-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 1-(7-fluoro-naphthalen-1-ylmethyl)-4-methoxy-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 348.3 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.ClC1C=CC(C([NH:21][C:22]2[CH:23]=[N:24][C:25]([OH:28])=[CH:26][CH:27]=2)=O)=CC=1>>[OH:28][C:25]1[N:24]=[CH:23][C:22]([NH:21][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:27][CH:26]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(O)nc1)c1ccc(C(F)(F)F)cc1

Procedure:
Starting from 4-trifluoromethylbenzoyl chloride (2.09 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:4]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>C(=O)(O)[O-].[Na+]>[OH:1][C:2]1[C:3]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:4]=2[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:6][C:7]=1[C:8]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:9]
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2c(-c3ccc(OC)cc3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)nc(-c4ccccc4)c23)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Ethyl 7-hydroxy-3-(4-methoxyphenyl)-4-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (70 mg, 0.18 mmol) and glycine (539 mg, 7.18 mmol) were added to sodium methoxide solution (10.8 mL, 5.38 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in minimum amount of water and 0.25 M hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 79 mg of crude solid. The solid was dissolved in 15 mL of saturated sodium bicarbonate solution and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid and the precipitate was collected by filtration. The solid was dried under vacuum to afford 47 mg of the title compound. MS: (+) m/z 420.37 (M+1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]1[C:25](=[O:46])[N:26]2[C:34](=[N:35][C:36]=1[C:37](O)=[O:38])[C:33]1[C:28](=[CH:29][CH:30]=[CH:31][C:32]=1[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[O:27]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[Cl:56])[CH2:51][NH2:52].ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[Cl:56])[CH2:51][NH:52][C:37]([C:36]1[N:35]=[C:34]2[N:26]([O:27][C:28]3[C:33]2=[C:32]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[CH:31]=[CH:30][CH:29]=3)[C:25](=[O:46])[C:24]=1[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:38]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1nc2c3c(N4CCOCC4)cccc3on2c(=O)c1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1nc2c3c(N4CCOCC4)cccc3on2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (110 mg, 0.522 mmol) was added to a stirred solution of the product from Example 19.6 (200 mg, 0.475 mmol) in dichloromethane (100 mL), After 30 min, N,N-dimethylaminopyridine (6 mg, 0.05 mmol), 3,4-dichlorobenzylamine (92 mg, 0.52 mmol) and 1-hyroxybenzotriazole (70 mg, 0.52 mmol) were added successively. The mixture was stirred at room temperature overnight and aqueous work-up and extraction afforded the crude product was further purified by column chromatography (hexane/ethyl acetate 4:1) as eluent to afford the desired product (120 mg, 44%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])[C:5]2=[CH:4][CH:3]=1.[CH3:31]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])([CH3:31])[CH3:15])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21

Procedure:
To the alcohol 67 (380 mg, 0.89 mmoles) dissolved in DCM (30 mL) was added dess-martin periodinane (509 mg, 1.35 eq, CAS 87413-09-0). The resulting mixture was stirred at Rt overnight. Diethylether was added (150 mL) and the mixture was stirred for 15 minutes. The mixture was filtrated and the filtrate washed quickly with an aqueous Na2S2O3 solution, dried on Na2SO4, filtrated and evaporated. The resulting solid was purified by flash chromatography (10% MeOH in DCM) and the aldehyde 75 was obtained as a light yellow solid (218 mg, 58% yield). LCMS m/z=425 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:21]#[N:22])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:6]([C:21]#[N:22])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNCC1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc2c(F)cc(Cl)cc2c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCCC2)nc2c(F)cc(Cl)cc2c1-c1ccccc1
Temperature: 70 °C
Yield: 37.4 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 6-chloro-3-cyano-8-fluoro-4-phenyl-quinolin-2-yl ester (189 mg, 0.439 mmol), piperidine (150 mg, 174 μl, 1.76 mmol) and potassium carbonate (121 mg, 0.878 mmol) in THF (6 ml) was heated to 70° C. for 60 min. The yellow suspension was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated with dichloromethane and the off-white solid was filtered off. The filtrate was evaporated and the remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 98:2-95:5) to afford the title compound (60 mg, 37%) as yellow solid. MS (ESI): 366.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=[C:6]2[CH:5]=[C:4]([CH3:14])[N:3]=1.[NH2:15][C@@H:16]([CH3:33])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[C:29]([F:31])[C:26]([C:27]#[N:28])=[C:25]([Cl:32])[CH:24]=2)=[N:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:11]([C:9]3[N:10]=[C:6]4[CH:5]=[C:4]([CH3:14])[N:3]=[C:2]([CH3:1])[N:7]4[CH:8]=3)=[O:13])[CH3:33])[N:19]=2)[CH:30]=[C:29]([F:31])[C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1cc2nc(C(=O)O)cn2c(C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc2nc(C(=O)N[C@@H](C)Cn3ccc(-c4cc(F)c(C#N)c(Cl)c4)n3)cn2c(C)n1
Yield: 18.5 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5,7-dimethyl-imidazo[1,2-c]pyrimidine-2-carboxylic acid (0.753 mmol, 0.144 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (0.538 mmol, 0.2 g). DMF (6 ml) was used as a solvent and HBTU (0.054 mmol, 0.020 g) was used instead of HOBt. The crude product was purified by trituration from ACN. 0.045 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.26 (d, 3H), 2.53-2.56 (m, 3H), 2.82 (s, 3H), 4.30 (dd, 1H), 4.48 (dd, 1H), 4.60-4.72 (m, 1H), 6.63 (d, 1H), 7.23-7.26 (m, 1H), 7.52 (d, 1H), 7.75-7.83 (m, 2H), 8.00-8.06 (m, 1H), 8.27 (d, 114).
Reaction SMILES: [CH2:1]([N:4]([CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:5]1[C:6]([CH3:25])=[C:7]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:8]([NH:10][CH2:11][C:12]1[C:13](=[O:20])[NH:14][C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])=[O:9])[CH:2]=[CH2:3]>CO.[Pd]>[Cl:24][C:22]1[CH:23]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:6]([CH3:25])=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[C:13](=[O:20])[NH:14][C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])=[O:9]
Reactant: C=CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CCCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
To a stirred solution of 3-(allyl(tetrahydro-2H-pyran-4-yl)amino)-5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.10 g) in MeOH (10 mL) was added 10% Pd/C (0.03 g) and the reaction stirred at room temperature under hydrogen (balloon pressure) for 2 h. On completion, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain crude solid which was purified by column chromatography to afford the title compound (0.02 g, 20%). LCMS: 445.25 (M+1)+; HPLC: 90.40% (@ 254 nm) (Rt; 5.609; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.23 (t, 1H), 7.19 (s, 1H), 6.93 (d, 1H, J=1.6 Hz), 5.88 (s, 1H), 4.24 (d, 2H, J=4.4 Hz), 3.83 (d, 2H, J=10.4 Hz), 3.22-3.25 (m, 2H), 2.94 (t, 2H, J=7.2 Hz), 2.88-2.90 (m, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H), 1.56 (m, 4H), 1.14-1.23 (m, 2H), 0.75 (t, 3H, J=8 Hz).
Reaction SMILES: [ClH:1].COC1C=CC(C[N:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([CH3:25])=[C:14]([O:19][C@@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:15]=3)[C:10]2=[O:26])=CC=1.F[C:30](F)(F)C(O)=O>>[ClH:1].[CH3:25][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[CH:18][NH:9][C:10]2=[O:26])=[CH:15][C:14]=1[O:19][CH2:20][C@@H:24]1[CH2:30][CH2:21][NH:22][CH2:23]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cn2ccc3cc(O[C@@H]4CCNC4)c(C)cc3c2=O)cc1
Agent: Cl
Product: Cc1cc2c(=O)[nH]ccc2cc1OC[C@@H]1CCNC1
Temperature: 150 °C
Yield: 74.4 %

Procedure:
245 mg of 2-(4-Methoxy-benzyl)-7-methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one hydrochloride were dissolved in 1.4 g trifluoroacetic acid and the mixture was heated for 2 h in a microwave oven at 150° C. Then the excess trifluoroacetic acid was distilled off in vacuo and the residue was diluted with 10 ml 1 M hydrochloric acid. The aqueous phase was washed with methylene chloride twice and then it was freeze dried to give 134 mg 7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-one hydrochloride. Rt=0.92 min (Method B). Detected mass: 245.1 (M+H+).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][C:5]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2>[Pd]>[ClH:1].[N:2]12[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C=CC12CCN(CC1)CC2
Agent: [Pd]
Agent: Cl
Product: O=C(O)CCC12CCN(CC1)CC2
Yield: 91 %

Procedure:
3-(Quinuclidin-4-yl)-acrylic acid (Example 26, Step 4) (0.2 g, 0.0009 moles) was hydrogenated at atmospheric pressure and ambient temperature over 10% palladium on charcoal (0.05 g) for 18 hours. The catalyst was filtered off and the filtrate evaporated to dryness to give the title compound 0.18 g (89%); MS (+ve ion electrospray) m/z 184 (MH+, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[C:12]1=[O:27])[C:4]([O:6]C(C)(C)C)=[O:5].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[C:12]1=[O:27])[C:4]([OH:6])=[O:5]
Reactant: Cn1c(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)nc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution containing the product from Example 59E (0.025 g, 0.070 mmol) in a mixture of THF (0.3 mL) and water (0.3 mL) was treated with lithium hydroxide monohydrate (0.004 g, 0.094 mmol), and the mixture was stirred at 25° C. for 18 hours. The solvent was concentrated to give the crude product, which was used without purification.
Reaction SMILES: [Si]([O:8][C:9]([C:18]1[CH:49]=[CH:48][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][C:41]4[CH:46]=[CH:45][N:44]=[CH:43][N:42]=4)=[O:39])=[C:33]([F:47])[CH:32]=3)=[O:30])[CH2:25][CH2:24]2)=[CH:20][CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])(C(C)(C)C)(C)C.[F-].[K+]>O1CCCC1>[F:47][C:33]1[CH:32]=[C:31]([C:29]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:20]=[CH:19][C:18]([C:9]([OH:8])([C:10]([F:13])([F:11])[F:12])[C:14]([F:15])([F:17])[F:16])=[CH:49][CH:48]=3)[CH2:24][CH2:25]2)=[O:30])[CH:36]=[CH:35][C:34]=1[NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][N:42]=1)=[O:39]
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccncn4)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1ccncn1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Yield: 15.1 %

Procedure:
1-(4-(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)benzyl)-piperazine-1-carbonyl)-2-fluorophenyl)-3-(pyrimidin-4-yl)urea (0.088 mmol, 0.0627 g) and potassium fluoride (50% on celite) (0.877 mmol, 0.102 g) were combined and heated to reflux in tetrahydrofuran (5 mL) overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (eluant dichloromethane/methanol 0% to 5%) to afford the title compound (8 mg). MS (ESI) m/z 601.3 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].Cl[C:10]1[N:22]=[CH:21][CH:20]=[CH:19][C:11]=1[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].[H-].[Na+].O>O1CCOCC1>[CH2:17]([N:14]([CH2:15][CH3:16])[C:12](=[O:13])[C:11]1[CH:19]=[CH:20][CH:21]=[N:22][C:10]=1[NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:18]
Reactant: Cc1ccncc1N
Reactant: CCN(CC)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C(=O)c1cccnc1Nc1cnccc1C
Yield: 84.9 %

Procedure:
Into a 1-neck round-bottom flask was added 4-methylpyridin-3-amine (1.02 g, 0.00940 mol) and 2-chloro-N,N-diethylnicotinamide (2.00 g, 0.00940 mol) in 1,4-dioxane (20 mL), and then sodium hydride (0.94 g, 0.024 mol) was added. The reaction was heated at reflux for 1 hour. The mixture was allowed to cool and water was added. The mixture was then extracted with ethyl acetate 3× and the combined organic extracts were washed with water, brine, dried over MgSO4, and concentrate in vacuo. Upon cooling, the product crystallized. The crystalline solid was filtered off, washed with ether and dried to give 2.27 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 9.15 (s, 1H), 8.21-8.24 (m, 2H), 7.90 (br s, 1H), 7.47 (dd, 1H J1=7.5, J2=1.8 Hz), 7.11 (d, 1H, J=4.8 Hz), 6.75 (dd, 1H, J1=7.5, J2=5.1 Hz), 3.46-3.51 (m, 4H), 2.29 (s, 3H), 1.25 (t, 6H). MS [M+1]=285.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[CH3:7][CH:8]([CH3:16])[CH2:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13].C(N(CC)CC)C>CCO>[CH2:9]([C:10]1[CH:11]=[C:12]([CH3:13])[C:3]([C:1]#[N:2])=[C:4]([SH:5])[N:6]=1)[CH:8]([CH3:16])[CH3:7]
Reactant: N#CCC(N)=S
Reactant: CC(=O)CC(=O)CC(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(CC(C)C)nc(S)c1C#N
Temperature: 50 °C
Yield: 61.7 %

Procedure:
To a stirred solution of cyanothioacetamide (2.20 g, 22 mmol) and 6-methyl-2,4-heptanedione (3.12 g, 22 mmol) in anhydrous EtOH (40 ML) was added triethylamine (0.4 mL) and the reaction was heated at 50° C. for 1 h before it was allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH gave 6-isobutyl-2-mercapto-4-methylnicotinonitrile as a yellow solid (2.8 g, 61%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][CH:22]([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[Cl:19][C:17]1[CH:18]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[C:7]=3[CH2:8]2)[CH:14]=[N:15][C:16]=1[O:20][CH2:21][CH:22]([F:24])[F:23]
Reactant: O=COc1ccccc1
Reactant: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)F)c(Cl)c1
Product: O=C(Oc1ccccc1)c1nccc2c1CN(Cc1cnc(OCC(F)F)c(Cl)c1)C2=O
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (220 mg, brown solid) from 4-chloro-2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.62 mmol, Intermediate-13) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:38])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26][C:27](=[O:36])[CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][C@H:16]([OH:37])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=O)C.C(=O)([O-])O.[K+]>CO>[OH:37][C@@H:16]1[CH2:17][CH2:18][C@@:19]2([CH3:20])[C@@H:14]([CH2:13][CH2:12][C@@H:11]3[C@@H:21]2[C@@H:22]([O:26][C:27](=[O:36])[CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])[CH2:23][C@@:24]2([CH3:25])[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C:6](=[O:38])[CH2:5][OH:4])[CH2:15]1
Reactant: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(=O)COC(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(=O)CO)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21
Temperature: 0 °C
Yield: 29.7 %

Procedure:
21-Acetoxy-11β-N,N-dipropylaminoacetoxy-3α-hydroxy-5α-pregnan-20-one (800 mg) in methanol (16 ml) was refluxed with 20% aqueous potassium hydrogen carbonate solution (4 ml) under nitrogen for 1 hour. The mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed, dried and evaporated. The residue was purified by preparative TLC (ethyl acetate-petroleum ether b.p. 40°-60° (2:1)×2) and triturated with pentane to give title compound (219 mg) m.p. 98°-102°, [α]D +66°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([OH:12])=O)[NH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:21]([CH:28]1[CH2:33][CH2:32][N:31]([C:10]([C:8]2[NH:7][C:6]3[CH:13]=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)=[O:12])[CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1nc2ccc(O)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1nc2ccc(O)cc2[nH]1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A mixture of 3.0 g (16.75 mmol) of 6-hydroxi-1H-benzoimidazol-2-carboxilic acid, 2.4 ml (17.2 mmol) of triethylamin, 3.0 g (17.1 mmol) of 4-benzyl-piperidine, 7.0 g (18.5 mmol) of HBTU and 100 ml of dimethylformamide is stirred at room temperature for 16 h. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent, then the product is recrystallized from toluene to yield 3.58 g (63.5%) of the title compound. Mp.: 186° C. (toluene).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Cl[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CS(C)=O>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1[N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Clc1cnccn1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(c3cnccn3)CC1)O2
Temperature: 100 °C
Reaction time: 3 h
Yield: 7.4 %

Procedure:
A mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.150 g, 0.50 mmol), 2-chloropyrazine (0.57 g, 1.67 mmol), triethylamine (0.1 ml, 0.72 mmol), and DMSO (50 ml) was stirred for three hours at 100° C. The crude reaction mixture was purified directly by reverse phase HPLC to give the product as a purple solid (0.014 g, 0.7%) MP=255-256° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.41 (s, 1H), 8.10-8.07 (m, 1H), 7.91-7.81 (m, 3H), 7.76-7.70 (m, 1H), 7.58-7.52 (m, 1H), 4.28-4.22 (m, 2H), 3.39-3.28 (m, 2H), 3.12 (s, 2H), 2.11-2.04 (m, 2H), 1.88-1.79 (m, 2H); LCMS: 380 [M+H].