Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30]Cl)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[CH2:1]([S:8][CH2:30][C:25]1[C:22]2[CH2:23][CH2:24][N:18]([C:16]([O:15][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:17])[CH2:19][CH2:20][C:21]=2[CH:28]=[CH:27][C:26]=1[Cl:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSCc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.9 %

Procedure:
Dissolve benzylmercaptan (230 mg, 1.84 mmol) in anhydrous DMF (5 mL). Add sodium hydride (100 mg, 2.5 mmol, 60% dispersion in mineral oil) and stir the mixture for 10 min. Add then a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (550 mg, 1.67 mmol) in anhydrous DMF (1 mL). Stir under nitrogen at room temperature overnight. Pour reaction mixture into water (150 mL) and extract with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo to afford crude 6-benzylthiomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (1.13 g) suitable for use without additional purification.
Reaction SMILES: [Cl:1]C(Cl)C.S(Cl)(Cl)=O.[CH3:9][C:10]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:11]=1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>CN(C)C=O>[CH3:9][C:10]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:11]=1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([Cl:1])=[O:17]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)O)c1
Reactant: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)Cl)c1

Procedure:
Dichloroethane (20 ml), thionyl chloride (1.31 g, 0.011 mol) and N,N-dimethylformamide (0.1 ml) were added to 2-(2,5-dimethylphenoxymethyl)benzoic acid (2.56 g, 0.01 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride. 1.6M n-butyllithium/n-hexane solution (6.25 ml, 0.01 mol) was added to a mixture of 1-methylpyrazole (0.99 g, 0.012 mol) and THF (10 ml) at −70 to −60° C. over 15 minutes, and then the mixture was stirred at −70° C. to room temperature for 1 hour. The reaction mixture was cooled to −70° C., and a solution of the crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride in THF (10 ml) was added, and the mixture was stirred at −70° C. for 1 hour. After completion of the reaction, iN hydrochloric acid (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.50 g, 15.6%) as colorless crystals.
Reaction SMILES: N[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:3]=1[C:20]#[N:21].[I:22]CI.N(OCCC(C)C)=O>C(#N)C>[C:20]([C:3]1[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:6][C:2]=1[I:22])#[N:21]
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(Cl)cc1Cl
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 38 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a suspension of ethyl 5-amino-4-cyano-3-(2,4-dichlorophenyl)thiophene-2-carboxylate (2.92 g, 0.00856 mol) in acetonitrile (10 mL) was added diiodomethane (2.41 mL, 0.0300 mol) under an atmosphere of argon and was heated at 38° C. Isoamyl nitrite (2.61 g, 0.0214 mol) was added dropwise and the reaction mixture was cooled to room temperature and stirred for one hour. The reaction was concentrated in vacuo and column chromatography was performed to yield the title compound (1.44 g, 37%) as an orange solid. 1H NMR (400 MHz, d1-chloroform) δ: 7.53 (d, 1H, J=2.00 Hz), 7.38-7.34 (m, 1H), 7.21 (d,1H, J=8.28 Hz), 4.25-4.15 (m, 2H), 1.21-1.16 (m, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCC.CCOC(C)=O>[C:20]([C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccccc1)OCO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
To a solution of methyl 3,4-methylenedioxyphenylacetate (150 mg, 0.77 mmol) in CH2Cl2 (5 mL) was added SnCl4 (1.0M solution in CH2Cl2 ; 1.5 mL, 1.5 mmol) at 0° C. Then benzoyl chloride (130 μL, 1.1 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature. After 24 h, the mixture was added to a saturated NaHCO3 solution (30 mL), diluted with 1:1 hexane/EtOAc (60 mL), washed with water and brine, and dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was separated by chromatography on silica gel (4:1 hexane/EtOAc) to yield the title compound (110 mg, 48%). 1H NMR (CDCl3) 7.78-7.45 (m, 5H), 6.88 (s, 1H), 6.84 (s, 1H), 6.04 (s, 2H), 3.80 (s, 2H), 3.61 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Clc1cccc(Cl)c1CC1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)N2CCCC2Cc2c(Cl)cccc2Cl)c(C(F)F)n1
Reaction time: 15 h
Yield: 78.8 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.97 g; 5.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of 2-(2,6-dichloro-benzyl)-pyrrolidine (1.20 g; 5.0 mmol), which was prepared as described in example P17, and triethylamine (1.5 g; 15.0 mmol) in dichloromethane (15 ml). The ice bath was removed and reaction mixture was allowed stirring for 15 hours. The reaction mixture was washed with 2M NaOH (20 ml), 2M HCl (20 ml) and saturated NaCl (20 ml) and then dried over Na2SO4. After removal of the solvent, the residue (1.9 g oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 3:7). 1.53 g (78.8% of theory) of [2-(2,6-dichloro-benzyl)-pyrrolidin-1-yl]-(3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanone was obtained in form of an oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[C:13]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][C:16]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2ccc(-c3ccccc3)cc2)c2ccccc12
Yield: 52 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-biphenylboronic acid as described in Step 1 of Example 29 to afford 1-biphenyl-4-yl-2-chloro-1H-indole-3-carboxaldehyde (52% yield) as a yellow solid. ESI/MS 332 (M+H), RT=4.14 min; NMR 10.15 (1H, s); 8.23 (1H, d, J=9 Hz); 7.99 (2H, d, J=9 Hz); 7.82 (2H, d, J=9 Hz); 7.69 (7H, m); 7.54 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([O:20][CH3:21])=[C:15]([NH2:22])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38].[OH-].[Na+]>CN(C=O)C.O>[NH2:19][C:17]1[N:18]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:14]=[C:15]([NH:22][C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:16]=1[O:20][CH3:21]
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Reactant: COCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(=O)Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(N)c1OC
Temperature: 50 °C

Procedure:
300 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy pyrimidine-4,6-diamine 1-6-1 were suspended in 3.8 mL DMF. After addition of 86 mg of triethylamine (0.85 mmol, 1.0 eq.) and 92 mg of methoxyacetylchloride (0.85 mmol, 1.0 eq.), the resulting reaction mixture was heated for four h at 50° C. For completition of reaction further 64 mg of triethylamine (0.64 mmol, 0.75 eq.) and 69 mg of methoxyacetylchloride (0.64 mmol, 0.75 eq.) were added and the suspension was heated for two h at 50° C. After cooling and dilution with water, the pH was adjusted to 7 using 3N aqueous sodium hydroxide solution. The precipitated crude product was filtered off and dried in vacuo yielding 267 mg (0.63 mmol, 74%) of target compound. The crude material was pure enough for further processings.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]3[C:13]=1[C:12](C(O)=O)=[CH:11][C:10]3=[C:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][CH:22]=1)[C:18]=2[CH2:19][CH3:20])(=[O:3])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>[Cu]>[C:1]([NH:4][C:5]1[C:13]2[N:9]3[C:8](=[CH:7][CH:6]=1)[C:18]([CH2:19][CH3:20])=[C:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH:22]=1)[C:10]3=[CH:11][CH:12]=2)(=[O:3])[CH3:2]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(=O)O)c3c(NC(C)=O)ccc1n23
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2ccc3c(NC(C)=O)ccc1n32
Temperature: 200 °C

Procedure:
A mixture of 7-acetylamino-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-1-carboxylic acid, copper powder (0.52 g), and 130 ml of freshly purified quinoline was heated to 200 ° C. for 2 hours in a nitrogen atmosphere. The copper catalyst was filtered off from the warm mixture. Ice (200 g) was added to the filtrates and the pH was adjusted to 1.5 by addition of a 6M hydrochloric acid solution. The resulting mixture was extracted with dichloromethane. The extract was washed with a 1M hydrochloric acid solution (2×300 ml) followed by a saturated sodium hydrogen carbonate solution (2×250 ml). The dried extract (magnesium sulfate) was evaporated and the residue chromatographed over silica gel with toluene/ethyl acetate (2:1) as eluent to yield 1.52 (64%) of the title compound. M.p. 211-13° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.38 (t, 3H), 2.22 (s, 3H), 3.18 (q, 2H), 5.18 (s, 2H), 7.23 (d, 2H), 7.35-7.55 (m, 7H), 7.75 (d, 2H), 8.03 (d, 1H), 8.22 (d, 1H), 10.50 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8](O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:24][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(F)c2)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(Br)c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
A 250 mL round bottom flask was charged with 0.4845 g (1.56 mmol, 1.0 equiv) of (R)-tert-butyl 3-((R)-(3-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate, 0.7920 g (2.39 mmol, 1.52 equiv) of carbon tetrabromide, and 15 mL of CH2Cl2. The flask was cooled with an ice bath and then 0.6258 g (2.38 mmol, 1.52 equiv) of triphenylphosphine was added in portions over 5 min. The reaction mixture was allowed to slowly warm to rt while stirring overnight. Analysis of the mixture by LC-MS showed two peaks with the same mass 236 [M-C4H8—Br]+, consistent with a ca 62:38 mixture of two isomers: tR=10.48 min and 10.93 min in 16 min chromatography, respectively. After the solvent was removed in vacuo, the residue was purified by ISCO (40 g silica gel column, 0%→30% ethyl acetate/hexanes over 40 min, flow rate 40 mL/min) to afford 0.2470 g (42%) of (3R)-tert-butyl 3-(bromo(3-fluorophenyl)methyl)piperidine-1-carboxylate. MS ESI +ve m/z 236 (M-C4H8—Br). Isomer 1 and 2, MS ESI +ve m/z 236 (M-C4H8—Br), tR=2.13, 2.17 min in 3 min chromatography.
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[S:17][C:16]([C@H:18]4[CH2:22][CH2:21][CH2:20][N:19]4C(OC(C)(C)C)=O)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2]>C(O)(C(F)(F)F)=O>[NH:19]1[CH2:20][CH2:21][CH2:22][C@@H:18]1[C:16]1[S:17][C:13]([C:10]2[NH:9][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]=3[N:11]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2[nH]c(-c3ccc([C@H]4CCCN4)s3)nc12

Procedure:
A solution of EXAMPLE 16C (2.2 g) in TFA (50 mL) was stirred at ambient temperature for 30 minutes. After concentration, the concentrate was purified by HPLC (Zorbax, C-18, Mobile phase A: 0.1% TFA in water; B: 0.1% TFA in acetonitrile; 0-100% gradient). 1H NMR (CD3OD) δ 2.19-2.29 (m, 1H), 2.28-2.41 (m, 2H), 2.55-2.67 (m, 1H), 3.43-3.56 (m, 2H), 5.01 (dd, J=9.3, 6.9 Hz, 1H), 7.36 (d, J=3.7 Hz, 1H), 7.39 (d, J=4.6 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.79 (d, J=3.7 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:27]1([C:36](=O)[CH2:37][CH2:38][S:39][CH3:40])C2C=CC=CC=2N=[N:28]1.O.NN>C1COCC1.CCO>[CH3:40][S:39][CH2:38][CH2:37][C:36]1[NH:27][N:28]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSCCC(=O)n1nnc2ccccc21
Reactant: Cc1ccc(C(=O)Cc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NN
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CSCCc1[nH]nc(-c2ccc(C)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-phenyl-1-p-tolylethanone (2.0 g, 9.51 mmol) in THF (10 mL) was added LiHMDS (1.0 M in THF) (19.02 mL, 19.02 mmol) slowly via syringe at 0° C. After stirring for 10 min, 1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-(methylthio)propan-1-one (2.53 g, 11.41 mmol) was added in one portion. The reaction was stirred at 0° C. for 30 min before quenched with AcOH (2 mL). To the reaction were added EtOH (30 mL), hydrazine hydrate (1.428 g, 28.5 mmol), and brought to reflux for 2 h. After cooled to room temperature, the reaction was concentrated and extracted with EtOAc/H2O, washed with brine, dried over MgSO4, and purified by column chromatography to give the title compound a as clear oil (1.50 g). LCMS m/z=309.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.96 (s, 3H), 2.29 (s, 3H), 2.66 (t, J=7.71 Hz, 2H), 2.90 (t, J=7.58 Hz, 2H), 7.01-7.06 (m, 2H), 7.18-7.25 (m, 3H), 7.26-7.37 (m, 3H).
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH:23][C@H:24]([C:28]([NH:30][C:31]2([C:34]#[N:35])[CH2:33][CH2:32]2)=[O:29])[CH2:25][CH2:26][CH3:27])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:34]([C:31]1([NH:30][C:28](=[O:29])[C@@H:24]([NH:23][C@@H:18]([C:15]2[CH:16]=[CH:17][C:12]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)[C:19]([F:22])([F:21])[F:20])[CH2:25][CH2:26][CH3:27])[CH2:33][CH2:32]1)#[N:35]
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(C)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was synthesized in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1%-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between p-tolylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex. MS (+ESI): 430 [M+1]+
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3(C)[C@H:5]1[CH2:4][CH2:3]2.CC([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2CC1)=[O:24].CC([C@@H]1[C@@]2(C)CC[C@@H]3[C@]4(C)C(=CC(CC4)=O)CC[C@H]3[C@@H]2CC1)=O.O[C@H]1CC[C@H]2C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1.C[C@]12CC[C@H]3[C@@H](CC[C@@H]4[C@]3(C)CCC(=O)C4)[C@@H]1CCC2=O.C[C@]12CC[C@H]3[C@@H](CC=C4[C@]3(C)CC[C@H](O)C4)[C@@H]1CC[C@@H]2O.C[C@]12CC[C@H]3[C@@H](CC=C4[C@@H]3CC[C@H](O)C4)[C@@H]1CC[C@@H]2O.C[C@]12CC[C@H]3[C@@H](CC[C@@H]4[C@]3(C)CC[C@H](O)C4)[C@@H]1CC[C@@H]2O>>[CH3:1][C@:2]12[CH2:3][C@H:4]([OH:24])[C@H:5]3[C@@H:6]([CH2:12][CH2:13][C:14]4[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=43)[C@@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:11]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Product: C[C@]12C[C@H](O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
This reduction procedure is useful for the preparation of the 11α-acid succinates of 11α-hydroxy analogs of dehydroepiandrosterone, pregnenolone, progesterone, 3β-hydroxy-estr-5-en-17-one, and 5α-androstane-3,17-dione to 11α-hydroxy succinate derivatives of androst-5-ene-3β,17β-diol, pregn-5-ene-3β,20α and 20β diols, pregn-4-ene-3,20α and 20β diols, estr-5-en-3β,17β-diol and 5α-androstane-3β,17β-diol.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:12]=[C:13]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=4)[N:17]([CH3:31])[C:14]3=[N:15][CH:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.C(O)C.N>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:12]=[C:13]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:28](=[NH:29])[NH2:30])=[CH:26][CH:27]=4)[N:17]([CH3:31])[C:14]3=[N:15][CH:16]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)cnc21
Yield: 85 %

Procedure:
Prepared analogously to Example 2 from 3-methyl-2-[2-(4-amidinophenyl)ethyl]imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-ethoxycarbonylmethylamide hydrochloride and sodium hydroxide solution. Yield: 85% of theory, C25H24N6O3 (456.51); Rf value: 0.19 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5); EKA mass spectrum: (M+H)+=457.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:14][N:13]=2)=[CH:7][N:6]=1)=[O:4].CO.O.[Li+].[OH-]>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[N:13][C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)=[N:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc(Nc3ccc(C(=O)O)nc3)nc2)cc1
Reaction time: 12 h

Procedure:
To a suspension of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]pyridine-2-carboxylic acid methyl ester 4 (0.3 mmol) in THF:MeOH:H2O=3:2:1 (5 mL), is added 6M LiOH (1.8 mmol). The reaction mixture is stirred at it for 12 h. After this time the solvent is removed under vacuum, the residue is diluted with H2O (6 mL) and the pH neutralized with 6M HCl. The solid that precipitates out is collected, washed with water and dried in a vacuum oven for 12 h to afford 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid 5 as a yellow solid, which is used in the next step without further purification. MS (m/z) (M+1)+: 323.2.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH:7][C:10](=[O:13])[CH:11]=[CH2:12])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CC(=O)N[C@@H](C)C(=O)OCC
Reaction time: 2 h

Procedure:
To 0.5 moles of alanine ethyl ester hydrochloride in 500 ml. of benzene is added 0.5 moles of acryloyl chloride. To this stirred mixture is added portionwise 0.6 moles of anhydrous sodium carbonate. The reaction mixture is then refluxed for 1 hour, stirred an additional 2 hours, filtered, and the filtrate concentrated to give N-acryloylalanine ethyl ester.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:6]=[CH:7][C:8]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:9]=2[N:10]=1.N.[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C)C=O.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:9]2[N:10]=[C:5]([S:4][CH3:3])[N:6]=[CH:7][C:8]=2[CH:14]=[CH:13][C:12]1=[O:15]
Reactant: CSc1ncc2ccc(=O)[nH]c2n1
Reactant: BrCc1ccccc1Br
Agent: N
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2ccc(=O)n(Cc3ccccc3Br)c2n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60%, 47 mg, 1.19 mmol) in anhydrous dimethylformamide (2 mL) was added 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.78 mmol, prepared by the method in example 1, Steps 1-5, using ammonia in the first step) at room temperature and stirred at 60° C. for 0.5 h. The reaction mixture was cooled down to room temperature and 2-bromobenzyl bromide was added and stirred for 48 h. The mixture was diluted with ethyl acetate (20 mL) and 10% brine solution (10 mL), the two phases were separated, the aqueous layer was washed with ethyl acetate (1×20 mL), the combined organic layer was dried over sodium sulfate, filtered and evaporated to give 8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one, an orange oil (0.24 g, 0.66 mmol, 84%). ESMS m/z 362 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (s, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.59 (dd, J=7.4, 1.4 Hz, 1H), 7.05-7.15 (m, 2H), 6.74 (d, J=9.5 Hz, 1H), 6.65 (d, J=7.0 Hz, 1H), 5.69 (s, 2H), 2.38 (s, 3H).