Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][CH:7]=3)[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1ccc(C(N)=O)c(N)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-4-methoxy-benzamide (1.00 g, 6.01 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was stirred at 115° C. for 16 hours, and cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 hour, filtered, and dried under vacuum, to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.20 g (58%).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].O>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[CH:11][CH:12]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 4-isobutylbenzaldehyde (2.4 g) in methanol (10 mL) was added sodium borohydride (0.85 g) at room temperature, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[C:29]([O:33][CH2:34][CH2:35][O:36][NH2:37])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([O:33][CH2:34][CH2:35][O:36][NH:37][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1])=[O:21])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: CC(C)(C)OCCON
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2Cl)c(C(=O)NOCCOC(C)(C)C)c(=O)n(C)c1=O
Temperature: 100 °C

Procedure:
Phenyl 6-(2-chloro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 23; 100 mg, 0.195 mmol, 1 eq) and O-(2-tert-butoxyethyl)hydroxylamine (See, WO05/110410; 260 mg, 1.95 mmol, 10 eq) were mixed in anhydrous THF (3 ml) and heated at 100° C. for 50 minutes in a microwave reactor. The protected product Example 24 was isolated by HPLC. [M+H] calc'd for C19H24ClIN4O5, 551; found, 551.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=O.Cl>C(OCC)C.CCCCCC>[CH3:17][C:18]1[CH2:22][CH:21]=[C:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH:19]=1
Reactant: CC1CCCC1=O
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(c2ccc(C(C)(C)C)cc2)=CC1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
1-Bromo-4-t-butylbenzene (18 mL, 104 mmol) was dissolved in diethyl ether (100 mL) and added dropwise at −30° C. with a solution (66 mL, 104 mmol, 1.57 N) of n-butyllithium in hexane. The resultant solution was warmed to room temperature, stirred night and day and added dropwise at −20° C. to a solution of 3-methyl-2-cyclopentanone (10 g, 104 mmol) in diethyl ether (10 mL). Immediately after dropwise addition, the solution was warmed to room temperature and stirred for 3 hours. After termination of the reaction, the reaction solution was added with dilute hydrochloric acid and subjected to layer separation. The organic layer was dried with magnesium sulfate and then had the solvent distilled off under reduced pressure. The crude product was distilled under reduced pressure (105 to 115° C./0.16 mmHg) to obtain 1-methyl-3-(4-t-butylphenyl)-cyclopentadiene (15.3 g, yield: 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11])([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11]
Reactant: CCN(CC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)S(=O)(=O)c1ccccc1N
Yield: 104.6 %

Procedure:
In a pressure vessel a mixture of 133 g of o-nitro-N,N-diethylbenzenesulfonamide, 5 g of 10% palladium on carbon, and 500 ml of ethyl acetate was taken at 130° under 500 psi hydrogen pressure until hydrogen was no longer absorbed. The reaction mixture was cooled and the catalyst filtered off. Evaporation of the solvent in-vacuo gave 123 g of o-amino-N,N-diethylbenzenesulfonamide as a viscous oil which slowly crystallized to a solid, m.p. 45°-51°.
Reaction SMILES: C1([O:7][S:8](=O)(=[O:10])[NH2:9])C=CC=CC=1.[F:12][C:13]([F:20])([F:19])[C:14]1([OH:18])[CH2:17][CH2:16][CH2:15]1>>[F:12][C:13]([F:20])([F:19])[C:14]1([O:18][S:8](=[O:10])(=[O:7])[NH2:9])[CH2:17][CH2:16][CH2:15]1
Reactant: OC1(C(F)(F)F)CCC1
Reactant: NS(=O)(=O)Oc1ccccc1
Product: NS(=O)(=O)OC1(C(F)(F)F)CCC1

Procedure:
Sulfamic acid 1-trifluoromethyl-cyclobutyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-trifluoromethyl-cyclobutanol to obtain sulfamic acid 1-trifluoromethyl-cyclobutyl ester: 1H NMR (CDCl3, 300 MHz) δ 5.85 (s, 2H), 3.40 (t, 1H), 3.01 (m, 1H), 2.56 (m, 1H), 2.42 (t, 1H), 2.04 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:13][N:12]=1.Cl.[OH-].[Na+].ClCCl>C(O)C>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Yield: 57.7 %

Procedure:
Compound 4 (34 mg, 0.09 mmol) was dissolved in ethanol (5 ml) followed by the addition of stannous chloride (51.4 mg, 0.27 mmol) and concentrated HCl (0.25 ml). The reaction mixture was refluxed for 2 hours and cooled down. 2N NaOH was used to adjust pH to 10. Dichloromethane was added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by PTLC (3% MeOH in DCM as developing solvent) to give product 5 (18 mg, Yield: 58%): 1H NMR (200 MHz, CDCl3): δ.8.14 (1H, d, J=2.2 Hz), 7.76 (1H, d, d, J=8.6 Hz, J2=2.4 Hz), 7.32 (2H, d, J=8.4 Hz), 6.80 (5H, m), 4.53 (2H, d, t, J1=47.6 Hz, J2=4.2 Hz), 4.49 (2H, t, J=4.8 Hz), 3.85 (3H, m), 3.70 (5H, m), 1.8-3.0 (2H, br); HRMS (EI) m/z calcd. for [C19H23FN2O3]+ 376.1693.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:21]3[CH:20]=[N:19][CH:18]=[C:17]([F:16])[CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cncc(F)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cncc(F)c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 3-fluoro-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([O:19][C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Boc-4-iodophenylalanine was dissolved in acetonitrile and DUB (1 equivalent) was added followed by benzyl bromide (1 equivalent). The mixture was stirred for 2 h at room temperature. After removal of the solvent under reduced pressure, the residue was dissolved in EtOAc and the solution washed with 10% aqueous HCl and water. Drying (MgSO4) and concentration under reduced pressure gave a crude product that was purified by crystallization from hexane.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:14]([C:10]1[S:9][CH:13]=[CH:12][N:11]=1)(=[O:16])=[O:15]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1nccs1
Product: Cc1noc(NS(=O)(=O)c2nccs2)c1Br
Yield: 57 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and thiazole-2-sulfonyl chloride in 57% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid., m.p. 175-177° C.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][C:22]1[NH:39][C:25]2=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[C:24]2[C:23]=1[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:22]1[NH:39][C:25]2=[N:26][CH:27]=[C:28]([C:2]3[C:6]([C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=4)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=3)[CH:29]=[C:24]2[C:23]=1[CH3:40]
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Reactant: Cc1[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1[nH]c2ncc(-c3nn(C(C)C)cc3-c3ccnc(NC[C@H](C)O)n3)cc2c1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (0.34 g, 0.885 mmol) in toluene (30 mL) and EtOH (10 mL) were added 2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (B-6-5) (0.7 g, 1.77 mmol in theory) and 2 N aq. Na2CO3 (1.3 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (68 mg, 0.058 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(3-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-6) (0.170 mg, 23.6%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([OH:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2O)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
To a 0° C. solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, (6.79 g, 16 mmol) in pyridine (160 mL) was added p-toluenesulfonyl chloride (3.06 g, 16 mmol). The solution was left to warm slowly to room temperature with stirring under nitrogen. After 2.5 hours, the mixture was poured into H2O with constant stirring. The resulting off-white solid was filtered, rinsed with H2O and dried to provide the desired product (yield: 6.26 g, 79%). mp 198-200° C. 1H NMR (300 MHz, DMSO d6) δ 2.35 (s, 3H), 3.28 (s, 3H), 7.20 (m, 2H), 7.52-7.64 (M, 5H), 7.70 (m, 3H), 7.89 (m, 2H), 8.32 (s, 1H). MS APCI+ 531 (M+H)+, 548 (M+H2O)+, APCI−493 (M+35)−. Anal. calc. for C24H19ClN2O6S2: C, 54.29; H, 3.61; N, 5.28. Found: C, 54.55; H, 3.46; N, 5.57.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (52 mg, 45%).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[OH:29])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:18]([CH2:17]/1)[CH2:19][C:20](=[O:50])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:12]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C/C(=N\O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 50 %

Procedure:
The title compound II-bq was prepared in 50% yield from 3,3:17,17-bis(ethylendioxy)-7(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS: δ 10.37 (s, 1H), 2.99 (m, 1H), 2.58-0.67 (m, 19H), 1.12 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: CO[C:3](=[O:19])[C@H:4]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:5][C:6]([NH:8][C:9]1[S:10][C:11](=[S:14])[NH:12][N:13]=1)=[O:7].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[S:14]=[C:11]1[S:10][C:9]([NH:8][C:6]([NH:5][C@@H:4]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:3]([NH:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[O:7])=[N:13][NH:12]1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)Nc1n[nH]c(=S)s1
Product: CC(C)C[C@H](NC(=O)Nc1n[nH]c(=S)s1)C(=O)NCc1ccccc1

Procedure:
Following the general procedure outlined in EXAMPLE 5, and making non-critical variations but starting with N-[[(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino]carbonyl]-L-leucine methyl ester (EXAMPLE 28) and benzylamine, the title compound is obtained (mp 206°-208° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[N:12])[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=1.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>ClCCl.N1C=CC=CC=1>[Cl:20][C:21]1[S:25][C:24]([S:26]([N:1]([S:26]([C:24]2[S:25][C:21]([Cl:20])=[CH:22][CH:23]=2)(=[O:28])=[O:27])[C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[C:11]#[N:12])[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=2)(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2c(C#N)cccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1nc(N(S(=O)(=O)c2ccc(Cl)s2)S(=O)(=O)c2ccc(Cl)s2)c2c(C#N)cccc21
Temperature: 45 °C
Reaction time: 60 h
Yield: 56 %

Procedure:
1,1-Dimethylethyl 3-amino-4-cyano-1H-indazole-1-carboxylate (for a preparation see Intermediate 63) (4.3 g, 16.65 mmol) was dissolved in a mixture of dichloromethane (40 mL) and pyridine (40 mL). 5-Chloro-2-thiophenesulfonyl chloride (7.23 g, 33.3 mmol) was added to the solution and it was stirred at 45° C. under nitrogen for 60 h. LCMS showed approx 30% starting material remaining, so further quantity of 5-chloro-2-thiophenesulfonyl chloride (3.5 g, 16.12 mmol) was added to the reaction, and the mixture was stirred for 2 h. LCMS showed no change in product so the reaction was concentrated under vacuo. The residue was dissolved in DCM (200 mL) and washed 3 times with water (200 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue (10 g) was dissolved in DCM and loaded onto a 750 g silica column and purified by chromatography on the Companion system using a 0-25% ethyl acetate-DCM gradient. Appropriate fractions were evaporated in vacuo to give the title compound (5.8 g, 56%) as an orange solid. LCMS (System A) RT=1.45 min, ES+ve m/z 636/638 (M+NH4)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:30][C:29]4[CH:28]=[CH:27][C:26]([N:23]5[CH2:24][CH2:25][O:20][CH2:21][CH2:22]5)=[CH:32][CH:31]=4)[N:14]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Clc1nccc(Sc2ccc(-n3cnnn3)cc2)n1
Product: c1cc(Sc2ccc(-n3cnnn3)cc2)nc(Nc2ccc(N3CCOCC3)cc2)n1
Yield: 38.1 %

Procedure:
In a procedure analogous to Example 8, reaction of 4-(4-(1H-tetrazol-1-yl)phenylthio)-2-chloropyrimidine (100 mg, 0.34 mmol) and 4-morpholinoaniline (75 mg, 0.41 mmol) furnished the product (56 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[N:6]=1.[Li+].[BH4-].CO>C1COCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([OH:9])[CH3:8])[N:6]=1
Reactant: CC(=O)c1csc(N)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
To a stirred solution of 1-(2-amino-1,3-thiazol-4-yl)ethanone (10 g, 70.33 mmol, 1 eq.) in 100 ml dry THF cooled to 5° C., was added LiBH4 (2M in THF, 38.7 ml, 77.36 mmol, 1.1 eq.) followed by MeOH (3.2 ml, 78 mmol, 1.11 eq.). The reaction was allowed to warm to r.t. and was stirred for further 18 hrs. The solvent was evaporated and the residue was partitioned between 250 ml EtOAc/250 ml water. Stirring was allowed for 10 mins. And the brown solid was filtered. The organic layer was separated, washed with brine, dried with MgSO4 and evaporated to give viscous orange oil. The residue was purified by chromatography on silica gel to give 1-(2-amino-1,3-thiazol-4-yl)ethanol (2 g, 19% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([O:34]CC)=O)[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[N:37]1([CH2:42][CH2:43][NH2:44])[CH2:41][CH2:40][CH2:39][CH2:38]1>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:44][CH2:43][CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:34])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NCCN1CCCC1
Solvent: CO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCN2CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 67.9 %

Procedure:
Ethyl 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (Intermediate A) (200 mg, 0.41 mmol) and 2-pyrrolidin-1-ylethanamine (928 mg, 8.12 mmol, 20 eq) were dissolved in MeOH (2.5 mL) and heated to 100° C. in a sealed vial by a microwave oven for 40 min The solvent was evaporated and EtOH (3 mL) was added and heated to 50° C. for two hours and then water (3 mL) was added and the mixture was stirred at room temperature over night. The precipitate was centrifuged (4000 rpm, 3 min) and washed three times with EtOH/H2O 1:1 (5 mL) and dried over night. The residue was dissolved in acetonitrile and purified by HPLC (30-95% MeOH in H2O+0.1% TFA), the pure fractions were freeze-dried, dissolved in acetonitrile and desalted with Na2CO3 (solid phase) and evaporated to afford 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-N-(2-pyrrolidin-1-ylethyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide as a white solid (156 mg, 65%); 1H NMR (500 MHz, DMSO): δ 1.67-1.59 (4H, m), 1.72 (3H, s), 2.43-2.37 (4H, m), 2.49-2.47 (2H, m), 3.38-3.33 (2H, m), 6.72 (1H, d), 7.67-7.63 (2H, m), 7.71 (1H, d), 7.88-7.82 (2H, m), 7.96-7.89 (4H, m), 8.07 (1H, s), 9.35 (1H, t);