Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([NH2:8])(=[O:7])[CH2:3][C:4]([NH2:6])=[O:5].C(O[C:12](=O)[CH2:13][NH:14][C:15](=[O:21])[C:16]1[S:20][CH:19]=[CH:18][CH:17]=1)C.C(O)(=O)C>C(O)C.O>[C:16]1([C:15]([NH:14][CH2:13][C:12]2[N:6]=[C:4]([OH:5])[CH:3]=[C:2]([OH:7])[N:8]=2)=[O:21])[S:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)CC(N)=O
Reactant: CCOC(=O)CNC(=O)c1cccs1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C(NCc1nc(O)cc(O)n1)c1cccs1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
To a solution of sodium (1.4 g) in ethanol (120 ml) was added malonamide (3.8 g) and the mixture was heated at 60° C. for an hour under stirring. Then after added N-(2-thenoyl)glycine ethyl ester (8 g), the mixture was refluxed for 6 hours. The mixture was concentrated to give the residue which was diluted with water. The aqueous mixture was neutralized by adding acetic acid to deposit a crystalline product which was collected by filtration and recrystallized from dimethylformamide (DMF) to give the objective product (2.8 g) as colorless crystals, mp 270°-275° C. (decompd.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:21][C:22]1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][C:13]2[O:14][C:15]([CH2:22][OH:21])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)occ1O
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Product: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)oc(CO)c1O
Yield: 45.62 %

Procedure:
4-Chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-07) (7.01 g, 45.62%) was synthesized as a light yellow solid from 4-chloro-N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-07) (14.0 g, 44.44 mmol) following the procedure described for N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-01).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:11])=[C:4]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:3]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:31][O:32][CH2:33]OC.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH2:9][CH2:31][O:32][CH3:33])[C:5]([F:11])=[C:4]([Si:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:17][CH3:18])[CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(C)=O)c1F
Reactant: COCOC
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)CCOC)c1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 72 %

Procedure:
To a solution of 1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-ethanone (11.6 g, 33.9 mmol, example 1, step b) in dichloromethane (50 ml) was added Hünigs-base (6.21 ml, 35.6 mmol) at 0° C. followed by TMS-triflate (6.43 ml, 35.52 mmol, 1.05 eq.) under nitrogen. The reaction mixture was stirred at 0° C. for 40 minutes. Dimethoxymethane (2.71 g, 35.6 mmol) and 2,6-di-tert-butylpyridine (0.648 g, 3.39 mmol) was added drop wise at 0° C. TMS-triflate (0.61 ml, 3.39 mmol) was then added to the reaction mixture. After 30 min the cooling bath was removed and stirring was continued at rt over night (18 h). The reaction mixture was poured onto cold brine, diluted with ethyl acetate and the organic phase was washed thoroughly with 10% NaHSO4 solution, sat. sodium bicarbonate solution (saturated with NaCl) and brine, dried over sodium sulfate, filtered and evaporated. The crude product (13.52 g) was chromatographed over silica gel (320 g, cyclohexane/ethyl acetate 95:5) to give the title compound as a yellow liquid: 9.18 g (72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:27]=[CH:26][C:18]3[C:19]([CH3:25])([CH3:24])[O:20][C:21](=[O:23])[NH:22][C:17]=3[CH:16]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:28]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:27]=[CH:26][C:18]3[C:19]([CH3:24])([CH3:25])[O:20][C:21](=[O:23])[NH:22][C:17]=3[CH:16]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccc(Cl)c(Cl)c3)ccc21
Product: CC1(C)OC(=O)Nc2cc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)ccc21

Procedure:
Prepared analogously to Example 2 from 7-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:2]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccsc1)c1cccnc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccnc3)=C2c2ccsc2)cc([N+](=O)[O-])c1O
Yield: 32.9 %

Procedure:
A mixture of 1-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone (Intermediate 56) (100 mg, 0.492 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (94 mg, 0.45 mmol), urea (81 mg, 1.34 mmol), concentrated HCl (0.04 mL, 0.45 mmol) in EtOH (5 mL) was refluxed overnight. Then the mixture was evaporated in vacuo and the residue was purified by preparative HPLC to give Compound 116 (65 mg, yield 33%). 1H NMR (DMSO-d6 400 MHz): δ 10.30 (s, 1H), 8.92 (s, 1H), 8.56-8.54 (m, 1H), 8.46-8.44 (m, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 7.48-7.43 (m, 2H), 7.25-7.22 (m, 2H), 6.94 (s, 1H), 6.35 (d, J=5.2 Hz, 1H), 5.27 (d, J=2.8 Hz, 1H), 4.12-4.04 (m, 2H), 1.35 (t, J=6.8 Hz, 3H); MS (ESI): 438.9 m/z [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1>CN(C)C=O>[BrH:11].[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]1=[NH:1]
Reactant: NC(=O)c1cccnc1N
Reactant: Clc1cccc(CBr)c1
Solvent: CN(C)C=O
Product: Br
Product: N=c1c(C(N)=O)cccn1Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
To a solution of 2-aminonicotinamide (0.1 g) in N,N-dimethylformamide (3 ml) was added 1-(bromomethyl)-3-chlorobenzene (0.3 g), and the mixture was stirred at 80° C. for 15 hr. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (90 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[O:3]1.[H-].[Na+].I[CH3:22]>CN(C=O)C.C1COCC1.C(Cl)Cl>[CH3:22][N:13]1[C:14]2[C:10](=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:18])([CH3:1])[O:3]3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[N:12]1.[CH3:22][N:12]1[CH:11]=[C:10]2[C:14]([CH:15]=[CH:16][CH:17]=[C:9]2[B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:18])([CH3:1])[O:3]2)=[N:13]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc2c(B3OC(C)(C)C(C)(C)O3)cccc2n1
Product: Cn1ncc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (400 mg) in dry DMF (4 mL) precooled to 0° C. was added to a suspension of sodium hydride (80 mg) in dry THF (5 mL) at −78° C. under inert atmosphere. After 30 min, iodomethane (112 uL) was added to the mixture at −78° C. The reaction mixture was allowed slowly to warm up to room temperature overnight and then diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (143 mg) and 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (160 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[Na+].C(O)(=O)C.CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cc(C(=O)O)cnc2N)c1
Temperature: 50 °C
Yield: 93.2 %

Procedure:
Methyl 6-amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinate (0.550 g, 1.47 mmol) was dissolved in THF (15 mL) and then treated with 1.0 M NaOH (7.33 mL, 7.33 mmol). The reaction mixture was heated to 50° C. Once the reaction was done by TLC, the reaction was cooled to room temperature and then acidified with acetic acid. The reaction mixture was taken up in of EtOAc (˜15 mL) then extracted with H2O (2×15 mL). The water layer then was re-washed with EtOAc (˜15 mL) and the combined organic layers were dried over anhydrous Na2SO4(s). The mixture was then filtered and concentrated in vacuo to give the title compound (0.495 g, 1.37 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[N:17]1([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.CCCCCC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:27][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(CN2CCCC2)cc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(CN2CCCC2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 106.2 %

Procedure:
To a solution of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, (0.15 g, 0.53 mmol) in N,N′-dimethylformamide is added 4-(pyrrolidinyl-methyl)aniline (0.10 mL, 0.58 mmol). The reaction mixture is heated at 120° C. under N2. Reaction is monitored by mass spectroscopy. After reaction is completed after 1.5 h. After evaporating the solvent, warm ethyl acetate is added to the residue to generate reddish orange residue. It is filtered through a pad of celite to give a yellow solution, which upon addition of hexane generated 0.24 g (62.8% yield) of orange solid: mp 165-166° C., Analysis for C21H20BrN3O2, Calcd: C, 59.17; H, 4.73; N, 9.86. Found: C, 58.77; H, 4.42; N, 9.81.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[C@H:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.O[NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[NH:20]>ClCCl>[NH2:8][CH:9]([CH2:15][CH3:16])[C@@H:10]([C:11]1[O:13][N:20]=[C:19]([CH:21]2[CH2:23][CH2:22]2)[N:18]=1)[OH:14]
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Reactant: N=C(NO)C1CC1
Solvent: ClCCl
Product: CCC(N)[C@H](O)c1nc(C2CC2)no1
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A solution of (S)-3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (2.00 g, 8.57 mmol) and N-hydroxy-cyclopropanecarboxamidine (1.03 g, 10.29 mmol) in dichloromethane (20 mL) was stirred at 0° C. and 1.25 equivalents of N-cyclohexylcarbodiimide-N′-methyl polystyrene (1.70 mmol/g, 6.30 g, 10.72 mmol) was added in portions. The reaction mixture stirred under nitrogen for three hours while warming to 15° C. The reaction mixture was filtered, the resin washed with dichloromethane and the filtrate evaporated under vacuum to dryness. [LC/MS m/z=338 (M+H+Na)].
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=3[S:6][CH:5]=2)[CH2:3][CH2:2]1.[Br:21]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:21][C:5]1[S:6][C:7]2[CH2:8][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:11][O:12][C:13]=2[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(C3CC3)csc2C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOc2c(sc(Br)c2C2CC2)C1
Yield: 75.6 %

Procedure:
A solution of tert-butyl 8-cyclopropyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (375 mg) obtained in Example 3, step 1, N-bromosuccinimide (237 mg) and acetonitrile (3 ml) was stirred at room temperature for 2 hr, 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2→10% ethyl acetate/hexane) to give the title compound (359 mg, 75%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].Cl.Cl.[CH3:38][N:39]1[C:43]([CH2:44][CH2:45][NH2:46])=[CH:42][N:41]=[CH:40]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)(=[O:25])=[O:26])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:46][CH2:45][CH2:44][C:43]5[N:39]([CH3:38])[CH:40]=[N:41][CH:42]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: Cn1cncc1CCN
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: Cl
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCCc4cncn4C)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 95.4 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (j) starting with 0.06 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.05 g of 3-methylhistamine dihydrochloride instead of the cyclopropylamine used in example 34 stage (j). After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluents), 0.070 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-[2-(3-methyl-3H-imidazol-4-yl)-ethyl]amine is obtained with the following characteristics:
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:26]O>C(O)CC>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Reactant: OO
Solvent: CCCO
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Reaction time: 72 h

Procedure:
Following the general procedure of Example 5, to a solution of 50 grams (0.14 mol) of didodecylamine dissolved in 200 ml of n-propanol at 40° C. is added dropwise 9.62 grams (0.14 mol) of 50% aqueous hydrogen peroxide solution. After 72 hours at 40-45° C., the reaction mixture is filtered to give a crude product which is subsequently recrystallized from 300 ml of hexane. The above-named product is obtained in a yield of 24.8 grams (48%) as white needles melting at 90-92° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[OH-].[Na+].[O:12]1[C@H:14]2[CH2:15][C@H:16]3[C@:29]([CH3:31])([CH2:30][C@@H:13]12)[C@@H:28]1[C@H:19]([C@H:20]2[C@@:24]([CH2:26][CH2:27]1)([CH3:25])[C@@H:23]([C:32]#[N:33])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3.O>C(O)CO>[OH:12][C@@H:14]1[C@@H:13]([N:5]2[CH2:6][CH2:7][O:8][C:3]([CH3:9])([CH3:2])[CH2:4]2)[CH2:30][C@@:29]2([CH3:31])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:28]2[CH2:27][CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C:32]#[N:33])[CH2:15]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]12
Reactant: CC1(C)CNCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C#N)CC[C@@H]43)C[C@@H]2O)CCO1
Temperature: 135 °C
Yield: 54.3 %

Procedure:
2,2-Dimethylmorpholine hydrochloride (2.43 g) and sodium hydroxide (640 mg) were added to a mixture of (2α,3α,5α,17β)-2,3-epoxyandrostane-17-carbonitrile (1.2 g) (prepared as described in British patent 1,434,919) in 1,2-ethanediol (12 ml) and the mixture was heated at 135° C. in an atmosphere of nitrogen for 24 h. The reaction mixture was poured into water (100 ml) and the precipitated solid was filtered off and then dissolved in dichloromethane. The solution was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue (1.55 g) was chromatographed on silica gel. The purified product (1.18 g) was crystallised from ether-heptane to give (2β,3α,5α,17β)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)androstane-17-carbonitrile (903 mg). m.p. 170°-173° C.; [α]D +117.5° (c 0.8).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH2:17][CH2:16]1)=O)(C)(C)C.Cl[CH2:32][Cl:33]>>[Cl:33][C:32]1[C:23]2[O:24][C@@H:2]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([CH2:21][NH:22][C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:24])[CH2:19][CH2:20]3)[CH2:3][O:5][C:25]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccnc2)CC1
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Product: O=C(NCC1CCN(C[C@H]2COc3cccc(Cl)c3O2)CC1)c1cccnc1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (1.56 g) in dichloromethane (25 ml) and the mixture stirred for 2 hours then the solvent was removed in vacuo. The residue was dissolved in dry acetonitrile (10 ml) and potassium carbonate (5.0 g) was added, followed by a solution of (R)-7-chloro-1,4-benzodioxan-2-ylmethyl 4-toluenesulphonate (1.7 g) in dry acetonitrile (15 ml), and the mixture was stirred and heated under reflux for 6 hours. The cooled mixture was poured into water then extracted with dichloromethane (2×100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulphate, and the solvent removed in vacuo. The residue was purified by flash chromatography over silica eluting with a 20:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvent removed in vacuo to give (S)-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide (1.04 g) as a colourless solid m.p. 52-54° C. [α]D -35.3° (c=1.024, methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](B(O)O)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cc2c(cc1-c1ccc(F)cc1)OCO2
Reactant: NS(=O)(=O)c1ccc(Br)cc1
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: NS(=O)(=O)c1ccc(-c2cc3c(cc2-c2ccc(F)cc2)OCO3)cc1
Yield: 75.8 %

Procedure:
Under nitrogen, 500 mg of Pd(PPh3)4 was added to a stirred solution of 1.55 g (6.0 mmol) of [6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]boronic acid (Step 2) and 1.09 g (4.62 mmol) of 4-bromobenzenesulfonamide (Lancaster) in 30 mL of toluene, 20 mL of ethanol, and 15 mL of 2M Na2CO3. After vigorous stirring at reflux for 6 hours, the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The resulting solution was washed with water and dried over Na2SO4. Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 1.3 g (76%) of 4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide as a colorless solid: mp 191.0-192.5° C.; NMR (CDCl3) δ 4.80 (s, 2H), 6.06 (s, 2H), 6.83-6.92 (m, 4H), 6.97-7.06 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H). MS (FAB): m/e 372 (M+H). Anal. Calc'd for C19H14FNO4S: C, 61.45; H, 3.80; N, 3.77. Found: C, 61.48; H, 3.92; N, 3.68.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3OC(C)=[C:37]([CH:39]([CH3:41])[CH3:40])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:43]([NH:46][CH:47]=O)([CH3:45])[CH3:44].[CH:49](N)(C)C>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:46]([CH:43]([CH3:44])[CH3:45])[C:47]([CH3:49])=[C:37]([CH:39]([CH3:40])[CH3:41])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CC(C)NC=O
Reactant: CC(C)N
Reactant: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)n3C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-isopropyl-formamide/isopropylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]1([CH3:22])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17]([O:20][NH2:21])(=[O:19])=[O:18].C(OCC)C>ClCCl>[NH2:21][N+:3]1[CH:4]=[C:5]([CH3:8])[N:6]=[CH:7][C:2]=1[CH3:1].[CH3:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:22])[C:10]=1[S:17]([O-:20])(=[O:19])=[O:18]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1cnc(C)cn1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c[n+](N)c(C)cn1
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A solution of 2,5-dimethylpyrazine (3.24 g, 30.0 mmol) in dichloromethane (DCM) (30 mL) was cooled to 0° C. A solution of O-(mesitylsulfonyl)hydroxylamine (12.9 g, 60.0 mmol) in DCM (30 mL) was added. The mixture was stirred at 0° C. for 1 h. Then diethyl ether (Et2O) (150 mL) was added. The precipitate was filtered and collected to give 9.42 g (97% yield) of the title compound as a white solid. ESI MS: m/z 124.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10]1)=[O:8].[CH3:24][C:25]1C=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C[N:34](C)C=O>>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:24][C:25]2[CH:32]=[CH:31][CH:30]=[C:27]([CH3:28])[N:34]=2)[CH:10]=1)=[O:8]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)C2CNc3ccccc3C2=O)cc1C
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3ccccc32)n1

Procedure:
Compound 4z was prepared following the procedure outlined in Step 3 of Example 1 using 15.6 mg (0.39 mmol) of sodium hydride (60%), 83.2 mg (0.30 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 73.0 mg (0.39 mmol) of 3-methylbenzylbromide. The crude product was purified by flash chromatography to yield 61 mg of a colorless solid 4z: LC-MSD, M/z for C25H22N2O2, [M+H]+=383.4, [M+2H]+=384.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.484 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.32 (d, 6H), 2.58 (s, 3H), 5.42 (s, 2H), 6.83 (d, 1H), 7.08 (d, 1H), 7.16 (d, 1H), 7.36-7.43 (m, 2H), 7.48-7.60 (m, 3H), 7.64 (s, 1H), 8.31 (s, 1H), 8.46 (d, 1H).