Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Li+].[Cl-].C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:31][O:32][C:33](=[O:54])[C@@H:34]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Sn](C)(C)C)=[CH:38][CH:37]=1>CN1CCCC1=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][O:32][C:33](=[O:54])[C@@H:34]([NH:46][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H](Cc1ccc([Sn](C)(C)C)cc1)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2C#N)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
In a dry 25 ml round bottom flask fitted with a reflux condenser vented through a three way valve attached to a vacuum source and nitrogen gas, 2-bromobenzonitrile (557 mg, 3.06 mmol), tris(dibenzylideneacetone)dipalladium (0), (51 mg, 0.056 mmol), LiCl (353 mg, 8.34 mmol), and AsPh3 (68 mg, 0.22 mmol) were added, followed by 13 ml of N-methylpyrrolidinone. The mixture was degassed and stirred for 10 minutes. A solution of (S)-2-tert-butoxycarbonylamino-3-(4-trimethylstannylphenyl) propionic acid methyl ester (1.23 g, 2.78 mmol) in N-methylpyrrolidinone (4.5 ml) was then added and the reaction was heated at 80° C. for 5 h and left overnight at room temperature. The reaction mixture was diluted with EtOAc (25 ml), quenched by addition of 10 ml of saturated KF solution and stirred for 20 minutes. The reaction mixture was partitioned between water (40 ml) and EtOAc (100 ml). The organic layer was separated, washed with water (6×40 mil and dried (MgSO4). The solvents were removed under reduced pressure and the resulting crude was purified by flash chromatography (9:1 to 7:3 hexanes/EtOAc) to give (S)-2-tert-butoxycarbonylamino-3-(2′-cyano-biphenyl-4-yl) propionic acid methyl ester (570 mg, 54%) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:38]2[CH2:43][CH2:42]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:42]1([C:2]2[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=2)[CH2:43][CH2:38]1
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)Nc1cnc(C2CC2)cn1
Temperature: 150 °C
Yield: 11.5 %

Procedure:
In a sealed tube were added methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 1.00 g, 3.47 mmol), K3PO4 (2.58 g), palladium (II) acetate (0.0795 g), tricyclohexyl phosphine (0.195 g), cyclopropylboronic acid (0.447 g), toluene (3 mL) and water (0.05 mL). Argon was bubbling through the mixture for ca. 5 min. The mixture was then heated under microwave irradiation for 5 min at 150° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried and evaporated. The product was purified by flash chromatography (AcOEt/cyclohexane: 1/99→99/1) to give methyl 4-[(5-cyclopropylpyrazin-2-yl)amino]-4-oxo-butanoate (A31, 0.020 g, 0.080 mmol, 2.31% Yield). 1H NMR (400 MHz, CDCl3) 9.28 (1H, s), 8.24 (1H, s), 8.10 (1H, s), 3.72 (3H, s), 2.75-2.65 (4H, m), 2.00 (1H, m), 1.00 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C@H:9]2[C@@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:20]([O:15][C@H:14]1[C@@H:13]([CH2:16][O:17][CH2:7][C:6]2[CH:18]=[CH:19][CH:3]=[CH:4][CH:5]=2)[O:12][CH:11]=[CH:10][C@H:9]1[O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CO[C@@H]2C=CO[C@H](CO)[C@@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2C=CO[C@H](COCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 3-O-(4-methoxybenzyl)-D-galactal (2.28 g, 8.56 mmol) and benzyl bromide (3.75 mL, 3.68 mol equiv; freshly passed through basic alumina) in DMF (30 mL) under N2 at 0° C. was treated with NaH (1.37 g, 4.0 mol equiv) in two portions. The reaction was stirred 0.5 h at 0° C. and 1 h at rt. The reaction was carefully poured into 50 g of crushed ice, diluted to 100 mL with water, then extracted with EtOAc-hexanes (1:1, 100 mL×3). Organic extracts were washed with water (100 mL×2), dried (Na2SO4) and concentrated. Flash chromatography with 15% EtOAc-hexanes gave 3.58 g (94%) of the title compound as a clear liquid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12
Agent: Cl
Product: C[C@H](O)C(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(O)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-hydroxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A188) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.CO.[NH4+].[Cl-]>[Fe].O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(Cl)cc1Nc1ccccc1
Temperature: 90 °C
Yield: 81.9 %

Procedure:
To a mixture of (5-chloro-2-nitrophenyl)phenylamine (1.36 g, 5.47 mmol) in a 3:1 mixture of MeOH:water (120 mL) were added NH4Cl (1.76 g, 32.81 mmol) and iron powder (1.22 g, 21.88 mmol) and the reaction mixture heated at 90° C. for 2 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound as a brown oil (980 mg, 82%). LCMS (Method C): RT 3.57 min [M+H]+ 219.0
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[OH:16][CH:17]1[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]1[NH2:19].O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([NH:19][C@@H:18]1[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@@H:24]([CH2:26][OH:27])[O:25][CH:17]1[OH:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
55 g of dodecanoyl chloride were dissolved in 170 ml of tetrahydrofuran and added dropwise, with vigorous stirring, to a solution of 54 g of D-glucosamine hydrochloride in 330 ml of aqueous sodium carbonate solution (20%). After completion of the addition of the acid chloride, the mixture was stirred for a further hour, then 500 ml of water were added to the batch and the solid material was filtered off with suction and washed with water. The residue was recrystallised from isopropanol/water 10/1 (v/v) and dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[OH-].[K+]>O1CCCC1>[C:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(4-aminophenyl)quinazoline-4-carboxylic acid (25.3 mg, 0.95 mmol, 1.00 equiv), acetyl acetate (18.36 mg, 0.18 mmol, 2.00 equiv), potassium hydroxide (5.07 mg, 1.00 equiv) and tetrahydrofuran (10 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 20 mg (68%) of 2-(4-acetamidophenyl)quinazoline-4-carboxylic acid as a yellow solid. MS (ESI) m/z 308 ([M+H]+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]/[N:12]=[C:13](/[C:21](=[O:23])[CH3:22])\[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:27])(=O)=O>C(O)(=O)C>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]/[N:12]=[C:13](/[C:21](=[O:23])[CH2:22][Cl:27])\[C:14]([OH:16])=[O:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)O[C@H]1CC[C@@H](O/N=C(/C(C)=O)C(=O)OC(C)(C)C)CC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@@H](O/N=C(\C(=O)O)C(=O)CCl)CC1

Procedure:
tert-Butyl (Z)-2-(cis-4-Acetoxycyclohexyloxyimino)-3-oxobutyrate (327 mg, 1 mmol), as prepared in Example 61a, was reacted with sulphuryl chloride (0.8 ml) in glacial acetic acid (2 ml) as described in Example 57d to give the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:21]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)N(C)c4ccccc4)cc23)CC1

Procedure:
Beginning with 13.0 mg (0.056 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 10.1 mg (0.059 mMol) N-methyl-N-phenyl carbamoyl chloride, 17.4 (86%) of the title compound were recovered.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:21][CH:20]=1.O.[NH2:34][NH2:35]>C(O)C>[Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([C:23](=[N:34][NH2:35])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccc(CO)cc1
Reactant: NN
Agent: O=C(c1ccccc1)c1ccc(CBr)cc1
Solvent: O
Solvent: CCO
Product: NN=C(c1ccccc1)c1ccc(CO)cc1
Yield: 98 %

Procedure:
4-Bromomethyl benzophenone (2) was prepared as described in Reference Example 1. 4-Bromomethyl benzophenone (2) was converted into 4-Hydroxylmethyl benzophenone (3) as described in Reference Example 2. To solution of 3 (2.5 g, 12 mmol) in ethanol (20 ml) was added hydrazine hydrate (2.9 g 59 mmol). The mixture was heated to reflux for 24 h. then concentrated in vacuo. The residue was portioned between DCM and water and the organic layer collected and concentrated to yield 4 (2.6 g, 98%) a mixture of cis and trans isomers and as a yellow semi solid; δH (CDCl3) 2.84, 3.09 (2×bs, 1H, OH), 4.51, 4.61 (2×s, 2H, CH2OH), 5.32 (bs, 2H, NNH2), 7.13-7.17 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.30-7.43 (m, 5H, 2-, 2′-, 4′-, 6-, 6′-H) ppm; δC (CDCl3) 64.4, 64.6 (2×CH2OH), 126.4, 126.6, 127.7, 128.0, 128.1, 128.6, 128.8, 128.9, 129.3 (Ar—C), 131.8, 132.7 (2×1′-C), 137.5, 138.2 (2×1-C), 141.0, 141.8 (2×4′-C), 149.2 (C═N) ppm; νmax (thin film) 3384, 2870, 1583, 1444, 1412, 1015 cm−1; found (ES) 227.1180, C14H15N2O requires 227.1179.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH2:25])=[O:5])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][CH:41]=O)[CH:33]=1.[BH4-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:41][CH2:40][CH2:39][CH2:38][C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(Cl)cc(Cl)c3)c(CCN)c2c1
Reactant: O=CCCCc1cccnc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(Cl)cc(Cl)c3)c(CCNCCCCc3cccnc3)c2c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(2-aminoethyl)-2-(3,5-dichlorophenyl)-1H-indole-5-carboxylic acid ethyl ester (prepared essentially as described in Example 5.1, 100 mg in 7.0 mL chloroform) at -5° C. was added 172 mg of magnesium sulfate followed by 46.3 mg of 4-pyridin-3-yl-butyraldehyde and the mixture stirred at low temperature for 15 minutes. At this time, a solution of sodium borohydride (13.7 mg in 1.2 mL dry methanol) was added and after another 40 minutes, the reaction was quenched by the addition of water. The mixture was partitioned between ethyl acetate and saturated potassium carbonate, extracted and the organic portion washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 92:8) gave the title compound (100 mg).
Reaction SMILES: [O:1]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1.[BH3-]C#N.[Na+]>>[CH:19]1([CH2:22][N:4]2[CH2:3][CH2:2][O:1][C:9]3[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=3[O:7][CH2:6][CH2:5]2)[CH2:21][CH2:20]1
Reactant: O=CC1CC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CS(=O)(=O)Nc1ccc2c(c1)OCCN(CC1CC1)CCO2

Procedure:
In a manner similar to example 4, react N-(3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonin-9-yl)methanesulfonamide with cyclopropanecarboxaldehyde and NaBH3CN to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([Cl:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1

Procedure:
Then, trans-4-(p-chlorophenyl)cyclohexane carboxylic acid (160 g, 0.67 mole) was stirred together with 100 ml of thionyl chloride and 500 ml of carbon tetrachloride at a reflux temperature for one day and a night. Then the solvent was distilled off by an evaporator. The residue was distilled under reduced pressure, whereby trans-4-(p-chlorophenyl)cyclohexane carboxylic acid chloride was obtained as a yellow liquid. The amount was 152 g, the yield was 88%, and the boiling point was 144° C./0.3 mmHg.
Reaction SMILES: [C:1]12([C:11]([C:13]3[C:18]([OH:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=3[Cl:21])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:23][OH:24].N1C=CC=CC=1>CCOC(C)=O.C1(C)C=CC=CC=1>[C:1]12([C:11]([C:13]3[C:18]([OH:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=3[Cl:21])=[N:23][OH:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NO
Reactant: O=C(c1c(O)cc(O)cc1Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: ON=C(c1c(O)cc(O)cc1Cl)C12CC3CC(CC(C3)C1)C2

Procedure:
1-adamantyl-(2-chloro-4,6-dihydroxyphenyl)methanone (1.9 g, 6.2 mmoles), hydroxylamine hydrochloride (100 g) and pyridine (50 ml) were refluxed for 4 h. The mixture was concentrated under vacuum, poured into water, extracted with ethyl acetate, washed with HCl 1N, dried over Na2SO4 and concentrated under vacuum to give the crude product. Flash chromatography (AcOEt/toluene 3/7) gave the pure oxime (1 g as a solid, 50%).
Reaction SMILES: [CH3:1][Li].[CH3:3][C@:4]12[CH2:20][CH2:19][C:18]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C:17]=3[CH2:16][CH2:15][C:14](=[O:21])[CH:13]=4)[C@@H:8]1[CH:7]=[CH:6][C:5]2=[O:22]>C(OCC)C.O1CCCC1.N.[Cu]I.[Cu](I)I>[CH3:1][C@H:7]1[C@H:8]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:4]2([CH3:3])[C:5](=[O:22])[CH2:6]1)=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1C=CC2=O
Reactant: [Li]C
Agent: I[Cu]I
Agent: [Cu]I
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H]1CC(=O)[C@@]2(C)CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]12
Temperature: -20 °C

Procedure:
5.2 ml of a 5% solution of methyllithium in diethyl ether are mixed with 570 mg of copper(I) iodide by portions at -5° C. Stirring is performed at a temperature between -5° and 0° C. until the copper iodide is fully dissolved. Then it is cooled to -20° C. and a solution of 1.1 g of 4,9,15-estratriene-3,17-dione in 15 ml of absolute tetrahydrofuran is slowly added drop by drop. It is stirred for 20 minutes at -20° C., then poured in concentrated aqueous ammonia solution and extracted with ethyl acetate. After chromatography with silica gel with hexane/ethyl acetate and crystallization of the main fraction from ethyl acetate/diisopropyl ether, 720 mg of 15β-methyl-4,9-estradiene-3,17-dione with a melting point of 125° to 126° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[O:17]1[CH:19]([CH:20]([OH:22])[CH3:21])[CH2:18]1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH2:21][CH:20]([OH:22])[CH:19]([OH:17])[CH3:18])=[CH:9][CH:8]=1
Reactant: CC(O)C1CO1
Reactant: Nc1ccc(OCc2cccc(Cl)c2)cc1
Solvent: CC(C)O
Product: CC(O)C(O)CNc1ccc(OCc2cccc(Cl)c2)cc1
Yield: 50.3 %

Procedure:
A solution containing 50 g (0.21 mol) of 4-(3'-chlorobenzyloxy) aniline and 21.6 g (0.24 mol) of the mixture obtained in Example 1 in 850 ml of isopropanol is refluxed for 6 hrs 30 mins. When the isopropanol has evaporated, the crude mixture is purified by flash silica chromatography (eluant: CH2Cl2 --CH3OH: 97-3). 34 g (yield: 49%) of white solid is recovered, corresponding to the product expected and having a melting point of from 95°-96° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][N:22]1[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][CH:19]=[C:18]1[C:16]#[N:17]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)N2CCCC2)cc1
Reaction time: 16 h
Yield: 5.5 %

Procedure:
According to general procedure B, 1-[(4-bromophenyl)sulfonyl]pyrrolidine (116 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 1-methyl-5-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile (7 mg, 6%) was provided after purification. HRMS: calcd for C16H17N3O2S+H+, 316.11142; found (ESI, [M+H]+), 316.1114. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[Li][C:13]#[N:14].P(C#N)(OCC)(OCC)=O.C(O)(C)(C)C>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][C:13]#[N:14])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: [Li]C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: N#CCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-indolecarboxaldehyde (1.0 g, 6.90 mmol) and LiCN 1.5THF (72.5 mg, 0.69 mmol) in 50 ml THF, was added (EtO)2P(O)CN (1.36 ml) at 0° C. The reaction was stirred at rt overnight, and then t-butanol (0.79 ml) was added. The mixture was cannulated into a flask containing an 0.1 M solution of SmI2 in THF (159 ml). Additional SMI2 (10 mol %) was added until no color change was observed. The mixture was stirred for 30 min, and then concentrated and the residue poured into ethyl acetate. The organic layer was washed with 1.0 N HCl, saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography with Hexane:Ethyl acetate=2:1, to give (1H-Indol-7-yl)-acetonitrile as white solid, (300 mg, 30%). MS (m/z) 157.0 (M++1), 155.0 (M+−1). 1HNMR (DMSO) 11.26 (s, 1H), 7.50 (d, J=6.0 Hz, 1H), 7.39 (m, 1H), 7.06 (d, J=5.4 Hz, 1H), 6.97 (dd, J=5.4 Hz, 1H), 6.46 (m, 1H), 4.18 (s, 2H).