Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:35]=[CH:36][C:37]=1[F:38])[C:22]([NH:24][CH2:25][CH2:26][N:27]1[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH3:34])=[O:23]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:18][C:19]3[CH:20]=[C:21]([C:22](=[O:23])[NH:24][CH2:25][CH2:26][N:27]4[C@H:32]([CH3:33])[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:34])[CH:35]=[CH:36][C:37]=3[F:38])=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1) (1.150 g, 4.77 mmol) was suspended in toluene (10 ml) and treated with thionyl chloride (1.045 ml, 14.32 mmol). The mixture was at 100° C. for 2 hrs. The solvent was removed in vacuo and the solid was added to a stirred solution of 3-amino-N-(2-(2,6-cis-dimethyl piperidin-1-yl)ethyl)-4-fluorobenzamide (1.4 g, 4.77 mmol) in dry pyridine (5 ml) containing oven dried molecular sieves. The mixture was stirred at RT under nitrogen atmosphere overnight. The solvent was removed in vacuo and purification of the crude product by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:19][CH3:20])=[C:10]([CH:12]3[C:16](=[O:17])[CH:15]=[CH:14][C:13]3=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.C[Si]([CH2:27][S:28]([CH2:30][Si](C)(C)C)=O)(C)C>CN1CCCN(C)C1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:19][CH3:20])=[C:10]([CH:12]3[C:16](=[O:17])[CH:15]4[CH2:27][S:28][CH2:30][CH:14]4[C:13]3=[O:18])[CH:11]=2)=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)CS(=O)C[Si](C)(C)C
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1=O
Solvent: CN1CCCN(C)C1=O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2CSCC2C1=O
Temperature: 100 °C

Procedure:
A suspension of 2-(4′-chloro-4-ethylbiphen-3-yl)cyclopent-4-ene-1,3-dione (0.200 g, 0.65 mmol) and crude bis(trimethylsilylmethyl)sulphoxide (0.406 g, 0.97 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3 ml) is heated at 100° C. for 20 minutes under microwave irradiation. The reaction mixture is then partitioned between diethylether and distilled water, and the organic phase is washed with water (×2) then brine. After drying over magnesium sulfate the crude mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by preparative reverse phase HPLC to afford 5-(4′-chloro-4-ethylbiphenyl-3-yl)-tetrahydrocyclopenta[c]thiophene-4,6-dione.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[NH:4].[C:14]1([C:20]2[CH:21]=[C:22]([C:29](OC)=O)[S:23][C:24]=2[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]CC.[Na+]>>[C:14]1([C:20]2[CH:21]=[C:22]([C:29]3[O:1][N:2]=[C:3]([C:5]4[CH:6]=[C:7]5[C:11](=[CH:12][CH:13]=4)[NH:10][CH:9]=[CH:8]5)[N:4]=3)[S:23][C:24]=2[C:25]([F:28])([F:26])[F:27])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: N=C(NO)c1ccc2[nH]ccc2c1
Agent: CC[O-]
Agent: [Na+]
Product: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Temperature: 120 °C
Yield: 29.9 %

Procedure:
D1 (174 mg) and methyl 4-phenyl-5-(trifluoromethyl)-2-thiophenecarboxylate (286 mg) were combined, treated with sodium ethoxide (21% wt in EtOH, 411 ul) and heated to 120° C. in a microwave reactor for 30 minutes. LCMS analysis showed the reaction was incomplete so microwave heating was continued for a further two periods of 30 minutes. The reaction mixture was then cooled to RT, quenched with H2O (2 ml) and evaporated to dryness under reduced pressure to give the crude product (411 mg) as a brown solid. The crude residue was purified on a 40+S Biotage cartridge, eluting with a 0 to 50% mixture of Et2O in petroleum ether. This gave the title compound (122 mg) as an off-white solid. δH (CDCl3, 400 MHz): 6.68 (1H, s), 7.30 (1H, t), 7.41-7.55 (6H, m), 7.92 (1H, s), 7.99 (1H, d), 8.36 (1H, br. s), 8.50 (1H, s). MS (ES): C21H12F3N3OS requires 411; found 410 (M−H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:12]1[O:20][C:17]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:15])[O:13]1)[CH:6]=[CH:5]2.CCN([CH2:26][CH3:27])CC>C(Cl)Cl>[O:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:12]1[O:20][C:17]([CH3:19])([CH3:18])[C:14]([CH3:15])([CH3:16])[O:13]1)[CH:6]=[CH:5]2)[C:27]1[CH:26]=[CH:10][CH:11]=[CH:2][CH:3]=1
Reactant: CC1(C)OB(c2ccc3cc(O)ccc3c2)OC1(C)C
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc3cc(Oc4ccccc4)ccc3c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenylboronic acid (140 mg, 1.1 mmol, 2.0 eq.) was coevaporated with PhMc twice to produce the anhydride. This was treated with crude 6-hydroxynaphthalene-2-boronic acid pinacol ester (150 mg, 0.56 mmol), DCM (5 mL), NEt3 (400 uL, 3 mmol, 5 eq.), and cupric acetate (100 mg, 0.53 mmol, 0.95 eq.) and stirred at ambient temperature during 16 h. The mixture was extracted from 0.1M NaOH into DCM, dried on Na2SO4, concentrated, and chromatographed on silica gel (0→2% EtOAc/hexanes) to give 6-phenoxynaphthalene-2-boronic acid pinacol ester, which was deprotected via Method 5 to provide compound 216 (54 mg, 37%). [M−H]−=263.1 m/z. Activity: A
Reaction SMILES: Cl.[NH2:2][OH:3].O[C:5]1[C:6](=[O:15])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.C([O-])(=O)C.[Na+]>CO>[O:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:13]=2[C:14]([CH2:5][C:6]([OH:15])=[O:7])=[N:2]1
Reactant: NO
Reactant: O=c1oc2ccccc2cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1noc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
Hydroxylamine hydrochloride (7.5 g, 107.93 mmol) is added to a solution of hydroxy coumarin (5 g, 30.84 mmol) in MeOH (50 mL) at rt. Sodium acetate (8.8 g, 107.93 mmol) is added portionwise in 1.5 h. The reaction is stirred for 1.5 h at rt and then is heated at reflux overnight. Volatiles are evaporated, water is added and the mixture is cooled with ice-water bath. The aqueous layer is acidified to pH=3 with 4N HCl. A precipitate is filtered out and washed several times with water. The precipitate is dried under reduce pressure at 50° C. to give benzo[d]isoxazol-3-yl-acetic acid (4.3 g, 78%)
Reaction SMILES: COC1C=C(C=C(OC)C=1)C[NH:7][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH:13]3[O:20][C:21]([N:23]3[CH2:28][CH2:27][C:26]4([C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]([CH2:37][C:38]([OH:40])=[O:39])[CH2:29]4)[CH2:25][CH2:24]3)=[O:22])[CH2:11]1)[CH2:17]2)=[O:9].C(O)(C(F)(F)F)=O>>[C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH:13]3[O:20][C:21]([N:23]3[CH2:28][CH2:27][C:26]4([C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]([CH2:37][C:38]([OH:40])=[O:39])[CH2:29]4)[CH2:25][CH2:24]3)=[O:22])[CH2:11]1)[CH2:17]2)(=[O:9])[NH2:7]
Reactant: COc1cc(CNC(=O)C23CC4CC(C2)C(OC(=O)N2CCC5(CC2)CC(CC(=O)O)c2ccccc25)C(C4)C3)cc(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C12CC3CC(C1)C(OC(=O)N1CCC4(CC1)CC(CC(=O)O)c1ccccc14)C(C3)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.5 %

Procedure:
To a solution of 2-(1′-((1-(3,5-dimethoxybenzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (40 mg, 0.096 mmol) was added 50% TFA (2.5 mL) at 0° C. The reaction mixture was stirred for 4 h at rt. The TFA was neutralized, and the solution was dried and concentrated to give crude product which was purified by preparative HPLC to give 2-(1′-((1-carbamoyl-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (2 mg, 7%). LC-MS Method 4 tR=2.078 min, m/z=467.2; 1H NMR: (400 MHz, CDCl3): δ=0.88 (m, 3H), 1.29 (m, 3H), 1.52-1.68 (m, 8H), 1.60-1.69 (m, 4H), 1.78-1.94 (m, 13H), 1.95-2.10 (m, 9H), 2.19-2.30 (m, 3H), 2.46 (m, 1H), 2.68 (m, 1H), 2.90-3.15 (m, 3H), 3.65 (m, 1H), 4.12-4.27 (m, 2H), 4.83-4.91 (m, 1H), 5.65-5.79 (m, 1H), 7.15-7.24 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=O)[C:7](=[O:16])[CH2:6]1)=[O:4].[CH2:17]([OH:20])[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C.C(Cl)Cl.O>[CH2:17]1[O:20][C:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]2=[O:16])([O:13][CH2:14][CH3:15])[O:19][CH2:18]1
Reactant: CCOC(=O)C1CCN(C(=O)OC)CC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC1(C2CCN(C(=O)OC)CC2=O)OCCO1

Procedure:
A mixture of ethyl 1-methoxycarbonyl-3-oxopiperidine-4-carboxylate (9.0 g; 39 mmol), ethylene glycol (100 ml), 4-toluenesulfonic acid (0.7 g), and benzene (500 ml) was refluxed for 6 days using a Dean-Stark water separator. The mixture was washed with aqueous sodium carbonate (300 ml; 1 M), water (300 ml), and saturated aqueous sodium chloride (300 ml). The organic phase was dried (K2CO3) and evaporated in vacuo to give 8.6 of an oil. CC [silica gel (Woelm 0.063-0.1 mm): 350 g; eluents: methylene chloride to which ethyl acetate (20-35%) was added] followed by ball-tube distillation at 40 Pa (oven temperature 170° C.) gave VIIIa (7.0 g; 65%) as a colourless oil. IR (film): 2970 (s), 2900 (s), 1730 (s) cm-1. 1H NMR (CCl4): δ4.05 (q, J 7 Hz) and 3.92 (s) (a total of 6H), 3.60 (s) and 3.7-3.0 (m) (a total of 7H), 2.8-2.5 (1H, t), 2.2-1.6 (2H, m), 1.23 (3H, t, J 7 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]([S:46]([CH3:49])(=[O:48])=[O:47])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:45])[C@H:28]([NH:37]C(OC(C)(C)C)=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:23][CH2:22]1.Cl>CCOC(C)=O>[ClH:36].[NH2:37][C@H:28]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C:27]([N:24]1[CH2:23][CH2:22][CH:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([S:46]([CH3:49])(=[O:47])=[O:48])[CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:26][CH2:25]1)=[O:45]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN2C(=O)c3ccccc3C2=O)S(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described in (Step b) from N-((1R)-2-[4-(2-{[2-(1,3-dioxoisoindolin-2-yl)ethyl] (methylsulfonyl)-amino}phenyl)-piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}(tert-butoxy)carboxamide (Step c) (1.77 g, 2.5 mmol) and satd anhydrous HCl in EtOAc (50 mL). The title compound was obtained as a white solid (1.61 g). MS (ESI, pos. ion) m/z: 609 (M+1); MS (ESI, neg. ion) m/z: 607 (M−1). Calc'd for C31H14Cl2N4O5S: 645.60.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]#[CH:20])=[CH:8][CH:7]=1.[CH2:22]([N:29]=[N+:30]=[N-:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[N:31]=[N:30][N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=2)=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCCN1CCCC1c1ccc(/C=C/C(=O)OC)cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2cn(Cc3ccccc3)nn2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a suspension of (E)-3-[4-(1-but-3-ynyl-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (50 mg, 0.176 mmol) and benzyl azide (23.5 mg, 0.176 mmol) in a mixture of water (0.7 mL) and tert-butanol (0.7 mL) were added a solution of sodium ascorbate (1 M in water, 18 μL) and copper sulfate pentahydrate (4.4 mg). The resulting mixture was stirred vigorously for 16 h, diluted with water, cooled to 0° C., and filtered, and the solid was washed with cold water and dried in vacuo to give (E)-3-(4-{1-[2-(1-benzyl-1H-[1,2,3]triazol-4-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (53 mg, 72% yield). LCMS (m/z): 417.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:3]=1[CH:23]([CH2:28][CH2:29][CH3:30])[C:24]([O:26]C)=[O:25].[OH-].[Na+]>CO.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:3]=1[CH:23]([CH2:28][CH2:29][CH3:30])[C:24]([OH:26])=[O:25]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC=CC=C3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC=CC=C3
Temperature: 60 °C
Yield: 91.4 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno [2,3-b]pyridin-3-yl]pentanoate (0.434 g; 1.03 mmol) in methanol (10 mL) and water (1 mL), was added a solution of sodium hydroxide 10 N (1 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.38 g (90%) of the title compound as a light yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([C:6]1[N:10]([CH3:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:8][N:7]=1)[CH3:5].[CH3:29]I>CN(C=O)C.O>[CH3:29][N:19]([C:4]([CH3:3])([C:6]1[N:10]([CH3:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:8][N:7]=1)[CH3:5])[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: CI
Reactant: Cc1ccccc1-c1nnc(C(C)(C)NS(=O)(=O)c2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-c1nnc(C(C)(C)N(C)S(=O)(=O)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Sodium hydride (55% oily, 13 mg) was suspended in DMF (2 ml) and then N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]ethyl}benzensulfonamide (100 mg) and methyl iodide (0.017 ml) were added thereto under ice cooling, followed by stirring at room temperature for 7 hours. The reaction solution was diluted with water (30 ml) and then extracted with chloroform (15 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting solid washed with diethyl ether to obtain 81 mg of N-methyl-N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]ethyl}benzensulfonamide (white solid).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH2:18][CH3:19])[C:13]([O:15]CC)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH2:18][CH3:19])[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(CC)c1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C(=O)O)c1cccc(OCc2c(C)cccc2C)c1
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 2-(3-(2,6-dimethylbenzyloxy)phenyl)-2-ethylacetate (Step C, 3.26 g, 10.0 mmol) in absolute ethanol (60 ml) was added 1N NaOH (20 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified by 1N HCl, and concentrated. The residue was taken into chloroform and washed with 1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:31])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:16][C:15]1=2.[C:32](=[O:34])=[O:33].Cl>C1COCC1>[CH3:30][O:29][C:27]([CH:26]([C:18]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:31])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:24])([CH3:25])[C:20]=2[CH:19]=1)[C:32]([OH:34])=[O:33])=[O:28]
Reactant: COC(=O)Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2.1 ml (14.6 mmol) of diisopropylamine and 80 ml of TEP were introduced into a three-necked flask under a nitrogen stream. At -78° C., 5.8 ml (14.6 mmol) of n-butyllithium (2.5M) were added dropwise, the mixture was stirred for 30 minutes, then a solution of 3.2 g (12.2 mmol) of methyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetate dissolved in 80 ml of THF was added dropwise and the mixture was stirred for one hour. While maintained at -78° C., CO2 was introduced for 30 minutes and then the temperature was permitted to increase to -40° C. and the reaction medium was poured into a 5N hydrochloric acid solution. The mixture was extracted with ethyl acetate, the organic phase decanted, dried over magnesium sulfate and evaporated. 3.7 g (100%) of expected acid were recovered in the form of a slightly yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.CS(C)=[O:24]>>[OH:24][C@@H:9]1[CH2:10][C:11]2[C@:16]([CH3:17])([CH2:15][CH2:14][C:13](=[O:21])[CH:12]=2)[C@@H:18]2[C@@H:8]1[C@H:5]1[C@@:3]([CH2:20][CH2:19]2)([CH3:4])[C@@H:2]([OH:1])[CH2:7][CH2:6]1
Reactant: CS(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Product: C[C@]12CC[C@H]3[C@@H]([C@H](O)CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 26.5 °C
Reaction time: 22 h

Procedure:
100 ml of the medium of Example 1 were inoculated with Mucor hiemalis FERM P-3800 and shaken at 26.5° C. for 22 hours. The culture was then treated with 50 mg of 17β-hydroxy-4-androsten-3one in 1 ml of dimethyl sulphoxide and incubated for 8 days. There were obtained from the culture filtrate 4.8 mg of 7α,17β-dihydroxy-4-androsten-3-one of melting point 191°-193° C.
Reaction SMILES: Br[C:2]1[C:25](=[O:26])[N:24]([CH2:27][CH3:28])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1.[Cl:29][C:30]1[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][C:31]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:39][O:38][C:36](=[O:37])[C:34]1[CH:33]=[CH:32][C:31]([C:2]2[C:25](=[O:26])[N:24]([CH2:27][CH3:28])[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[N:8]=[CH:9][C:4]=3[CH:3]=2)=[C:30]([Cl:29])[CH:35]=1
Reactant: CCn1c(=O)c(Br)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Reactant: COC(=O)c1ccc(B(O)O)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2ccc(C(=O)OC)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Yield: 60 %

Procedure:
6-Bromo-8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (5, 110 mg, 0.25 mmol), 2-chloro-4-(methoxycarbonyl)benzene boronic acid (58 mg, 0.27 mmol), K3PO4 (58 mg, 0.27 mmol) and PdCl2(dppf) (20 mg, 0.02 mmol) were mixed under argon in a degassed mixture of dimethylformamide and water (20:1, 4.5 mL). The resulting suspension was irradiated for 30 min at 140° C. in a microwave reactor. The reaction mixture was evaporated and the residue was purified by column chromatography, eluting with dichloromethane:methanol (95:5). The title compound (78 mg, 0.15 mmol, 60%) was obtained as a yellow solid. ESMS m/z 533 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (s, 1H) 8.15 (d, J=1.5 Hz, 1H) 7.97 (dd, J=7.9, 1.5 Hz, 1H) 7.51-7.64 (m, 3H) 7.48 (d, J=7.8 Hz, 1H) 7.27 (br. s., 1H) 6.97 (d, J=9.0 Hz, 2H) 4.49 (q, J=7.3 Hz, 2H) 3.95 (s, 3H) 3.18-3.35 (m, 4H) 2.67 (br. s., 4H) 2.42 (br. s., 3H) 1.38 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[Cl:31][CH2:32][C:33]([N:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][N:15]2[C:16](=[O:19])[C:17]3[S:18][C:10]([C:7]4[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=4)=[CH:11][C:12]=3[N:13]=[CH:14]2)=[CH:23][CH:24]=1)[CH3:30])=[O:34]
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)CCl
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of the compound (200 mg) obtained in Example 4, chloroacetyl chloride (51 mg), triethylamine (146 mg) and tetrahydrofuran (2 ml) was stirred at 60° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-methanol (20:1, volume ratio)] and crystallized from hexane to give the title compound (130 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[C:14]([S:17][CH:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH:20]([C:36](O)=[O:37])[CH2:19]1)(=[O:16])[CH3:15].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C1(C)C=CC=CC=1.CCOC(C)=O>[C:14]([S:17][C@@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([C:36](=[O:37])[NH:1][C:2]2[CH:13]=[CH:12][CH:11]=[C:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:3]=2)[CH2:19]1)(=[O:16])[CH3:15]
Reactant: CC(=O)SC1CC(C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C=CCOC(=O)c1cccc(N)c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
The above allyl 3-aminobenzoate (26.6 g, 0.15 M) was condensed with 4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (55.2 g, 0.15 M) by suspension in toluene (750 ml) and addition of EEDQ (44.5 g, 0.18 M). The mixture was stirred overnight, diluted with EtOAc (2 l) and washed with dilute HCl, water and brine. The EtOAc phase was dried and evaporated, and the residue recrystallised from ethanol giving (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidine (67.7 g). Nmr (DMSO-d6): δ 1.93 (quintet, 1H); 2.9 (m, 1H); 3.35 (m, 1H); 3.91-4.14 (m, 2H); 4.49 (quintet, 1H); 4.81 (dd, 2H); 5.22 (dd, 2H); 5.2-5.44 (m, 2H); 5.95-6.10 (m, 1H); 7.47 (d, 2H); 7.66 (t, 2H); 7.8-7.93 (m, 2H); 8.18-8.3 (m, 2H); 10.31 (s, 1H).