Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([CH3:9])=[C:6]([Cl:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][Br:11])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cc(Br)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)cc(Cl)c1CBr
Yield: 87.8 %

Procedure:
Heat to reflux a solution of 5-bromo-1,3-dichloro-2-methylbenzene (97 mg, 0.40 mmol), N-bromosuccinimide (76 mg, 0.425 mmol) and benzoyl peroxide (16 mg, 0.06 mmol) in CCl4 (5 mL) for 3 hours under N2. Cool the reaction to room temperature and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 112 mg (87%) of the product as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[CH2:12]Br.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][O:14][CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(Br)cc1)N1CCOCC1
Yield: 58.9 %

Procedure:
(1S)-(−)-1-(4-Bromophenyl)ethylamine (2.4 g), 2,2′-dibromodiethylether (3.25 g) and N,N-diisopropylethylamine (6 ml) were heated to 100° C. in dimethylformamide (40 ml) for 18 h, allowed to cool and partitioned between water and ethyl acetate. The organic phase was dried (MgSO4), evaporated under vacuum and purified by column chromatography using a 0–40% ethyl acetate/iso-hexane gradient. The product was obtained as a yellow oil (1.91 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[C:32](=[CH:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[C:31](=[O:41])[NH:30][C:29]1=[O:42]>>[NH:28]1[C:32](=[CH:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:36][CH:35]=2)[C:31](=[O:41])[NH:30][C:29]1=[O:42]
Reactant: Nc1ccc(C=C2NC(=O)NC2=O)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C=C2NC(=O)NC2=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((imidazolidin-2,4-dion-5-ylidene)-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=10:1) C27H20N4O5
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([Cl:21])[CH:15]=1.[NH2-].[Li+].Cl>C(#N)C>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[C:16]([Cl:21])[CH:15]=1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [NH2-]
Solvent: CC#N
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of 2,3,4-trifluorobenzoic acid (1 g, 5.68 mmol) and 4-bromo-2-chloroaniline (1.2 g, 5.68 mmol) in acetonitrile (10 mL) was added lithium amide (0.39 g, 17.04 mmol) and the reaction stirred at 60° C. for 1.5 hours. The mixture was cooled to room temperature and then to 0° C. and acidified with aq. hydrochloric acid. The obtained precipitate was collected by filtration and washed with cold water and dried in vacuo to afford 2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorobenzoic acid (1.92 g, 94% yield) as a beige solid. MS (EI) for C13H7BrClF2NO2: 363 (MH+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:34][C:15]3[N:16]=[C:17]([C:26]4[CH:27]=[N:28][CH:29]=[C:30]([CH:33]=4)[CH:31]=[O:32])[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(Cl)Cl>ClCCCl>[O:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]4)[S:34][C:15]=3[N:16]=[C:17]([C:26]3[CH:33]=[C:30]([CH2:31][OH:32])[CH:29]=[N:28][CH:27]=3)[N:18]=2)[CH2:21][CH2:22]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncc(C=O)c4)nc3s2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncc(CO)c4)nc3s2)CC1
Reaction time: 4 h
Yield: 38.8 %

Procedure:
5-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)nicotinaldehyde (95 mg) and sodium triacetoxyborohydride (55 mg) in dry 1,2-dichloroethane (10 mL) was heated at 40° C. overnight. A further portion of sodium triacetoxyborohydride (49 mg) was then added and heating continued for another 4 h. Water/CH2Cl2 work up then purification on silica yielded 232 (37 mg). NMR (CDCl3): 2.65-2.67 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.27-3.30 (m, 4H, 2×CH2), 3.82 (s, 2H, CH2), 3.88-3.91 (m, 4H, 2×CH2), 3.97-4.0 (m, 4H, 2×CH2), 4.84 (s, 2H, CH2), 7.17 (s, H, ArH), 8.67 (s, H, ArH), 8.69 (s, H, ArH), 9.55 (s, H, ArH). MS: (ESI+): MH+505.18
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[C:5]([N+:32]([O-])=O)[CH:4]=1)#[N:2].[CH2:35](OC=C(C#N)C#N)C.C(OCC)(=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH:35]=[N:32][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC=C(C#N)C#N
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(-n4cnc5cc(C#N)ccc54)cc23)CC1
Yield: 10 %

Procedure:
5-(4-Cyano-2-nitrophenyl)amino-3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-1H-indole was used. Reduction was by catalytic hydrogenation, the cyclization reaction used ethoxymethylene malononitrile, and the cyclization reaction was heated for 48 hours. Chromatography using 10% ethyl acetate in methylene chloride afforded the title compound (10%) as a brown foam: Rf =0.2 in 10% ethyl acetate in methylene chloride; HRMS calculated for C26H27N5O2 441.2167, found 441.2169.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:26]=3)=[O:32])=[C:3]([C:19]([F:22])([F:20])[F:21])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1C(F)(F)F
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(C(F)(F)F)c2)c1[N+](=O)[O-]
Yield: 99 %

Procedure:
Method H3 was used with 4-(4-amino-3-(trifluoromethyl)phenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethyl-phenyl isocyanate to afford the title compound (416 mg, 99%). 1H-NMR (δ, ppm, DMSO-d6): 6.06 (d, 1H, HPy,5, J=5.7 Hz), 7.26 (m, 2H, Harom), 7.54 (m, 2H, Harom), 7.64 (s, 2H, NH2,Py), 7.96 (m, 1H, Harom), 8.05 (d, 1H, HPy,6, J=5.7 Hz), 8.11 (m, 1H, Harom), 8.28 (s, 1H, NHurea1), 9.76 (s, 1H, NHurea3). LC-MS (m/z): 536 (M+H, 100).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C1(S([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH:21]=3)[C:16]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)=[C:15]2[CH2:43][C:44]([CH3:50])([CH3:49])[C:45]([O:47]C)=[O:46])(=O)=O)C=CC=CC=1>>[CH2:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:21]=2)[C:16]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[C:15]1[CH2:43][C:44]([CH3:50])([CH3:49])[C:45]([OH:47])=[O:46])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Product: C=CCn1c(CC(C)(C)C(=O)O)c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
The title compound was prepared under the conditions described in Step A and Step B of Example 38, but substituting allyl bromide for the benzenesulfonyl chloride from Example 38 (Step A).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:18].[H][H]>CO.[Pd]>[ClH:18].[OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC#N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCN)cc1
Reaction time: 20 h

Procedure:
To a solution of (S)-3-hydroxy-4-(p-toluenesulfonyloxy)butyronitrile (17.0 g) in methanol (120 ml), 10 wt. % Pd on carbon (3.0 g) and conc. hydrochloric acid (30 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4. 0 kg/cm2 at room temperature for 20 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 3/7) to obtain pure (S)-3-hydroxy-4-(p toluenesulfonyloxy)butylamine hydrochloride (17.5 g). Yield, 89 %.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:5]1.[Cl-].[NH4+]>C(O)C>[OH:3][CH:4]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)C2
Reaction time: 0.42 h
Yield: 93.3 %

Procedure:
300 ml ethanol was ice-cooled, and 6.13 g of sodium borohydride was dissolved therein. 100 ml solution of 38.9 g of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate in ethanol was added dropwise thereinto over 25 min. The reaction solution was treated with saturated aqueous ammonium chloride and evaporated. The resulting residue was partitioned into ethyl acetate and water, and the ethyl acetate layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 36.6 g of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([N:30]1[C@@H:35]2[C@H:36]([C:38]([NH2:40])=O)[CH2:37][C@@:31]1([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C@H:32]([O:41][CH2:42][C:43]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=1)[CH2:33][CH2:34]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH2:23]([N:30]1[C@@H:35]2[C@H:36]([C:38](=[S:10])[NH2:40])[CH2:37][C@@:31]1([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C@H:32]([O:41][CH2:42][C:43]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=1)[CH2:33][CH2:34]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Solvent: Cc1ccccc1
Product: NC(=S)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
Lawesson's reagent (0.23 g, 0.57 mmol) was added to a solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxyl}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 0.64 g, 1.14 mmol) in toluene (20 ml). The mixture was stirred at 100° C. for 1 hour then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2 and 3% methanol/dichloromethane to yield the title compound (0.162 g, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.C([O:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])C.[O-]CC.[Na+].Cl>C(O)C.O.O1CCCC1>[F:19][C:18]([F:21])([F:20])[C:17](=[O:16])[CH2:11][C:10]([C:6]1[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:13])=[O:12]
Reactant: COc1cc(C)c(C(C)=O)cc1C
Reactant: CCOC(=O)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(C(=O)CC(=O)C(F)(F)F)cc1C
Yield: 88.4 %

Procedure:
At room temperature, to a mixture of 1-(4-methoxy-2,5-dimethylphenyl)-ethanone (described in Reference Preparation example 82) 5 g and tetrahydrofuran 200 ml was added trifluoroacetic acid ethyl ester 7.9 g and 20% sodium ethoxide solution in ethanol 19 g. The resulting mixture was stirred with heating under reflux for seven hours, and then to the reaction mixture was added water 70 ml, and the resulting mixture was acidified with 6N aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4,4,4-trifluoro-1-(4-methoxy-2,5-dimethyl-phenyl)-butane-1,3-dione 6.8 g.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH:5]=1)=[O:3].ClCCCl.C([OH:31])(C)C>>[CH3:1][C:2]([C@:4]1([OH:31])[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3]
Reactant: CC(C)O
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCCl
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of 16-dehydroprogesterone 3 (0.041 g, 0.131 mmol, 1.0 equ) and Mn(dpm)3 (0.002 g, 0.003 mmol, 0.02 eq) in a mixture of isopropanol (1.5 mL) and enough 1,2-dichloroethane (0.6 mL) to completely dissolve the starting material at 0° C. for 20 min. then at room temperature for 2 h under O2. The solvents were removed by distillation under reduced pressure, affording a cream solid. Purification by flash column chromatography over silica, eluting with 30% EtOAc-hexanes afforded the 17 α-hydroxyprogesterone 4 as a white crystalline solid (0.037 g, 85%) which was identical in all respects with an authentic sample.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[C:15]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:23][CH2:22][C:21]2([CH2:13][C:12](=[O:14])[C:3]3[CH:4]=[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(S(C)(=O)=O)ccc1O
Product: CC(=O)N1CCC2(CC1)CC(=O)c1cc(S(C)(=O)=O)ccc1O2

Procedure:
2'-Hydroxy-5'-methanesulfonylacetophenone and 1-acetyl-4-piperidone were condensed according to the method of Example 434 to give the ketone as a white solid, m.p. 105°-110° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1ccc(CCOC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1ccc(CCO)cc1
Yield: 115.4 %

Procedure:
A solution of the product from step (b) (55.3 g) in methanol (250 ml) and 1N aqu. NaOH (500 ml) was stirred at room temperature for 1 hour. The methanol was evaporated in vacuo and the remaining aqueous solution adjusted to pH 4 (2N aqu. HCl), saturated with NaCl, and extracted with ethyl acetate (×3). The combined extracts were washed with water and brine, dried over MgSO4 and evaporated in vacuo to give a brown oil which was flash chromatographed through a silica column using ethyl acetate and then crystallised from ethyl acetate to give the desired product (51.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](O)=[O:24]>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:24]
Reactant: O=C(O)c1cccs1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccs4)cc3c2C1
Yield: 46.5 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.0 mg (0.086 mMol) thiophene-2-carboxylic acid, 6.0 mg (47%) of the title compound were recovered as a beige solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@@H:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:5].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=1[F:22])([OH:14])[CH:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of 0.69 g (3.0 mmol) of (S)-1-chloro-3-(tert-butyldimethylsilyloxy)butan-2-one in 5 mL of toluene was cooled to −20° C., and 5.3 mL (3.3 mmol) of a solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 15 minutes. After the completion of the dropwise addition, stirring was continued for another 2 hours, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 3). Thereby, the title compound was obtained in a yield of 91% (2R,3S)/(2S,3S)=92/8). 1H-NMR (400 MHz, CDCl3) (2R,3S) δ: 0.10 (s, 6H), 0.92 (s, 12H), 3.85 (d, 1H, J=12.0 Hz), 4.07 (d, 1H, J=12.0 Hz), 4.35 (q, 1H, J=6.6 Hz), 6.77-6.79 (m, 1H), 6.93-6.93 (m, 1H), 7.69-7.71 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](OC)=[O:11])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ccc(CC=O)cc1
Reaction time: 0.33 h
Yield: 19.3 %

Procedure:
Methyl 4-methoxyphenylacetate (5.58 g, 0.031 mol) was added to anhydrous toluene (75 mL) and the reaction mixture was kept at −70° C. Diisobutylaluminum hydride (1.0 M, 34 mL) in toluene was added over 25 min. The reaction mixture was stirred for another 20 min then a sodium-potassium-tartrate solution (100 mL) was added to the reaction mixture. The organic layer was separated and the water layer was extracted with ether. The combined organic layers were washed with water, brine, and dried over sodium sulfate. The crude compound was purified by column chromatography (hexane:EtOAc 4:1) to yield 4-methoxyphenylacetaldehyde (0.90 g, 19.3%). A mixture of 4-methoxyphenylacetaldehyde (0.40 g, 2.66 mmol), morpholine (0.232 g, 2.66 mmol), and benzotriazole (0.304 g, 2.56 mmol) in ether (20 mL) with 3 Å molecular sieves was stirred at rt overnight. The molecular sieves were removed by filtration and the solvent was removed. The crude product was used for next step reaction without further purification. Sodium hydride (0.125 g, 5.2 mmol, 60% in mineral oil) was added to the crude product with anhydrous THF (20 mL). The reaction mixture was stirred at reflux for 3 h. THF was removed and the residue was poured into cold water (60 mL) and extracted with hexane (2×80 mL). The organic layer was dried over sodium sulfate and the solvent was removed to give the enamine (0.60 g). 2-Chloropyridine-3-carbonylchloride (0.44 g, 2.5 mmol) in dry DCM (5 mL) was added to the enamine (0.60 g), followed by triethylamine (0.5 mL) in anhydrous DCM (15 mL) at −70° C. The reaction mixture was allowed to warm to rt overnight. The mixture was then poured into water, and the organic phase was washed with sodium bicarbonate and brine. The crude residue was purified by column chromatography (EtOAc:MeOH 5:1) to the desired intermediate (0.45 g). The intermediate (0.45 g, 1.25 mmol) was stirred in HCl (8.0 mL, 6 N) overnight at rt. The desired compound was filtered off and washed with large amounts of water. The crude product (0.24 g, 1.18 mmol) was mixed with pyridine hydrochloride (1.4 g) and heated to 180-190° C. for 3 h. The mixture was poured into water and stirred for 30 min. The solid was filtered off and further washed with water and hexane to give 140 mg of 3-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one (49.6%). MS (ES) m/z: 239.90; Mp. 262-264° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Solvent: CO
Product: Cc1cc(N)ccc1Oc1ccccc1

Procedure:
The nitro compound prepared above was reduced under H2 using 10% Pd/C catalyst in MeOH to give 3-methyl-4-phenoxyaniline. 1H NMR (CDCl3) δ 7.27 (m, 2H), 6.97 (m, 1H), 6.83 (m, 2H), 6.80 (d, 1H), 6.60 (d, 1H), 6.52 (m, 1H), 3.53 (br s, 2H), 2.11 (s, 3H). MS (DCl/NH3) m/e 200 (M+H)+, 217 (M+H+NH3)+.