Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH2:9][OH:10].Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[N:9][OH:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(C=O)s1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(C=NO)s1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
1.20 kg (9.51 moles) of 5-methyl-2-thiophenecarboxaldehyde and 727 g (10.46 moles) of NH2OH.HCl were placed in a reaction vessel and cooled to 10° C. Then, 0.85 L (10.46 moles) of pyridine was dropwise added thereto for 1 hour (an exothermic reaction: 10° C.→43° C). After 10 minutes, 7 L of benzene was added thereto and heated to remove the obtained water by Dean-Stark apparatus (initial internal temperature: 80° C.). After 165 mL of water was collected for 8 hours, (theoretical quantity: 171 mL), the product was cooled to obtain 5-methyl-2-thiophenecarboxaldehyde oxime. At this time, if stirring was stopped, two-phases were formed. After 0.85 L (10.46 moles) of pyridine was completely added at 15° C., 1.26 kg (12.36 moles) of Ac2O was dropwise added thereto for 25 minutes, with maintaining a temperature less than 15° C. The reaction mixture was stirred for 1 hour at room temperature, and completion of the acetylation reaction was confirmed by HPLC (2 phases).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C@@H:5]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+]=[N-].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[C:19]([O:18][C:16]([NH:15][C@H:5]1[CH2:6][C@H:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9][C@H:4]1[NH2:1])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N=[N+]=[N-])[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC[C@@H](N)[C@@H](NC(=O)OC(C)(C)C)C1
Yield: 94.9 %

Procedure:
Ethyl (1R*,3S*,4R*)-4-azido-3-(tert-butoxy-carbonylamino)cyclohexane-1-carboxylate (5.4 g) was dissolved in a mixed solvent of ethanol (10 ml) and ethyl acetate (10 ml), and a catalytic amount of 10% palladium on carbon was added to stir the mixture at room temperature for 20 hours in a hydrogen atmosphere. After insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (4.7 g) as a pale yellow oil.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].CCN(CC)CC.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>CC(C)=O>[N+:27]([C:24]1[CH:23]=[C:22]([N+:30]([O-:32])=[O:31])[CH:21]=[CH:26][C:25]=1[O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])([O-:29])=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=[N+]([O-])c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a suspension of 2-hydroxyisoindoline-1,3-dione (20.0 g, 0.12 mol) in acetone (400 mL) was added Et3N (14.9 g, 0.15 mol), the mixture was stirred at room temperature until it became a homogeneous solution, then 1-bromo-2,4-dinitrobenzene Y-1 (30.2 g, 0.12 mol) was added. The reaction was stirred at room temperature for 3 h, then poured into ice-water, the resulting precipitate was filtered and washed three times with cold MeOH, dried in vacuum to afford the title compound (38.1 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7]2)[CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:43])([O:19][C:20]([NH:22][C:23]([CH3:42])([CH3:41])[C:24]([NH:26][C@H:27]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[C:28](O)=[O:29])=[O:25])=[O:21])[CH3:18]>>[N:1]1([C:28]([C@H:27]([NH:26][C:24](=[O:25])[C:23]([NH:22][C:20]([O:19][C:17]([CH3:43])([CH3:18])[CH3:16])=[O:21])([CH3:42])[CH3:41])[CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)=[O:29])[CH2:6][CH2:5][C:4]2([CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: c1ccc2c(c1)CCC1(CCNCC1)O2
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CCc3ccccc3O2)CC1

Procedure:
This intermediate was prepared from the product of Step A and α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid following standard peptide coupling methods.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCCC(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CCCC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 91 %

Procedure:
Methyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)pentanoate was heated to 100° C. overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2× EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 140 mg (91% yield) of acid 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl) pentanoic acid. MS found: (M+H)+=403.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH:31]=[CH:30][C:29]([NH2:32])=[N:28]2)[CH:24]=[CH:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH:32][C:29]1[CH:30]=[CH:31][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:19])[F:34])[CH:22]=2)[N:28]=1)=[O:8])([O-:3])=[O:2]
Reactant: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 2-nitro-5-(piperidin-1-yl)benzoic acid (5 g, 20.00 mmol, 1.19 equiv) in N,N-dimethylformamide (50 mL), 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine (3.8 g, 16.74 mmol, 1.00 equiv), HATU (9.5 g, 25.00 mmol, 1.49 equiv), and N,N-diisopropylethylamine (3.3 g, 25.58 mmol, 1.53 equiv). The resulting solution was stirred overnight at 50° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 200 mL of water, extracted with 4×50 mL of ethyl acetate, and the organic layers combined. The resulting mixture was washed with 2×50 mL of water and 2×50 mL of brine. The mixture was dried over sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (5:1) to yield 2.8 g (36%) of product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:45][CH3:46])(=[O:44])[C:35]1[CH:43]=[CH:42][CH:41]=[C:37]([C:38]([O-])=[O:39])[CH:36]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:38]([C:37]2[CH:36]=[C:35]([CH:43]=[CH:42][CH:41]=2)[C:34]([O:45][CH3:46])=[O:44])=[O:39])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.4 %

Procedure:
A mixture of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 44.6 mg of monomethyl isophthalate, and 51.7 mg of HOBt was dissolved in 1.0 mL of dichloromethane, and 36.5 mg of WSC/hydrochloride was added thereto, followed by stirring at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 122 mg of methyl 3-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate as a colorless foamy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:26])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:12]=1)[CH2:5]Br.[CH2:27]([O:29][P:30]([O:34]CC)[O:31][CH2:32][CH3:33])[CH3:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:26])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:12]=1)[CH2:5][P:30](=[O:34])([O:31][CH2:32][CH3:33])[O:29][CH2:27][CH3:28]
Reactant: Oc1ccc(Oc2c(Cl)cc(CBr)cc2Cl)cc1Cc1ccc(F)cc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc(Cl)c(Oc2ccc(O)c(Cc3ccc(F)cc3)c2)c(Cl)c1)OCC
Temperature: 120 °C
Yield: 70.8 %

Procedure:
To a stirred solution of 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4-hydroxyphenoxy] benzyl bromide (0.25 g, 0.55 mmol) in toluene (5 mL) at room temperature was added triethylphosphite (0.91 g, 5.5 mmol). The reaction mixture was heated at 120° C. for 8 h and cooled to room temperature. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford diethyl 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-hydroxyphenoxy]benzylphosphonate as a colorless oil (0.2 g, 68%): 1H NMR (300 MHz, CDCl3): δ 7.29 (d, J=2.7 Hz, 2H), 7.15 (dd, J=5.4, 9.0 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 6.66 (d, J=4.8 Hz, 1H), 6.65 (s, 1H), 6.46 (dd, J=3.0, 8.7 Hz, 1H), 4.07 (q, J=7.2 Hz, 4H), 3.89 (s, 2H), 3.04 (d, J=21.3 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:1); Rf=0.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][NH:25][C:24]2=[O:28])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[C:24](=[O:28])[N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[CH:27]=[N:26]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: COc1ccc(-n2cn[nH]c2=O)cc1
Product: COc1ccc(-n2cnn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Yield: 33.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.73 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol and 1.32 g of 4-(4-methoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-methoxyphenyl)-3(2H,4H)-1,2,4-triazolone (869 mg) was obtained as a colorless oil.
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.[CH3:15][NH:16]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:5]([C:15]#[N:16])[CH:6]=1
Reactant: CNCCNC
Reactant: Brc1cnc2ccccc2c1
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccccc2c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
An oven dried screw cap test tube was charged with NaCN (98 mg, 2.0 mmol), dried KI (32 mg, 0.168 mmol, 20 mol %) and CuI (56 mg, 0.337 mmol, 10 mol %), evacuated and backfilled with argon three times. 3-Bromoquinoline (225 μL, 1.66 mmol), N,N′-dimethylethylenediamine (180 μL, 1.69 mmol) and anhydrous toluene (1 mL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min, then the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate (3×2 mL). The combined organic layers were washed with 5 mL of water and dried over MgSO4. The solvent was removed at reduced pressure. Purification of the residue by flash chromatography on silica gel (2×15 cm; hexane/ethyl acetate 10:1) provided 188 mg (74% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: C1CCCNCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCCCCC2)cn1
Temperature: 80 °C
Yield: 58.4 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (419 mg, 2.59 mmole) in 5 mL of dry acetonitrile is 512 mg (5.18 mmol) of azacycloheptane followed by 358 mg (2.59 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 340 mg (59% yield) of 1-(6-Chloro-pyridin-3-ylmethyl)-azepane. Diagnostic 1H NMR (400 MHz, CDCl3) 1.40–1.70 (m, 8H), 2.50–2.65 (m, 4H), 3.65 (s, 2H), 7.28 (d, 1H, J=8.3 Hz), 7.65–7.70 (m, 1H), 8.30 (d, 1H, J=2.1 Hz); MS 225.3 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.O.[C:27]([OH:30])(=[S:29])[CH3:28]>>[C:27]([S:29][CH2:14][CH2:13][C:12](=[O:15])[C@@H:11]1[C@:16]2([CH3:25])[C@H:8]([C@H:7]3[C@H:19]([C:18](=[O:24])[CH2:17]2)[C@:20]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)(=[O:30])[CH3:28]
Reactant: CC(O)=S
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: O
Product: CC(=O)SCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 3 h

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (300 mg) was dissolved in thioacetic acid (2 ml) and left at room temperature for 3 hours. The mixture was poured into water and the precipitated oil extracted into ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and water, dried over anhydrous sodium sulphate, evaporated to a pale yellow foam and purified by preparative t.l.c. in ethyl acetate/petrol (1:1). The main band gave title compound (150 mg) as an off-white foam. [α]D + 60.5° (c 0.98).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1.Cl[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]=[C:17]([NH2:27])[N:16]=1>>[NH2:13][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][NH:3][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[C:17]([NH2:27])[N:16]=2)[CH:12]=[CH:11][N:10]=1
Reactant: NCCNc1ccnc(N)n1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Agent: Cl
Product: Nc1nccc(NCCNc2cc(-c3ccccc3)nc(N)n2)n1

Procedure:
The product of Example 1E (73 mg, 0.323 mmol) and 4-chloro-6-phenylpyrimidin-2-amine (51 mg, 0.248 mmol) were treated under the conditions of Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.84-7.93 (m, J=7.12, 2.37 Hz, 2H) 7.57-7.66 (m, 1H) 7.39-7.48 (m, 3H) 6.81-7.14 (m, 2H) 6.24 (s, 1H) 6.04 (s, 2H) 5.90 (s, 2H) 5.74 (d, J=5.76 Hz, 1H) 3.35-3.48 (m, 4H); MS (ESI+) m/z 323.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1Cc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To 5-chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide (57.0 mg, 0.121 mmol) in CH2Cl2 (3 mL) at −78° C. was added a solution of boron tribromide (1 M in CH2Cl2, 0.40 mL, 0.40 mmol) dropwise. The reaction mixture was warmed to room temperature gradually over several hours and allowed to stir overnight. Water (10 mL) was added slowly to the mixture. It was then extracted with EtOAc (3×20 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hex, 3:7) provided 40 mg (72%) of 5-chloro-N-{2-ethyl-1-[1-(4-hydroxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide as a white solid (mp=90-92° C.).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([NH2:11])=[O:10].[OH:14]O>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:8]=[CH:7][N+:6]([O-:14])=[CH:5][C:4]=1[C:9]([NH2:11])=[O:10]
Reactant: OO
Reactant: NC(=O)c1cnccc1C(F)(F)F
Solvent: CC(=O)O
Product: NC(=O)c1c[n+]([O-])ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
0.8 g of 4-trifluoromethyl-3-pyridine carboxamide was dissolved in 7 ml of acetic acid. Then, 0.72 g of a 30% hydrogen peroxide aqueous solution was gradually dropwise added thereto. After completion of the dropwise addition, the reaction solution was heated to 70° C. and stirred for 8 hours at this temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue thereby obtained was washed with n-hexane to obtain 0.6 g of 4-trifluoromethyl-3-pyridine carboxamide 1-oxide (melting point: 198.8° C.) as the desired product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].CN(C)C1C=CC=CC=1.[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18]>C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)O
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)CCCCl

Procedure:
A mixture of 4-chlorobutyryl chloride (93 g, 0.66 mol), N,N-dimethylaniline (80 g, 0.66 mol) and tert-butanol (0.66 mol) in ethyl ether (100 mL) was refluxed for 5 h. The reaction was cooled, diluted with ether and washed with water, 10% citric acid, saturated NaCl and dried over Na2SO4. Crude product obtained after evaporation of the solvent was distilled under vacuum (10 mmHg). Pure product (79 g, 67%) boiling at 57-58° C. was collected. 1H NMR (DMSO-d6) δ 3.64 (t, J=7 Hz, 2H), 2.35 (t, J=7 Hz, 2H), 1.93 (q, 2H), 1.41 (s, 9H).
Reaction SMILES: C(O[CH:5]1[CH2:10][O:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][N:6]1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:22])(=O)C.[CH2:34]([SH:38])[CH2:35][CH2:36][CH3:37].B(F)(F)F.CCOCC>ClCCl>[CH2:34]([S:38][CH:5]1[CH2:10][O:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][N:6]1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=1)=[O:22])[CH2:35][CH2:36][CH3:37]
Reactant: CC(=O)OC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: CCCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCSC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) mixture of 3.0 g 5,6-dihydro-5-acetyloxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoro-methyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (prepared in D above) and 2.0 ml butanethiol in 50 ml dichloromethane was added 1.0 ml borontrifluoride etherate. The cooling bath was removed and the mixture was stirred for 1 h. The mixture was then quenched with saturated sodium bicarbonate and the phases were separated. The organic phase was washed with 1 M sodium hydroxide and saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to give 5-(butylthio)-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.Br[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.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]>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:19]4[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=4)[C:22]#[N:23])=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1
Reactant: N#Cc1cccc(Br)c1
Reactant: CN1C[C@H]2CCN(c3ccc(CN)cc3)[C@H]2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C[C@H]2CCN(c3ccc(CNc4cccc(C#N)c4)cc3)[C@H]2C1
Temperature: 100 °C

Procedure:
The product of Example 69 (40 mg, 0.173 mmole), 3-bromobenzonitrile (47 mg, 0.258 mmole), tris(dibenzylideneacetone)dipalladium (16 mg, 0.017 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (21 mg, 0.034 mmole) and cesium carbonate (85 mg, 0.26 mmole) were dissolved in 1 ml of toluene and heated at 100° C. under N2 for 48 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (3×). The combined organics were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by chromatography (eluting with a mixture of 2% basic methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 9.73 (s, 1H) 7.72 (d, J=8.82 Hz, 2H) 7.30-7.54 (m, 2H) 7.14-7.22 (m, 1H) 6.77-6.88 (m, 1H) 6.56 (t, J=8.65 Hz, 2H) 4.22-4.33 (m, 1H) 4.19 (s, 2H) 3.36-3.64 (m, 2H) 2.90-3.08 (m, 1H) 2.66-2.79 (m, 2H) 2.52-2.63 (m, 2H) 2.32 (s, 3H) 2.09-2.26 (m, 1H) 1.87-2.04 (m, 1H); MS (M+H)+=333.