Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[CH:19][C:14]=2[C:13](=[O:29])[N:12]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:11][C:10]1=[O:37])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].IC.[C:42]([O-:45])(=[O:44])[CH3:43].[NH4+:46]>>[C:1]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:46])[NH2:28])=[CH:23][CH:22]=3)=[CH:19][C:14]=2[C:13](=[O:29])[N:12]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:11][C:10]1=[O:37])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2].[C:42]([O-:45])(=[O:44])[CH3:43]
Reactant: CCOC(=O)CCN1CC(=O)N(CC(=O)OC(C)(C)C)c2ccc(Cc3ccc(C#N)cc3)cc2C1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CCOC(=O)CCN1CC(=O)N(CC(=O)OC(C)(C)C)c2ccc(Cc3ccc(C(=N)N)cc3)cc2C1=O

Procedure:
1-(Carbo-t-butoxymethyl)-4-(2-carboethoxyethyl)-7-[(4-cyanophenyl)methyl]-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (16.0 g, 31 mmol) was placed in a dry 3-necked flask equipped with an inlet tube for gas dispersion and an outlet tube connected to a trap containing 1:1 2M NaOH/Clorox bleach. The flask was flushed with argon gas and anhydrous pyridine (90 mL) was added followed by the addition of triethylamine (70 mL). The resulting solution was saturated with hydrogen sulfide gas. The inlet and outlet tubes were removed and the reaction mixture was heated at 55° C.-60° C. for 21 hours. The reaction mixture was purged with argon and the volatiles removed in vacuo on a rotary evaporator. The residue was taken up in 5:4 dichloromethane/toluene (450 mL) and this was also removed in vacuo on a rotary evaporator. The treatment with dichloromethane/toluene was repeated once more. The residue was taken up in acetone (300 mL) and iodomethane (5.2 mL, 84 mmol) was added via syringe. The reaction mixture was stirred and heated at 60° C.-65° C. for 5.5 hours. The reaction mixture was cooled and the volatiles removed in vacuo on a rotary evaporator. The residue was taken up in anhydrous methanol (200 mL) under and atmosphere of argon and ammonium acetate (9.25 g, 120 mmol) was added. The reaction mixture was stirred at room temperature under an atmosphere of argon for 21 hours. The volatiles removed in vacuo on a rotary evaporator and the residue was taken up in acetonitrile (200 mL) and filtered through a sintered glass funnel. The reaction vessel was rinsed with additional acetonitrile (100 mL) which was also filtered through the sintered glass funnel. The filtrate was concentrated in vacuo on a rotary evaporator and the residue pumped on under high vacuum to yield 1-(carbo-t-butoxymethyl)-4-(2-carboethoxyethyl)-7-[(4-amidinophenyl)methyl]-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione, acetate (18.2 g, 99% yield)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:27]=[CH:26][C:25](OS(C(F)(F)F)(=O)=O)=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].P>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)([C:22]2[CH:27]=[CH:26][C:25]([C:37]3[S:36][CH:40]=[CH:39][CH:38]=3)=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: COc1cccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: COc1cccc(C2(c3ccc(-c4cccs4)cc3)CCN(Cc3ccccc3)CC2)c1
Yield: 91 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl ester (0.1 g, 0.2 mmol) in ethanol (4.5 mL) and water (0.5 mL) was added 2-thiophene boronic acid (0.052 g, 0.5 mmol) and sodium carbonate (0.037 g, 0.29 mmol) and tetrakis tripheny;phosphine palladium (0.02 g, 0.18 mmol). The reaction mixture was heated to reflux for 2 hours. The mixture was then filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography with hexanes/EtOAc (3:1) to afford 0.08 g (92% yield) of 1-Benzyl-4-(3-methoxy-phenyl)-4-(4-thiophen-2-yl-phenyl)-piperidine. 1HNMR (400 MHz, CDCl3) δ 7.50 (d, 2H), 7.33-7.18 (comp, 10H), 7.07-7.00 (m, 1H), 6.89-6.63 (comp, 2H), 6.69 (d, 1H), 3.76 (s, 3H), 3.42 (s, 2H), 2.61-2.39 (comp, 8H); MS (M+1) 440.2.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: Nc1ccccc1Br
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2ccccc2Br)cc1
Temperature: 40 °C

Procedure:
To a suspension of 2-bromoaniline (7.3 mL) and pyridine (13.5 mL) in toluene (110 mL) was added 4-methoxybenzoyl chloride (11 mL) and the mixture was heated at 40° C. for 2.5 hours. The solid was filtered, washed with diethyl ether and water and dried to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH:21]([F:23])[F:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH:21]([F:23])[F:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)F)C2CCOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cc(Br)cc1N(CC(F)F)C1CCOCC1
Temperature: 50 °C
Reaction time: 7 h
Yield: 92.7 %

Procedure:
To a stirred solution of methyl 5-bromo-3-[(2,2-difluoroethyl)(oxan-4-yl)amino]-2-methylbenzoate (571 mg, 1.5 mmol) in a mixture of THF (14.6 ml) and MeOH (2.2 ml), was added 4M NaOH (14.6 ml). The reaction mixture was stirred at 50° C. for 7 hours. The heat was switched off and the reaction mixture was stirred at room temperature for 16.5 hours. THF was removed in-vacuo and the aqueous residue was acidified to pH 4 by the addition of 6M HCl (aq) (10 ml) with ice cooling. The resulting solid was collected by filtration and washed with water (20 ml), dried in-vacuo at 30-40° C. for 3 hours to give the title compound (526 mg, 96%) as a light beige solid. LC-MS 100%, 1.98 min (3.5 minute LC-MS method), m/z=377.9, 378.9, 379.9, 380.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.91 (d, J=1.58 Hz, 1H) 7.49 (d, J=1.58 Hz, 1H) 5.43-5.75 (m, 1H) 4.01 (dd, J=11.43, 3.55 Hz, 2H) 3.42 (td, J=13.95, 3.78 Hz, 2H) 3.32 (t, J=11.35 Hz, 2H) 2.98 (tt, J=11.37, 3.53 Hz, 1H) 2.52 (s, 3H) 1.77 (d, J=10.88 Hz, 2H) 1.56-1.69 (m, 2H). OH not visible.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:11]([CH3:12])=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[CH3:13].C1C=CC=CC=1.[Cl:25]N1C(=O)CCC1=O>C(OCC)(=O)C>[Cl:25][C:10]1[C:11]([CH3:12])=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[C:6]([CH3:13])=[CH:7][C:8]=1[NH2:9]
Reactant: Cc1cc(N)cc(C)c1Oc1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Cc1cc(N)c(Cl)c(C)c1Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Into a 200 milliliter three-necked, round bottom reaction flask was charged 6.76 grams (24.0 mmol) of 4-(2,4-dichlorophenoxy)-3,5-dimethyl aniline and 48 milliliters of benzene. N-chlorosuccinimide (3.85 grams, 28.8 mmol) was then added and the resultant heterogeneous mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed (2x) with saturated Na2SO3 solution and dried over Na2SO4. Concentration under reduced pressure afforded the crude product as a dark oil. This material was filtered through a short column of silica gel using 9:1 hexane: ethyl acetate as an eluant. Solvent removal under reduced pressure afforded 2-chloro-4-(2,4-dichlorophenoxy)-3,5-dimethylaniline (6.5 grams) contaminated with at least three other products. This material was placed in a Parr bottle and dissolved in toluene (50 milliliters). The Parr bottle was purged with nitrogen, 5% platinum on carbon (650 milligrams) was added and the mixture was hydrogenated for 1 hour at 40-50 psi and room temperature on a rocking Parr hydrogenator. Filtration through a pad of celite, solvent removal and flash chromatography (9:1 hexane: ethyl acetate afforded pure 2-chloro-4-(2,4-dichlorophenoxy)-3,5-dimethyl aniline (3.1 grams, 9.8 mmol, 41%) as a crystallized solid having a melting point of 89° C.-93° C. Elemental analysis of the crystalline solid indicated the following:
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:8][CH2:7][C@@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:5]1[C:27]#[N:28])(=[O:3])[CH3:2]>C(O)C.[Ni]>[C:1]([N:4]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH2:8][CH2:7][C@@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:5]1[CH2:27][NH2:28])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1C#N
Agent: [Ni]
Solvent: CCO
Product: CC(=O)N1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1CN
Reaction time: 4 h

Procedure:
Raney-Nickel (2800, slurry in water; washed with ethyl alcohol (2×); 0.5 g) was added to a solution of tert-butyl [(3R,6S)-1-acetyl-2-cyano-6-(2,3-difluorophenyl)azepan-3-yl]carbamate (80.0 mg, 0.20 mmol) in ethanol (10 mL). Ammonia gas was bubbled to the reaction mixture for 3 minutes and the mixture was stirred under hydrogen at 40 psi. After 4 h, the reaction mixture was filtered and concentrated. MS 398.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[F:10][CH:11]([F:17])[C:12]([F:16])([F:15])[CH2:13]I>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:13][C:12]([F:16])([F:15])[CH:11]([F:17])[F:10])=[CH:6][N:7]=1
Reactant: Cc1cc(Cl)ncc1O
Reactant: FC(F)C(F)(F)CI
Product: Cc1cc(Cl)ncc1OCC(F)(F)C(F)F
Yield: 89 %

Procedure:
The title compound is prepared in 89% yield (7.97 g, pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (5.00 g, 34.8 mmol) and 1,1,2,2-tetrafluoro-3-iodopropane (16.9 g, 69.7 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[NH2:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>C(O)C>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][NH:15][C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[O:4])=[CH:10][N:9]=1)=[O:13]
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Reactant: NCC(O)CO
Solvent: CCO
Product: O=C(NCC(O)CO)c1cnc(C(=O)NCC(O)CO)cn1

Procedure:
A solution of 490 mg of 2,5-dimethoxycarbonylpyrazine and 0.40 cm3 of 3-amino-1,2-propanediol in 5 cm3 of ethanol is heated at a temperature in the region of the reflux temperature for 3 hours. The reaction mixture is filtered while hot. The white solid is washed with 3 times 15 cm3 of boiling ethanol. 416 mg of N,N′-bis(2,3-dihydroxy-1-propyl)pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 234° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 3.20 to 3.60 (mt, 8H: 2×OCH2 and 2×NCH2); 3.68 (mt, 2H: 2×OCH); 4.67 (t, J=5.5 Hz, 2H: OH at 2γ and OH at 5γ); 4.95 (d, J=5 Hz, 2H: OH at 2β and OH at 5β); 8.79 (t, J=5.5 Hz, 2H: 2×CONH); 9.23 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: N1([C:4]2[C:5]([N+:22]([O-:24])=[O:23])=[CH:6][C:7]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:8]([CH:17]=2)[C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])CC1.[Cl:25]C1C([N+]([O-])=O)=CC(S(C)(=O)=O)=C(C=1)C(O)=O.O=S(Cl)Cl.NCC(O)CO>CN(C=O)C.O.CCOC(C)=O>[Cl:25][C:4]1[C:5]([N+:22]([O-:24])=[O:23])=[CH:6][C:7]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:8]([CH:17]=1)[C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(N2CC2)cc1C(=O)NCC(O)CO
Agent: NCC(O)CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCC(O)CO
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Preparation of 5-(aziridin-1-yl)-N-(2,3-dihydroxypropyl)-2-(methylsulfonyl)-4-nitrobenzamide (10) A mixture of 5-chloro-2-(methylsulfonyl)-4-nitrobenzoic acid (Somani et al., Br. J. Cancer 1994, 69 (Suppl. XXI), 38) (2.21 g, 7.9 mmol) and SOCl2 (20 mL) containing DMF (2 drops) was refluxed for 1 h, then evaporated to dryness under reduced pressure. The resulting crude acid chloride was dissolved in anhydrous Me2CO (40 mL), and the solution was cooled to −5° C. and treated in one portion with a cold solution of 3-aminopropane-1,2-diol (1.48 g, 1.62 mmol) in water (20 mL). The mixture was shaken at room temperature for 15 min, then diluted with water (20 mL) and concentrated under reduced pressure to ca. 30 mL. After addition of solid NaCl, the mixture was extracted with EtOAc (3x), and the extracts were worked up to give a solid. This was dissolbed in EtOAc and filtered through a column of silica gel to give 5-chloro-N-(2,3-dihydroxypropyl)-2-(methylsulfonyl)-4-nitrobenzamide (2.54 g, 91%), mp (EtOAc/iPr2O) 141-142° C. 1NMR [(CD3)2SO] δ8.83 (t, J=5.7 Hz, 1H, NH), 8.55 (s, 1 , H-3), 8.08 (s, 1H, H-6), 4.81 (d, J=5.0 Hz, 1H, CHOH), 4.55 (t, J=5.8 Hz, 1H, CH2OH), 3.70-3.58 (m, 1H, CHOH), 3.45 (s, 3H, CH3), 3.44-3.35 (m, 3H, CH2OH & CONHCHH), 3.17-3.06 (m, 1H, CONHCHH). Anal. Calcd for C11H13ClN2O7S: C, 3 71; N, 7.94; S, 9.09 Found: C, 37.73;H, 3.96; N, 7.83; S, 9.29%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCN2CCOCC2)ccc1Cl
Temperature: 80 °C
Reaction time: 20 h

Procedure:
4-chloro-3-nitrophenol (5 g, 28.8 mmol, 1 eq.) was placed in dimethylformamide (96 mL) with 4-(2-chloro-ethyl)morpholine (16 g, 86.4 mmol, 3 eq.), Cs2CO3 (65 g, 0.20 mmol, 7 eq.), KI (10.5 g, 63.4 mmol, 2.2 eq.). The reaction mixture was heated at 80° C. and stirred for 20 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1% NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 4-(2-(4-chloro-3-nitrophenoxy)ethyl)morpholine. (7.5 g, 96%).
Reaction SMILES: CCCCCC.C([Li])CCC.S1C=CC=C1C1C=C(C(F)(F)F)NN=1.ClC(OCC)=O.C(OC([N:37]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][C:39]([C:46]2[S:50][C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:48][CH:47]=2)=[N:38]1)=O)C.C(OC(N1C(C2SC(C(OCC)=O)=CC=2)=CC(C(F)(F)F)=N1)=O)C.C(=O)(O)[O-].[Na+]>O.O1CCOCC1.C(O)C.C1COCC1>[F:44][C:42]([F:43])([F:45])[C:41]1[NH:37][N:38]=[C:39]([C:46]2[S:50][C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:48][CH:47]=2)[CH:40]=1
Reactant: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)n(C(=O)OCC)n2)s1
Agent: CCOC(=O)Cl
Agent: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)nn2C(=O)OCC)s1
Agent: FC(F)(F)c1cc(-c2cccs2)n[nH]1
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)[nH]n2)s1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
An n-butyl lithium-n-hexane solution (1.6 M) was added to a mixture of 3-(2-thienyl)-5-trifluoromethyl-1H-pyrazole and THF at −60° C. or below, followed by stirring at 0° C. for 50 minutes. Ethyl chloroformate was added to the reaction solution at −60° C. or below. After stirring at −78° C. for 1 hour, it was subjected to purification in the usual way to give a mixture of ethyl 5-(1-ethoxycarbonyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylate and ethyl 5-(1-ethoxycarbonyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylate as a light yellow solid. Then, a mixture of this mixture with sodium bicarbonate, ethanol, 1,4-dioxane and water was stirred at room temperature for 3 days, and it was subjected to purification in the usual way to give ethyl 5-(5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylate as colorless powder crystals. This was hydrolyzed with a base in the usual way to give 5-(5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylic acid.
Reaction SMILES: [C:1]1([N:7]=[C:8](Cl)[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([N:7]2[C:8]([C:9]([F:12])([F:11])[F:10])=[N:16][N:15]=[N:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)C(Cl)=Nc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1nnnn1-c1ccccc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Five grams (24.1 mmol) of N-phenyl-2,2,2-trifluoroacetimidoyl chloride obtained in Example 1, 2.83 g (43.4 mmol) of sodium azide, 1.66 g (12.1 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 16.5 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×3). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.81 g of 1-phenyl-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 93.2%). IR (neat, cm−1): 3071, 1531, 1499, 1312, 1207, 1167, 1013, 766, 691 1H-NMR (CDCl3): δ 7.60-7.54 (m, 3H), 7.38 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 3.89 (s, 3H) 13C-NMR (CDCl3): δ 145.90 (q, J=42.0 Hz), 132.41, 131.59, 131.58, 129.79, 129.76, 125.05, 117.73 (q, J=270.0 Hz) Elemental analysis: Value calculated for C8H5F3N4: C, 44.87%; H, 2.35%; N, 26.16% Value found: C, 44.27%; H, 2.24%; N, 25.95% Decomposition temperature (DSC): 290° C. (1.17 kJ/g), 367° C. (1.55 kJ/g)
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[S:30][C:7]2[NH:8][C:9]([C:11]([NH:13][CH:14]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:24][C:25]([O:27]C)=[O:26])[C:15]3=[O:29])=[O:12])=[CH:10][C:6]=2[CH:5]=1>O.C1COCC1>[C:25]([CH2:24][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH:14]([NH:13][C:11]([C:9]2[NH:8][C:7]3[S:30][C:4]([Cl:3])=[CH:5][C:6]=3[CH:10]=2)=[O:12])[C:15]1=[O:29])([OH:27])=[O:26]
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 2 h
Yield: 88.4 %

Procedure:
LiOH (1.41 g, 33.6 mmol) in H2O (16.5 mL) was added to a stirring solution of 2-chloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 1; 7.00 g, 16.8 mmol) in THF (88 mL) and the reaction was stirred for 2 h. The reaction was quenched by addition of 1M aqueous HCl (200 mL) and EtOAc (400 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The resultant white foam was triturated with hot Et2O (100 mL) cooled, filtered and dried to afford the title compound (6.00 g, 89%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:14])=[N:10][O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18]N=1>>[CH:16]1([C:12](=[O:11])[CH2:8][CH2:5][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:9]([CH3:14])=[N:10][O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1noc(C)c1-c1ccc(Br)cc1
Reactant: Brc1ccccn1
Product: Cc1noc(C)c1-c1ccc(CCC(=O)C2CCCC2)cc1

Procedure:
The title compound was prepared as described in Step 1 of Example A(82), where 4-(4-Bromo-phenyl)-3,5-dimethyl-isoxazole from Step 1 of Example A(18), was substituted for 2-Bromopyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cc(CN2CCOCC2)cc(Cl)c1F

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (220 mg, 0.65 mmol), morpholine (57 mg, 0.65 mmol), acetic acid (0.056 mL, 0.9 mmol) and sodium triacetoxyborohydride (344 mg, 1.6 mmol) in THF (8 mL). TLC, Rf (EtOAc)=0.44; MS (LC-MS): 359.0 [M]+.
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:2]1([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: c1ccc(C(=C2CCCNC2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(C(c2ccccc2)C2CCCNC2)cc1
Yield: 99.3 %

Procedure:
A solution of 3-diphenylmethylenepiperidine hydrochloride (200 mg, 0.7 mmol) in ethanol (40 ml) was stirred under one atmosphere of hydrogen at 40° C. in the presence of 10% palladium on charcoal (20 mg) for 24 hours and filtered. The filtrate was concentrated to give the title compound (200 mg) as a pale brown gum which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](SC)=[N:22][C:23]#[N:24])[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(#N)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[N:29][CH2:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[NH:22][C:23]#[N:24])[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: NCc1ccncc1
Reactant: CSC(=NC#N)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Solvent: CC#N
Product: N#CNC(=NCc1ccncc1)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Yield: 84.7 %

Procedure:
Methyl 4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-N-cyano-1-piperazinecarboximidothioate (200 mg, 0.465 mmol) was dissolved in acetonitrile (1 ml) in a 25 ml flask, and 4-aminomethylpyridine (0.94 ml, 9.30 mmol) was added. The mixture was refluxed for 1.6 hours. The reaction mixture was cooled and then acetonitrile was distilled off. The resulting tar was dissolved in water and CH2Cl2. The layers were separated; the aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), filtered through `Celite` and concentrated. The residue was partially purified by flash chromatography, and the product (228 mg) was purified by further chromatography to afford the pure product (193 mg, 87%); MS (CI, M+H)=490.