Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][N:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])=[CH:21][CH:20]=2)[C:12]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][F:18])=[O:7].C(N(CC)CC)C.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([N:47]=[C:48]=[O:49])[CH:42]=1.O>ClCCl>[F:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1[N:11]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[O:26])=[CH:23][CH:24]=2)[N:10]=[N:9][C:8]=1[C:6]([NH:5][CH2:4][CH2:3][NH:2][C:48]([NH:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([F:40])[CH:42]=1)=[O:49])=[O:7]
Reactant: NCCNC(=O)c1nnn(-c2ccc(C(=O)NCC(F)(F)F)cc2)c1CCCCCF
Reactant: O=C=Nc1cccc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NCCNC(=O)c1nnn(-c2ccc(C(=O)NCC(F)(F)F)cc2)c1CCCCCF)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of N-(2-aminoethyl)-5-(5-fluoropentyl)-1-(4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxamide monohydrochloride (0.12 g) obtained in Example 296 in dichloromethane (5.0 ml) were added triethylamine (0.07 ml) and 1-fluoro-3-isocyanatobenzene (0.06 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resultant precipitate was collected by filtration, washed with water and recrystallized from ethanol-water to give the title compound as a white powder (0.14 g, 98%).
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.CO.[NH:30]1[CH2:33][CH2:32][CH2:31]1.C([BH3-])#N.[Na+]>CS(C)=O.C(O)(=O)C>[N:30]1([CH2:22][C:20]2[S:19][CH:18]=[C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:27])[CH2:3][CH2:4]3)[CH:21]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: NC(=O)c1cc(-c2csc(C=O)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2csc(CN3CCC3)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (105 mg, 0.26 mmol) was diluted in dimethylsulfoxide (0.5 mL) and methanol (0.5 mL) in a 2 dram vial. Azetidine (75 mg, 5 eq) was added, followed by glacial acetic acid (0.3 mL). The mixture was stirred at rt for 1 h, then sodium cyanoborohydride (35 mg, 0.56 mmol, 2.1 eq) was added and the mixture was stirred at rt overnight. The mixture was filtered through a 1 g silica gel pad (commercial, in syringe tube), and the solvent was removed in vacuo. The crude product was re-diluted in a mixture of methanol and DMSO, and purified by ammonium hydroxide Gilson HPLC. The desired fractions were concentrated in an EZ2 Genevac evaporator, giving 10 mg (9%) of title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[C:24]([CH3:32])([CH3:31])[C:23]2=[O:33])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[CH3:31][C:24]1([CH3:32])[C:25]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:17][CH:18]=2)[C:23]1=[O:33]
Reactant: CC1(C)C(=O)N(c2ccc(O)cc2)c2ncccc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(N3C(=O)C(C)(C)c4cccnc43)cc2)nc2cccnc21
Temperature: 180 °C
Yield: 73.1 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 1-(4-hydroxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (119 mg) and NaH (20.45 mg) in DMF (2 ml) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3,3-dimethyl-1-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (120 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][C:23]([F:25])([F:26])[F:24])[C:17]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
330 mg (766 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoic acid (racemate), 148 mg (766 μmol) of tert-butyl 4-aminobenzoate, 109 mg (766 μmol) of Oxima and 120 μl (766 μmol) of DIC in 7.7 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (40 g cartridge, 40 ml/min, cyclohexane/ethyl acetate gradient). Yield: 329 mg (64% of theory)
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([P:29](=[O:32])([OH:31])[OH:30])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:24]([NH:26][C@H:27]([P:29](=[O:30])([OH:32])[OH:31])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that given in Example 35 (b), from the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-valyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-valylamino)-ethylphosphonic acid of melting point 276°-277° C (decomposition); [α]D20 = - 9.3° (c = 0.5% in water).
Reaction SMILES: [C:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C:2]=1[CH2:3][CH2:4][CH2:5][CH2:6]2.[BH4-].[Na+]>O1CCCC1>[OH:11][CH:10]1[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[C:7](=[O:8])[O:9]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC(O)C2=C1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-cyclohexene-1,2-dicarboxylic anhydride (25.2 g, 165.6 mmol) in tetrahydrofuran (125 mL) placed in an ice bath was added sodium borohydride (1.51 g, 39.97 mmol). The ice bath was removed and the mixture was stirred at room temperature for 30 minutes, and under reflux for 5 hours. After cooling to room temperature, 1N HCl was added, and the reaction mixture concentrated. The residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, water and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes to provide the title compound. MS (ESI) m/z 155 (M+H)+.
Reaction SMILES: CN([C@@H]([C:24](=[O:36])[N:25](C)[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)CC1C=CC2C(=CC=CC=2)C=1)C(=O)/C=C/CC(N)(C)C.C(O)=O.C(OC(=O)C)(=O)C>O>[C:29]1([CH2:28][CH2:27][CH2:26][NH:25][CH:24]=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(CCCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.9 %

Procedure:
(2E)-5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)amide ##STR116## N-(3-Phenylpropyl)formamide ##STR117## 3-Phenylproylamine (10 ml, 70.0 mmol) was added at 0° C. dropwise to formic acid (80 ml). Acetic acid anhydride (30 ml) was added dropwise to the reaction mixture. After the addition the reaction mixture was warmed to room temperature. It was stirred for 2.5 h. It was cooled to 0° C. Water (30 ml) was added dropwise. The reaction mixture was warmed to room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 ml). The organic phase was washed with saturated sodium chloride solution (2×150 ml) and with saturated sodium hydrogen carbonate solution (200 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo to furnish 5.82 g of N-(3-phenylpropyl)formamide, which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:26][O:25][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]1)[N:13]=[CH:12][N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]2=[O:24]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCCl
Reactant: CN1CCNCC1
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCN(C)CC1
Yield: 92 %

Procedure:
A solution of 7-(3-chloropropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (3 g, 7.84 mmol) in 1-methylpiperazine (30 ml) was heated at 100° C. for 1 hour. After cooling, the mixture was partitioned between saturated ammonium chloride and methylene chloride. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10). The volatiles were removed by evaporation to give 6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (3.24 g, 92%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O>CCOC(C)=O>[CH2:20]([C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: CCOC(C)=O
Product: CCc1cccc(N2CCNCC2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
0.037 g (0.128 mmol) 1-Boc-4-(3-ethylphenyl)-piperazine from the previous step was dissolved in 10 mL EtOAc and cooled to 0° C. using an ice bath. HCl gas was then bubbled through the reaction for 10 min, followed by an additional 10 min of stirring. The reaction was warmed to ambient temperature and the solvent removed in vacuo. The residue was taken up in 10 mL CHCl3 that had been previously saturated with NH3 gas, the solid NH4Cl filtered, and the solvent removed to give 1-(3-ethylphenyl)piperazine as the free base.
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:14][C:15]1[CH:16]=[C:17]([C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]C)=O)[CH:24]=2)[CH:18]=[C:19]([Br:22])[C:20]=1[OH:21].O>CCCCCC.C(Cl)(Cl)Cl>[CH2:7]([N:6]([CH3:5])[C:28]([C:25]1[CH:24]=[C:23]([C:17]2[CH:18]=[C:19]([Br:22])[C:20]([OH:21])=[C:15]([Br:14])[CH:16]=2)[O:27][N:26]=1)=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cc(-c2cc(Br)c(O)c(Br)c2)on1
Reactant: CNCc1ccccc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(Cc1ccccc1)C(=O)c1cc(-c2cc(Br)c(O)c(Br)c2)on1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.9 %

Procedure:
Trimethylaluminium (0.1 mL of a 2 N solution in hexane, 0.2 mmol) was added to a solution of N-methylbenzylamine (27 mg, 0.22 mmol) in dry chloroform (2 mL) under nitrogen and the resulting solution was stirred at room temperature for 20 minutes. Methyl 5-(3,5-dibromo-4-hydroxyphenyl)isoxazole-3-carboxylate (75 mg, 0.2 mmol) was added and the reaction mixture was stirred at 50° C. for 48 hours. Water (1 mL) and chloroform (2 mL) were added to the solution; the chloroform was separated and evaporated to dryness. The residue was dissolved in dimethylsulphoxide (1 mL) and purified by preparative HPLC to give the title compound (42.8 mg, 46%) as a colorless powder. 1H NMR δ (ppm) (DMSO-d6): 2.96 and 3.09 (3 H, two s), 4.76 (2 H, s), 7.28-7.46 (6 H, m), 8.14 and 8.16 (2 H, t, two s), 10.73 (1 H, s). LCMS (10 cm_apci_formic) Rt 3.79 min; m/z 463/465/467 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][N+:14]([O-])=O)[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]>C(O)(=O)C.O.[Zn]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][NH2:14])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1cc(N[N+](=O)[O-])nnc1OCC
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(NN)nnc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
N-(5,6-Diethoxypyridazin-3-yl)-N-nitroamine (W4.120; 114 mg) was dissolved in acetic acid (5 ml) and added dropwise while cooling with ice and stirring at between 10 and 20° C. to a mixture of zinc (130 mg) in water (3 ml). Thereafter, the ice bath was removed and the mixture was stirred at RT for 1 h. Then the mixture was alkalized with 10 N sodium hydroxide solution, the aqueous phase was extracted three times with DCM, and the combined DCM phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A). The clean, product-containing fractions were each combined, freed of the ACN, basified with saturated potassium carbonate solution and then extracted three times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 50 mg of the title compound were obtained. LC-MS rt: 0.37 min
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C@H:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=1.[N+](C1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1C1N([C@H]2CCOC2)N=CC=1C(OCC)=O)([O-])=O.I[C:60]1[C:65]([CH3:66])=[CH:64][N:63]=[C:62]([O:67][CH:68]([CH3:70])[CH3:69])[C:61]=1[CH3:71].O>CN(C=O)C>[CH:68]([O:67][C:62]1[C:61]([CH3:71])=[C:60]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]([C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[N:11]=[CH:10][C:9]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([N+:23]([O-:25])=[O:24])[CH:3]=2)[C:65]([CH3:66])=[CH:64][N:63]=1)([CH3:70])[CH3:69]
Reactant: Cc1cnc(OC(C)C)c(C)c1I
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cnc(OC(C)C)c2C)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Ethyl 5-(4-bromo-2-nitrophenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 7-(1) (200 mg) was converted to ethyl 5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate by the same method as in Preparation Example 7-(2). A solution of 4-iodo-2-isopropyloxy-3,5-dimethylpyridine obtained in Preparation Example 47 (142 mg) in DMF (0.5 mL), and water (0.5 mL) were added to the reaction mixture, and the mixture was stirred at 110° C. for two hours. The reaction mixture was cooled to room temperature and then partitioned by adding ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (138.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cncnc1
Product: CCOC(=O)n1c(C(=O)c2cncnc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 5-bromoacetylpyrimidine (step 1). 1H-NMR (CDCl3) δ: 9.29 (1 H, s), 9.03 (2 H, s), 8.02 (1 H, d, J=1.6 Hz), 7.57 (1 H, d, J=8.4 Hz), 7.35 (1 H, dd, J=1.6, 8.4 Hz), 6.13 (2 H, br s), 4.01 (2 H, q, J=7.1 Hz), 1.02 (3 H, t, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)nnc2C(F)(F)F)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)cc3)c(C(F)(F)F)nn2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a stirred solution of 6-chloro-4-(4-fluorophenyl)-3-trifluoromethyl-pyridazine (D7) (0.81 g, 2.93 mmol) and N-Boc-piperazine (0.818 g, 4.39 mmol) in acetonitrile (10 ml) was added diisopropylethylamine (1 ml, 5.9 mmol) and the mixture was stirred at 80° C. for 30 min., under microwave irradiation. After this period, the reaction mixture was diluted with dichloromethane and extracted with water. The organic layer was separated, dried (MgSO4) and the solvents evaporated in vacuo to yield D8 (1.27 g, 62%). C20H22F4N4O2 requires 426; Found 427 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[NH:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH2:17][OH:18].CN1CCCC1=O.C(OCC)(=O)C>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:21][CH2:20][CH2:19][CH:16]2[CH2:17][OH:18])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: OC[C@@H]1CCCN1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCC2CO)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
A mixture of 4-chloro-2-nitrobenzoic acid methyl ester 100 mg, prolinol 235 mg and 1-methyl-2-pyrrolidinone 3 ml is stirred at 100° C. for 3 hours. After cooling to room temperature, ethyl acetate and water are added to the mixture. The organic layer is washed with water (twice) and brine, and dried over sodium sulfate. After removal of the sodium sulfate, the filtrate is concentrated in vacuo, and the residue is purified with preparative thin-layer chromatography (two plates, solvent; hexane:ethyl acetate=1:1) to give 4-(2-hydroxymethyl-1-pyrrolidinyl)-2-nitrobenzoic acid methyl ester 20 mg as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]=[O:21])[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CCC1CCC(C(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)C1CCC(CCO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Sodium borohydride (89 mg, 2.35 mmol) was added to a solution of 4-(2-oxo-ethyl)-cyclohexanecarboxylic acid benzyl ester (306 mg, 1.18 mmol) in methanol (6 ml) at 0° C. The mixture was stirred at 0° C. for one hour, and then quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-(2-hydroxy-ethyl)-cyclohexanecarboxylic acid benzyl ester (299 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:26][C:23]2[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 82.1 %

Procedure:
A solution of the compound prepared in Example 214A (1.0 g, 3.80 mmol), 4-aminothiophenol (0.5 g, 4.00 mmol), cesium carbonate (1.3 g, 4 mmol) in dimethylformamide (10 ml) was heated at 40° C. for 16 hours. Afterwards, ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving an orange oil as the title compound, (1.1 g, 83%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[CH2:30]([NH:37][S:15]([CH2:14][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:16])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol, 1.0 eq.) in DCM (1.0 mL) was combined with benzylamine (47.7 μL, 4.0 eq.) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (7.3 mg). MS m/z: [M+H]+ calcd for C20H23F3N2O3S, 429.14. found 429.0.
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[C:20](C=CCC)[CH:19]=2)(=[O:17])=[O:16])C=CC=1C(C)(C)C)=CCC.[CH3:32][SnH:33]([CH3:35])[CH3:34]>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([S:15]([CH2:7][CH2:6][CH2:5][CH2:1][Sn:33]([CH3:35])([CH3:34])[CH3:32])(=[O:17])=[O:16])=[CH:19][CH:20]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C[SnH](C)C
Reactant: CCC=Cc1cc(S(=O)(=O)c2ccc(C(C)(C)C)c(C=CCC)c2)ccc1C(C)(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)CCCC[Sn](C)(C)C)cc1
Reaction time: 70 h
Yield: 20.3 %

Procedure:
The procedure described in Example 1 was employed except that 10.7 g (42.5 mmoles) of 3-butenyl-4-t-butylphenyl sulfone and 7.0 g (42.5 mmoles) of trimethyltin hydride were the reactants. The irradiation proceeded for 70 hours. Recrystallization of the product from petroleum ether afforded 3.6 g of 4-(p-t-butylphenyl-sulfonyl)butyltrimethylstannane, m.p. 80°-81.8° C. The presence of both the sulfonyl and trimethyltin moieties was indicated by strong infrared absorption bands at 1300 cm-1, 1282 cm-1, 1147 cm-1 (--SO2 --) and 780 cm-1 [(CH3)3Sn--] employing a KBR disc. Nuclear magnetic resonance spectroscopy (NMR) showed the following: