Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C:12]1[CH:50]=[CH:49][CH:48]=[CH:47][C:13]=1[CH2:14][O:15][C:16]1[N:17]=[C:18]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][CH:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[C:19]([C:24]([NH2:26])=[O:25])=[N:20][C:21]=1[CH2:22][CH3:23].O1CCCC1.O.NN>C(O)C>[NH2:3][C:12]1[CH:50]=[CH:49][CH:48]=[CH:47][C:13]=1[CH2:14][O:15][C:16]1[N:17]=[C:18]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)[CH2:38][CH2:39]3)=[CH:32][CH:33]=2)[C:19]([C:24]([NH2:26])=[O:25])=[N:20][C:21]=1[CH2:22][CH3:23]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OCc1ccccc1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OCc1ccccc1N
Temperature: 25 °C
Reaction time: 30 h
Yield: 72.3 %

Procedure:
A mixture of 5-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (540 mg), tetrahydrofuran (10.8 mL), ethanol (10.8 mL), and hydrazine monohydrate (160 mg) was stirred at room temperature for 30 hours. The reactant was subjected to liquid separation by the addition of water and chloroform. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; ethyl acetate, and then chloroform:methanol=97:3) to obtain 5-[(2-aminobenzyl)oxy]-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (315 mg) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[NH:12][C:13]=2[C:14](O)=[O:15])=[CH:5][CH:4]=1.O.OC1C2N=N[NH:30]C=2C=CC=1.N.O1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[NH:12][C:13]=2[C:14]([NH2:30])=[O:15])=[CH:5][CH:4]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1ccc(-c2nc(-c3ccncc3)[nH]c2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(-c3ccncc3)[nH]c2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.7 %

Procedure:
To a solution of 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5-carboxylic acid (0.090 g, 0.3 mmol) and hydroxybenzotriazole monohydrate (0.047 g, 0.3 mmol) in DMF (2.5 ml) was added 0.5M ammonia in dioxane (2 m, 1.0 mmol) and the resulting solution stirred at room temperature for 10 minutes. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (0.064 g, 0.33 mmol) was added and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5-carboxamide (0.025 g, 0.08 mmol, 67%). 1H NMR (DMSO) 3.83 (3H, s), 7.03 (2H, d), 7.20 (1H, br. s), 7.50 (1H, br. s), 7.84 (2H, d), 8.03 (2H, dd), 8.68 (2H, dd), 13.12 (1H, br. s). LCMS (2) Rt 1.68 min; m/z (ES+) 295.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:20]=[CH:21][C:14]=23)[CH:8]=1)([CH2:5][CH3:6])[C:3]#[N:4].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH:19]1[C:15]2=[N:16][CH:17]=[CH:18][C:13]([C:9]3[CH:8]=[C:7]([C:2]([CH3:1])([CH2:5][CH3:6])[C:3]#[N:4])[CH:12]=[CH:11][CH:10]=3)=[C:14]2[CH:21]=[N:20]1
Reactant: CCC(C)(C#N)c1cccc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C#N)c1cccc(-c2ccnc3[nH]ncc23)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
2-Methyl-2-(3-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)butanenitrile (240 mg, 0.46 mmol) was dissolved in dichloromethane (10 ml) and cooled down in an ice-bath. Triethylsilane (2.5 ml) was added followed by trifluoroacetic acid (2.5 ml). The resulting mixture was stirred at 0° C. for 2 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (92 mg, 70% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(C2CCNC2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CN1CCC(c2ccccc2)C1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-phenyl-pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH3:15]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:15])(=[O:13])=[O:12]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: CO
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h

Procedure:
2-Chloro-5-nitrobenzenesulphonyl chloride (5.12 g, 20 mmole) was added in portions to liquid ammonia with stirring at -78° C. (methanol/dry-cold). The mixture was stirred for 0.5 h. and the excess ammonia then allowed to evaporate. The residue was crystallised from aqueous ethanol (1:1) to afford lustrous prisms of 2-chloro-5-nitrobenzenesulphonamide, 4.42 g, 93%, (m.p. 180°-187° C.). TLC analysis (CH2Cl2) showed one spot (Rf =0.2). Spectroscopic data was consistent with the product.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCC[C@H](C(OCC)=O)C1.C(Cl)(=O)C1C=CC=CC=1>>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Agent: CCOC(=O)[C@H]1CCCNC1
Solvent: O=C(Cl)c1ccccc1
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available (S)-ethyl nipecotate (203 mg; 1.29 mmol; Chemi SpA; Italy) and benzoyl chloride (150 μl; 1.29 mmol). The crude product was distilled at 200° C./0.1 torr, giving (S)-ethyl 1-benzoyl-3-piperidinecarboxylate (171.7 mg) as a colorless oil. MS m/z (positive ion) 545 (dimer+Na+; 15), 523 (dimer+; 10), 284 (M+Na+; 25), 262 (MH+; 100).
Reaction SMILES: [N-]=[N+]=[N-].[N:4]([C@@H:7]([CH2:37][CH2:38][CH2:39][CH3:40])[C@@H:8]([NH:16][C:17](=[O:36])[C:18]1[CH:23]=[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[N:21]=[C:20]([NH:30][CH2:31][CH:32]2[CH2:34][CH:33]2[CH3:35])[CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N+]=[N-]>CO.[Pd]>[NH2:4][C@@H:7]([CH2:37][CH2:38][CH2:39][CH3:40])[C@@H:8]([NH:16][C:17](=[O:36])[C:18]1[CH:23]=[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[N:21]=[C:20]([NH:30][CH2:31][CH:32]2[CH2:34][CH:33]2[CH3:35])[CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCC[C@H](N=[N+]=[N-])[C@H](Cc1ccccc1)NC(=O)c1cc(NCC2CC2C)nc(N(C)S(C)(=O)=O)c1
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Solvent: CO
Product: CCCC[C@H](N)[C@H](Cc1ccccc1)NC(=O)c1cc(NCC2CC2C)nc(N(C)S(C)(=O)=O)c1

Procedure:
Amide Formation A solution of acid intermediate A (35 mg, 0.112 mmol), amine intermediate I (28 mg, 0.134 mmol), N,N-diisopropylethylamine (36 mg, 0.28 mmol), and HOAT (15 mg, 0.112 mmol) in methylene chloride (1.5 mL) was treated with EDC (32 mg, 0.168 mmol). After stirring 2 hours at ambient temperature the solution was partitioned between water/methylene chloride. The organics were washed with 1N HCl followed by brine. The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo to give N-[(1S,2S)-2-azido-1-benzylhexyl]-2-{[(2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinamide as a crude oil. LCMS (M+H)=528.0 Step B: Azide Reduction A solution of crude N-[(1S,2S)-2-azido-1-benzylhexyl]-2-{[(2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinamide in methanol (2 mL) and 10% palladium on carbon (12 mg) in degassed methanol was placed under a hydrogen atmosphere for 1 hour. The reaction was filtered through celite, rinsed with methanol and evaporated in vacuo. Purification by reverse phase LC gave N-[(1S,2S)-2-amino-1-benzylhexyl]-2-{[(2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinamide. 1H NMR (CD3OD) δ 7.28 (m, 5H), 6.55 (s, 1H), 6.44 (s, 1H), 4.35 (m, 1H), 3.42 (m, 1H), 3.29 (s, 3H), 3.16 (m, 5H), 3.00 (m, 2H), 1.85 (m, 1H), 1.72 (m, 1H), 1.43 (m, 4H), 1.05 (d, J=5.96 Hz, 3H), 0.98 (t, J=7.14 Hz, 3H), 0.80 (m, 1H), 0.65 (m, 1H), 0.41 (m, 1H), 0.24 (m, 1H) LCMS [M+H]+=314.1. The following examples were prepared in an analogous manner to that described in Example 1 using various combinations of Intermediates I-XXX or related derivatives thereof and Intermediate acids of types A-H or related derivatives thereof.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)[N:11]=[C:10]([C:27]#[N:28])[N:9]=2)[N:3]=1.Cl.C([O-])(O)=[O:31].[Na+]>O1CCOCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:21]([CH3:22])[C:20]4[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=4[N:18]=3)[N:11]=[C:10]([C:27]([NH2:28])=[O:31])[N:9]=2)[N:3]=1
Reactant: O=C([O-])O
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C#N)n2)n1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)nc(C(N)=O)n2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidine-2-carbonitrile (21) (50.0 mg, 0.135 mmol, 1.0 eq.) in 1,4-dioxane (0.30 mL) was added concentrated HCl (0.30 mL, 3.6 mmol, 27 eq) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was neutralized with saturated aqueous NaHCO3 and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate, and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative TLC (5% methanol in dichloromethane) to afford trans-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl) pyrimidine-2-carboxamide (22) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.69 (m, 1H), 7.59 (br d, 1H, J=3.2 Hz), 7.33-7.21 (m, 3H), 6.44 (br d, 1H, J=3.2 Hz), 3.82 (s, 3H), 3.01 (m, 1H), 3.00 (s, 3H), 2.90 (m, 1H), 2.42 (s, 3H), 2.16-2.07 (m, 2H). LRMS m/z (M+H) 389 found, 389 required. m.p. 119-121° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: [Pd]
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Solvent: CCOCCO
Solvent: O
Product: Cc1ccc2cc(-c3ccc(F)cc3F)ccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution 6-Bromo-2-methylquinoline (4.7 g; 0.021 mol) in 2-ethoxyethanol (80 ml) was added tetrakis(triphenylphosphine) palladium (0.5 g; 0.0004 mol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 minutes. 2,4-Difluorophenylboronic acid (3.5 g; 0.022 mol) was added followed by ethoxyethanol (20 ml). Sodium carbonate (10 g; 0.094 mol) in water (50 ml) was added and the reaction mixture was magnetically stirred and heated under nitrogen at 90° C. for 16 h. The cooled reaction mixture was filtered through a pad of Celite, hyflo supercel and then extracted with dichloromethane (3×100 ml), after addition of de-ionised water. The organic layer was washed with brine, dried over anhydrous magnesium sulphate and solvent removed to give the residue, which was triturated with ether and cooling in the refrigerator gave a solid. This was filtered off and dried under vacuum at 60° C. to give a colourless solid. Yield 3.9 g (72%). Mp 86° C. (DSC, onset). Elemental analysis: Found C, 73.76; H, 4.39; N, 5.38; C16H11NF2 requires C, 75.28; H, 4.34; and N, 5.49%.
Reaction SMILES: C1(OC)C=CC=CC=1.C1(C([O:22][C:23]([C:25]2[N:30]3[C:31](=[O:44])[C@@H:32]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:29]3[S:28][CH2:27][C:26]=2[O:45][CH3:46])=[O:24])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:36]([CH2:35][C:34]([NH:33][C@@H:32]1[C:31](=[O:44])[N:30]2[C:25]([C:23]([OH:24])=[O:22])=[C:26]([O:45][CH3:46])[CH2:27][S:28][C@H:29]12)=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.87 ml of anisole is added to a solution of 2.0 g (3.78 mmols) of 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride and the mixture is cooled to 0° C. and left to stand for 1 hour after adding 1.2 ml of trifluoroacetic acid. The reaction mixture is concentrated in vacuo and the residue is crystallised from acetone/ether. 7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid of melting point 170° C. (decomposition) is obtained.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[C:4]2[CH:13]=[C:14]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)[O:15][C:3]=12>C1COCC1.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[C:4]2[CH2:13][CH:14]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)[O:15][C:3]=12
Reactant: CCCC1CCC(c2cc3c4c(c(F)c(F)c3o2)OCCC4)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC1CCC(C2Cc3c4c(c(F)c(F)c3O2)OCCC4)CC1

Procedure:
1.00 g (2.99 mmol) of 4,5-difluoro-2-(4-propylcyclohexyl)-8,9-dihydro-7H-furo[3,2-f]chromene is hydrogenated for 15 h at room temperature and atmospheric pressure in THF using elemental hydrogen in the presence of Pd/C (5% Pd). The reaction soln. is concentrated to dryness, and the residue is purified by column chromatography (SiO2, 1-chlorobutane pentane=2:1). Further purification is carried out by recrystallisation from ethanol, giving 4,5-difluoro-2-(4-propylcyclohexyl)-1,7,8,9-tetrahydro-2H-furo[3,2-f]chromene as a colourless solid having an m.p. of 96° C. (Δ∈=−7.0).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13]>C(#N)C>[Cl:17][C:16]([Cl:19])([Cl:18])[CH2:15][O:14][C:12](=[O:13])[NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CC#N
Product: O=C(NOCc1ccccc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under anhydrous conditions, 50 g of O-benzylhydroxylamine hydrochloride is suspended in 783 ml of acetonitrile. To the suspension is added 50.6 ml ofpyridine followed by dropwise addition of 43.15 ml trichloroethyl chloroformate in 235 ml of acetonitrile. The reaction is allowed to stir overnight at room temperature. The mixture is concentrated in vacuo and diluted with ethyl acetate. The organic layer is washed with 0.5M citric acid, water, saturated sodium bicarbonate, saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation (bp 150° C. at 0.5 mmHg.) to give 70 g of the desired product.
Reaction SMILES: [CH:1]1([C:6](=[O:17])[CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](OC)(=[O:23])[CH2:19][C:20]([CH3:22])=[O:21]>>[CH:1]1([C:6]2([CH2:7][S:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[O:17][C:18](=[O:23])[CH2:19][C:20](=[O:21])[CH2:22]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(SCC(=O)C2CCCC2)cc1
Product: COc1ccc(SCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1

Procedure:
1-Cyclopentyl-2-(4-methoxy-phenylsulfanyl)-ethanone (from Step 2 below) was subjected to the methyl acetoacetate dianion addition reaction described in the synthesis of Example A(82), to yield the title compound as a white solid. 1H NMR (CDCl3): δ 1.35-1.86 (brm, 8H), 2.35 (m, 1H), 2.61-3.62 (m, 6H), 3.85 (s, 3H), 6.82 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[N:9]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1.S(=O)(O)[O-].[Na+]>CO>[N:9]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]3[NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc(OCCCN2CCCC2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Product: c1ccc2[nH]c(-c3ccc(OCCCN4CCCC4)cc3)nc2c1
Yield: 34 %

Procedure:
1,2-Diaminobenzene (4.65 g), 4-[3-(1-pyrrolidinyl)propoxy]benzaldehyde (Step B) (10.0 g) and sodium bisulfite (4.60 g) are stirred at reflux in methanol (300 mL) for 14 hours. The mixture is filtered and evaporated. The residue is recrystallized from hot ethyl acetate/ethanol to give 4.68 g of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([O:16][CH3:25])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCN(C)CC2)c1

Procedure:
3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid (250 mg, 0.879 mmol) was refluxed in the presence of concentrated sulfuric acid (5.68 mg, 0.044 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, solvent was removed by vacuum and the crude material was used for further reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.O=C1C(C2C=CC=CC=2)(C2C=CC=CC=2)CCN1CC(O)=O.[NH2:47][C:48]1[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=1.FC(F)(F)C1C=CC(N)=NC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:47][C:48]3[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][N:49]=3)=[O:16])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: N#Cc1ccc(N)nc1
Agent: Nc1ccc(C(F)(F)F)cn1
Agent: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Product: N#Cc1ccc(NC(=O)CN2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2=O)nc1

Procedure:
The title compound was prepared using the procedure described in Example 246 substituting 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 58D for 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid and 6-aminonicotinonitrile for 5-(trifluoromethyl)pyridin-2-amine. 1H NMR (300 MHz, CDCl3) δ ppm 8.55 (s, 2H), 8.25 (d, J=8.7, 1H), 7.93 (dd, J=2.1, 8.7, 1H), 7.43-7.22 (m, 4H), 7.07-6.98 (m, 4H), 4.21 (s, 2H), 3.55 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (DCI) m/z 433.0 (M+H)+.
Reaction SMILES: [Br:1][C:2](=[CH2:19])[CH2:3][CH2:4][C:5]([NH:7][CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].[Cl-].[Na+].Cl>CN(C)C=O.O.O1CCOCC1>[Br:1][C:2](=[CH2:19])[CH2:3][CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6]
Reactant: C=C(Br)CCC(=O)NC(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: C=C(Br)CCC(=O)NCC(=O)OCC
Yield: 95 %

Procedure:
To a solution of the product of Example 3H (3.36 g, 10.0 mmol) in dimethylformamide (10 mL) was added sodium chloride (586 mg, 10.0 mmol), water (360 microliters, 20 mmol) and 4N hydrochloride acid in dioxane (0.012 mL, 0.5 mmol). The reaction vessel was Firestone purged three times and placed under a positive nitrogen pressure. The reaction mixture was heated at reflux for 24 hours and then concentrated in vacuo. The residue obtained was diluted with water (5 mL) and extracted with ether (3×15 mL). The combined organic extracts were decolorized with charcoal (0.5 g), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product (2.51 g, 95%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) 1.29 (t, 3H), 2.04 (s, 3H), 2.99 (m, 2H), 4.22 (q, 2H), 4.79 (m, 1H), 5.53 (d, 1H), 5.68 (m, 1H), 6.44 (d, 1H); IR (film) 1195, 1220, 1370, 1540, 1660, 1740, 2990, 3050, and 3300 cm-1. MS (DCI/NH3) m/e 264/266 (M+H)+, 281/283 (M+H+NH3)+. Anal. Calcd. for C9H14NO3Br: C, 40.92; H, 5.34; N, 5.30. Found: C, 42.04; N, 5.48; N, 5.26.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:18]=2[N:17]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:18]=2[N:17]=1
Reactant: CCCn1c(CCCCCNC(=O)OCc2ccccc2)nc2ccc(C#N)cc21
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(CCCCCN)nc2ccc(C#N)cc21
Reaction time: 20 h
Yield: 35.8 %

Procedure:
The compound (107 mg) obtained in Example 48-3 was dissolved in ethanol (10 ml) and added with palladium carbon (20 mg) and the whole was stirred for 20 hours under a hydrogen atmosphere. After filtration through Celite, the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (25.6 mg) as a white solid.