Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(CCN(C)C)C.C([Li])(CC)C.C1CCCCC1.[F:33][C:34]1[C:39](I)=[CH:38][CH:37]=[CH:36][N:35]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[NH4+].[OH-]>[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[F:33][C:34]1[C:39]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:38][CH:37]=[CH:36][N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: Fc1ncccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1c1cccnc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
To a −78° C. solution of tert-butyl piperidine-1-carboxylate (1.0 mL, 5.20 mmol), dry ether (20 mL) and TMEDA (0.82 mL, 5.47 mmol) was added sec-butyllithium, 1.4M in cyclohexane (3.90 mL, 5.46 mmol) dropwise over 5 minutes. After 2 hours, a solution of zinc chloride, 0.5M in ether (6.8 mL, 6.80 mmol) was added over 7 minutes. After 30 minutes, the mixture was warmed to ambient temperature and stirred for a further 30 minutes then 2-fluoro-3-iodopyridine (1511 mg, 6.78 mmol), palladium(ii) acetate (127 mg, 0.566 mmol), tri-t-butylphosphonium tetrafluoroborate (268 mg, 0.924 mmol) was added in one portion. After 18 hours, NH4OH (10 mL, 10% aqueous solution) was added dropwise, followed by Et2O (10 mL). The organic layer was extracted, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 0% to 40% EtOAc in hexane, to provide tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.250 mmol) as a colorless oil. [M+Na]=303.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1.[N:34]([C@@H:37]([C@H:41]([C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[C:51]([F:56])[CH:50]=1)[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[C:38](O)=[O:39])=[N+:35]=[N-:36].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:34]([C@@H:37]([C@@H:41]([C:42]1[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=1)[C:49]1[CH:50]=[C:51]([F:56])[CH:52]=[C:53]([F:55])[CH:54]=1)[C:38]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:11]1)=[O:39])=[N+:35]=[N-:36]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2R,5R)-2-(2-(3-amino-5-fluoropyridin-4-yl)ethyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-4-carboxylate (Example 89, step 4) (64 mg, 0.13 mmol) and (2S,3S)-2-azido-3-(3,5-difluorophenyl)-3-(4-fluorophenyl)propanoic acid (43 mg, 0.13 mmol) in pyridine (0.5 mL) was cooled to −10° C. in an ice-acetone bath. To the stirred solution was added POCl3 (0.014 mL, 0.15 mmol) and the mixture was stirred for 30 min. The reaction was quenched by the addition of aqueous NaHCO3 solution and the resulting mixture was extracted with two portions of EtOAc. The combined EtOAc layers were dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-80% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a gum. LC MS: RT=1.48 min, M+H=784 (2 min gradient)
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[N+]=[N-].C1CCC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CNS(=O)(=O)c1ccc(CN=[N+]=[N-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCC=C1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(CN)cc1
Temperature: 65 °C

Procedure:
A mixture of 4-azidomethyl-N-methyl-benzenesulfonamide (2.20 g, 10.0 mmol), cyclohexadiene (8.90 mL, 90.0 mmol) and palladium hydroxide (20% on carbon, 1.4 g, 2.0 mmol) in MeOH (20 mL) was warmed at 65° C. for 2 hours. The solution was cooled to room temperature and filtered through diatomaceous earth. The solvent was removed in vacuo to afford 4-aminomethyl-N-methyl-benzenesulfonamide
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[CH3:20][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N:4]2[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]2)[N:19]=1
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)nc1-n1ccc(C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-1H-pyrazole (1.1 g, 13.4 mmol) in DMF (5 ml) was added sodium hydride (1.0 g, 60% in oil) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then. A solution of methyl 2-chloro-6-methylnicotinate (4.3 g, 23.16 mmol) in DMF (5 mL) was added dropwise to the reaction mixture at 0° C. After addition, the mixture was heated to 80° C. and stirred for 12 h. After this time, the mixture was poured into ice-water and extracted and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo and then purified by normal phase silica gel column (EtOAc/hepate) to provide methyl 6-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinate as a brown semi-solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:46]([C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([Cl:39])[CH:41]=3)(=[O:48])=[O:47])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccc(Cl)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
Diisopropylethylamine (0.3 mL, 1.7 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 3-Chlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 110 mg, 0.52 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(3-chloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (97 mg, 56%) as a white solid. MS cald. for C24H24ClFNO4S [(M+H)+]: 476, obsd. 476.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](Cl)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C@H:24]([NH:34][CH3:35])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C@H:24]([N:34]([CH3:35])[C:10](=[O:11])[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)([CH3:14])[CH3:13])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1N(C)C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 2-(3,5-dichloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2005002577) (127 mg, 0.50 mmol) in CH2Cl2 (5 ml) was added drop wise to a stirred solution of ((3S,4R)-1-benzyl-4-o-tolyl-pyrrolidin-3-yl)-methyl-amine (the preparation of which is described herein above) (135 mg, 0.48 mmol) and ethyl-diisopropyl-amine (0.12 ml, 0.72 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:3) yielded 0.18 g (75%) of the title product as colorless oil.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:15]=2)[C:10]([NH:32][C:33](=[O:47])[C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)=[N:9]1)=O)(C)(C)C.C(Cl)Cl.CO>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:46][N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([C:33]([NH:32][C:10]3[C:11]4[C:16](=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH:20]=5)=[CH:13][CH:12]=4)[NH:8][N:9]=3)=[O:47])=[CH:39][CH:38]=2)[CH2:45][CH2:44]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4cc(OCc5cccc(Oc6ccccc6)c5)ccc34)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4cc(OCc5cccc(Oc6ccccc6)c5)ccc34)cc2)CC1
Yield: 97.1 %

Procedure:
A solution of 3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-6-(3-phenoxy-benzyloxy)-indazole-1-carboxylic acid tert-butyl ester (87 mg, 0.137 mmol) in DCM/TFA 8:2 (5 ml) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure and the residue purified by flash chromatography over silica gel eluting with DCM/MeOH/30% NH3 90:10:1 affording 71 mg (yield: 97%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[CH3:2].Cl.[NH2:18][OH:19]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13](=[N:18][OH:19])[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOCCCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCOCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Ethoxyhexyl)-4-piperidone oxime is prepared from 1-(6-ethoxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:34])[N:14]([CH3:33])[N:15]=[C:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[C:17]=1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[H-].[Na+]>CN(C=O)C.O>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12]1[C:13](=[O:34])[N:14]([CH3:33])[N:15]=[C:16]([CH2:28][O:29][CH2:30][O:31][CH3:32])[C:17]=1[O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:11]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(=O)(=O)c2ccc(C)cc2)c(COCOC)nn(C)c1=O
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(COCOC)nn(C)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-(4-methylphenylsulfonyl)-2-methyl-3(2H)-pyridazinone (2.38 g, 4.91 mmol) and benzylalcohol (797 mg, 7.37 mmol) in dry DMF (10 ml) was added 60% sodium hydride (294 mg, 7.35 mmol) at 5° C. The reaction solution was stirred at 0° C. for 1 hour. The reaction solution was diluted with water, and extracted with tert-butyl methyl ether 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 2.12 g of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-benzyloxy-2-methyl-3(2H)-pyridazinone (yield: 99%) as oil.
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10](O)=[O:11])[NH:5][C:4]=2[C:3]=1[N:13]([CH3:22])[S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:16])=[O:15].[NH2:23][CH2:24][C:25]1([S:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C.O1CCCC1>[CH2:39]([S:38][C:25]1([CH2:24][NH:23][C:10]([C:6]2[NH:5][C:4]3[C:3]([N:13]([CH3:22])[S:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)(=[O:16])=[O:15])=[C:2]([CH3:1])[S:9][C:8]=3[CH:7]=2)=[O:11])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(SCc2ccccc2)CC1
Reactant: Cc1sc2cc(C(=O)O)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1sc2cc(C(=O)NCC3(SCc4ccccc4)CCNCC3)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a mixture of 2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (1.0 g), tert-butyl 4-(aminomethyl)-4-(benzylthio)piperidine-1-carboxylate (944 mg), 1H-1,2,3-benzotriazol-1-ol (0.6 g), tetrahydrofuran (20 mL) and acetonitrile (20 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.8 g), and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give a colorless oil. To a solution of triphenylphosphine oxide (2.34 g) in acetonitrile (20 mL) was slowly added trifluoromethanesulfonic anhydride (0.71 mL) at 0° C., the mixture was stirred for 10 min, and the colorless oil was added. The reaction mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-{[4-(benzylthio)piperidin-4-yl]methyl}-2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxamide (1.03 g, yield 79%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:20→1:1, volume ratio). melting point 222° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[CH3:15][NH:16][CH3:17].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:16]([CH3:17])[CH3:15])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: CNC
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
Product: COC(=O)c1cc(I)cc(C(=O)N(C)C)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 5-iodo-isophthalic acid monomethyl ester (3.00 g, 9.8 mmol) in N,N-Dimethylformamide (80 ml) was added dimethyl amine(2M solution in Tetrahydrofuran, 9.8 m, 79.61 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 3.72 g, 9.8 mmol), and finally di-iso-propyl ethyl amine (5.1 ml, 29.41 mmol), this mixture was stirred at room temperature over night. The solvent was stripped under reduced pressure and the crude purifies by silica gel chromatography to give afford 5-Iodo-N,N-dimethyl-isophthalamic acid methyl ester (2.46 g, 75%). MS: m/z 333.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[C:6](=[C:12]([N+:16]([O-])=O)[CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]>O1CCOCC1.[Ni]>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[C:6](=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1C(=O)OCC
Agent: [Ni]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(N)c1C(=O)OCC

Procedure:
69.7 g (0.26 mol) of 3-nitrophthalic acid diethyl ester in 690 ml of dioxane are hydrogenated in the presence of 7 g of a Raney nickel catalyst to give 3-aminophthalic acid diethyl ester. The reaction solution is filtered and 30.4 g (0.31 mol) of maleic anhydride are added, at room temperature, to the filtrate. The reaction mixture is kept at 25° C. for 12 hours and then concentrated in vacuo. 75 ml of acetic anhydride and 12.7 g of sodium acetate are added to the residue and the mixture is heated to 80° C. for 45 minutes and diluted with 500 ml of water. The crystalline precipitate is rinsed with water and dried in vacuo at 45° C. 68 g (82% of theory) of crystalline 3-maleimidyl-phthalic acid diethyl ester are obtained; melting point 86°-90° C. When the product is recrystallised from ethanol, the melting point rises to 92°-93° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2.C(Cl)(Cl)(Cl)[Cl:24].C1C(=O)N(Cl)C(=O)C1>CN1C(=O)CCC1>[Br:1][C:2]1[C:14]([Cl:24])=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: O=C1CCC(=O)N1Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Temperature: 45 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a mixture of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (90 g, 249 mmol), CCl4 (2900 mL), and NMP (600 mL) was added NCS (36.1 g, 271 mmol). The reaction mixture was stirred at 45° C. for 2 h. After cooling to room temperature, the solid was collected by vacuum filtration. The solid was stirred in methanol (1 L) at 60° C. for 2 h and then cooled to room temperature. The solid was collected and dried to give ethyl 5-bromo-8-carbamoyl-6-chloro-9H-carbazole-2-carboxylate (69.5 g, 167 mmol, 67% yield) (95% purity).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]([CH3:11])[C:7]1=[O:12].C([N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1)(=O)C.CO>C(#N)C>[CH3:11][N:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:4]#[C:3][CH2:2][N:18]2[C:19]([CH3:21])=[CH:20][N:16]=[CH:17]2)[C:7]1=[O:12]
Reactant: Cn1ccn(CC#CCBr)c1=O
Reactant: CC(=O)n1cnc(C)c1
Solvent: CO
Solvent: CC#N
Product: Cc1cncn1CC#CCn1ccn(C)c1=O
Temperature: 85 °C
Yield: 79.6 %

Procedure:
A mixture of 1-(4-bromo-2-butynyl)-1,3-dihydro-3-methyl-2H-imidazol-2-one (4.12 g, 0.018 mol) and 1-acetyl-4-methylimidazole (4.47 g, 0.036 mol) in acetonitrile (6 mL) was heated in an oil bath (bath temperature 85° C.) for 1 hr. Methanol (20 mL) was added and, after 1 hr, the solvents were removed and the residue was partitioned between ethyl acetate and 4N NaOH solution. The ethyl acetate was removed and the residual oil was chromatographed on silica gel using methanol:chloroform as eluant to give 3.3 g of product.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.BrC1C=C(C(NC2C(C(NC(C)C)=O)=CC([Cl:38])=CC=2C)=O)N(C2C(Cl)=CC=CN=2)N=1.BrC1C=C(C(NC2C(C(NC)=O)=CC(Cl)=CC=2C)=O)N(C2C(Cl)=CC=CN=2)N=1>>[Cl:38][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)NC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Product: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl

Procedure:
The following Example 9 illustrates an alternative preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 3-bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide and 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, by further steps illustrated in Examples 5 and 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.7 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-nonadienoic acid (3.12 g) and 4-nitrophenol (2 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.49 g) and the mixture was stirred at room temperature for 3 days. After the normal work up, crystallization of the crude product from 2-propanol yielded 3.55 g of (E,E)-5-(4-methoxyphenyl)-2,4nonadienoic acid 4-nitrophenyl ester, mp 78°-80° C., resolidified and remelted at 115° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([C:15]2[S:19][C:18]([CH:20]=[O:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[BH4-].[Na+]>C1COCC1.C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]2=[N:12][S:13][N:14]=[C:10]2[C:9]([C:15]2[S:19][C:18]([CH2:20][OH:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)c3nsnc23)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(-c3cccs3)c3nsnc23)s1
Reaction time: 0.33 h
Yield: 99.2 %

Procedure:
To a solution of TBT-CHO (1.4 g, 4.27 mmol) in 80 mL THF and 5 mL dry ethanol was added 163.4 mg (4.3 mmol) sodium borohydride in small portions. The reaction mixture quickly changed color from red to orange and the stirring was continued for 20 min. Removal of the solvent under reduced pressure followed by purification with flash silica gel column chromatography using chloroform as eluent yielded orange crystals (1.4 g, 99.4%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:24][C:25](=[CH2:27])[CH3:26].C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:25]([O:17][C:16]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:10]([NH2:14])[C:9]2=[O:15])=[O:18])([CH3:27])([CH3:26])[CH3:24]
Reactant: C=C(C)C
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.04 mole) is added to 100 ml of dioxane, 10 ml of concentrated sulfuric acid and 50 ml of liquid isobutylene in a pressure bottle. The mixture is shaken overnight. The bottle is chilled, opened and the contents poured into an ice cold solution of sodium bicarbonate. Extraction of the aqueous phase with ethyl acetate followed by drying and evaporation of the ethyl acetate phase gives the title compound, M.P. 111°-112° C. See J. Med. Chem., 9, 444 (1966).