Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].[N+:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])([O-:14])=[O:13]>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[C:9]1[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCCCn1cccc1CC
Solvent: Cc1ccccc1
Product: CCCCn1c(CC)ccc1C(=O)c1cccc([N+](=O)[O-])c1
Yield: 27.5 %

Procedure:
A solution of 19 g (160 mmol) of 1-butyl-2-ethylpyrrole in 300 ml of toluene was treated with 38 g (200 mmol) of m-nitrobenzoyl chloride. The reaction mixture was refluxed under nitrogen atmosphere for 18 hours, cooled and purified by column chromatography on 1 Kg of deactivated alumina (containing 3% water), using hexane-acetone (90:10) as eluant. There were obtained 13.2 g (35%) of 1-butyl-2-(3'-nitrobenzoyl)-5-ethylpyrrole, the title compound, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1.FC1C=C(F)C=CC=1CN1C2=CN=C(C(OCC)=O)C=C2C(COCC)=C1.C(OCC1C2C(=CN=C([C:71]([NH:73][OH:74])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.Cl.CNO>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:73]([OH:74])[CH3:71])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Agent: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)OCC)cc12
Agent: CNO
Agent: Cl
Product: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)N(C)O)cc12

Procedure:
1-(2,4-Difluorobenzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(2,4-difluorobenzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6). δ: 8.96 (s, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.08-7.40 (m, 2H), 7.07 (m, 1H), 5.62 (s, 2H), 4.63 (s, 2H), 3.48 (q, 2H, J=7.0 Hz), 1.11 (t, 3H, J=7.0 Hz). LCMS (API-ES, M+H+): 347.0. (b) 1-(2,4-Difluorobenzyl)-3-ethoxymethyl-N-hydroxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and N-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ: 8.81 (s, 1H), 8.27 (s, 1H), 7.71 (s, 1H), 7.29 -7.30 (m, 1H), 6.98 -7.30 (m, 2H), 5.58 (s, 2H), 4.72 (s, 2H), 3.59 (q, 2H, J=7.0 Hz), 3.43 (s, 3H), 1.20 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 376.1. HRMS calcd for C19H20F2N3O3 (M+H) 376.1473, found 376.1454. Anal. (C19H19F2N3O3×0.2H2O) C, H, N. HPLC: 100% purity.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:19](=[O:20])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[O:30]=[C:31]1[N:35]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:34]2[CH:42]=[CH:43][CH:44]=[CH:45][C:33]=2[NH:32]1.[I-].[Na+]>C(OCC)(=O)C.O.CN(C=O)C>[O:30]=[C:31]1[N:35]([CH:36]2[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][CH2:4][CH:5]3[C:19](=[O:20])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:40][CH2:41]2)[C:34]2[CH:42]=[CH:43][CH:44]=[CH:45][C:33]=2[NH:32]1
Reactant: O=C1c2c(-c3ccccc3)noc2CCC1CCCCl
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3)noc2CCC1CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 78 °C
Yield: 27.9 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one (4.19 g) and DMF (150 ml) was added diisopropylethyl amine (6.31 ml), 4-(2-keto-1-benzimidazolinyl)piperidine (3.46 g) and sodium iodide (2.17 g) at room temperature with stirring. The reaction was heated at 78° C. under nitrogen atmosphere with stirring (11hours). Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer extracted three times with ethyl acetate and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash chromatography (silica gel, 1% methanol/2% Et3N/ether) afforded 1.90 g of 6,7-dihydro-5-[3-(4-(2-keto-1-benzimidazolinyl)-1-piperidinyl)-propyl]-3-phenyl-1,2-benzisoxazol-4(5H)-one, m.p. 212°-218° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:49])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:24]=3[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:12]([CH2:45][CH2:46][CH3:47])[C:11]=2[OH:48])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:50](OC(=O)C)(=[O:52])[CH3:51]>N1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9](=[O:49])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:24]=3[O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[C:12]([CH2:45][CH2:46][CH3:47])[C:11]=2[O:48][C:50](=[O:52])[CH3:51])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1c(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)ccc(C(=O)OCc2ccccc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)ccc(C(=O)OCc2ccccc2)c1OC(C)=O

Procedure:
A solution of 1.15 g of 2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl ester in 15 mL of pyridine and 15 mL of acetic anhydride was stirred and heated at 50° for 15 hours. The reaction mixture was concentrated on the oil pump. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate solution, dried and concentrated under reduced pressure to give 1.03 g of 2-acetyloxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl ester as an oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:27]4[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-])=O)[CH:28]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]>[Pd].CO.C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:27]4[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)c([N+](=O)[O-])c4)nc(N4CCOCC4)c3s2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)c(N)c4)nc(N4CCOCC4)c3s2)CC1
Yield: 52.4 %

Procedure:
4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-2-nitro-phenylamine (200 mg) was stirred under hydrogen balloon with palladium on carbon (10%, 70 mg) in a mixture of MeOH and DCM (1:1, 10 ml) at room temperature overnight. The reaction mixture was then filtered through Celite®, volatiles removed in vacuo, and the residue purified by flash chromatography to give 4-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine (99 mg).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([C:44](Br)=[CH:45][N:46]=1)[C:40]([O:42][CH3:43])=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CN1C(=O)CCC1>[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([C:44]([CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])=[CH:45][N:46]=1)[C:40]([O:42][CH3:43])=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ncc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN1CCCC1=O
Product: COC(=O)C=Cc1cnc(OCc2ccccc2)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To NMP (1 mL) was added methyl acrylate (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), tri-o-tolylphosphine (8.5 mg, 28 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and palladium diacetate (2.5 mg, 11 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The solution was degassed three time with nitrogen. To this solution was then added a 1 mL NMP solution of methyl 2-(benzyloxy)-5-bromoisonicotinate (120 mg, 372 μmol). The reaction was stirred at 90° C. overnight and then purified by column chromatography (silica gel, 10% EtOAc/hexane) to give desired product H6.2 (50.2 mg, 41.4%). MS ESI (pos.) m/e: 328.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-])=O.[NH4+].[Cl-].C(OCC)(=O)C>CCO.O.[Fe]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc2cnccc12
Temperature: 80 °C
Reaction time: 10 h
Yield: 54 %

Procedure:
To a solution of 5-nitro-isoquinoline (150 g, 0.861 mol) in EtOH/H2O=4:1 (5 L) was added NH4Cl (92.2 g, 1.723 mol) and Fe (193 g, 3.445 mol) at room temperature. Then the mixture was heated to 80° C. and stirred for 10 hours. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was cooled to room temperature and filtered though a pad of celite. The filter cake was washed with EtOH (2 L×2). The filtrate was concentrated in vacuo to remove most of EtOH. The residue was extracted with EtOAc (500 ml×10). The combined layers were dried over Na2SO4, filtered and then concentrated in vacuo to afford 5-amino-isoquinoline (67 g, 54%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[CH3:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][O:22][CH3:21])=[N:26][N:27]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: COCC(=O)NN
Solvent: CCCCO
Product: COCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-7-chloro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 8-chloro-1-(methoxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:22]([OH:24])[CH3:23])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=[O:19])[O:9][CH2:8]1.C(N(CC)CC)C.CCOP(Cl)(OCC)=O>O1CCCC1>[CH3:1][C@@H:2]([CH:22]([OH:24])[CH3:23])[CH:3]1[O:5][CH:4]1[CH2:6][C@H:7]1[C@H:12]([OH:13])[C@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=[O:19])[O:9][CH2:8]1
Reactant: C/C(=C\C(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: CCOP(=O)(Cl)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C/C(=C\C(=O)O)C[C@@H]1OC[C@@H](CC2OC2[C@@H](C)C(C)O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of monic acid (1.032 g; 3 mM) and triethylamine (0.420 ml; 3 mM) in dry tetrahydrofuran (50 ml) was added diethyl phosphorochloride (0.518 g; 3 mM), at room temperature under an argon atmosphere. The mixture was stirred at room temperature for three hours and precipitated triethylamine hydrochloride was removed by filtration. The solid was washed with tetrahydrofuran and to the combined filtrate and washings was added the sodium salt of N-acetyl-β-mercaptoethylamine (0.423 g; 3 mM). The resulting suspension was stirred at room temperature for three days and then filtered through a celite plug. The solvent was removed at reduced pressure and the residue partitioned between ethyl acetate and sodium bicarbonate solution. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulphate. Removal of the solvent at reduced pressure gave the crude thiol ester as a pale yellow oil. This oil was purified by column chromatography over silica gel (Type 60; 50 g). Elution with 5% methanol/chloroform afforded the pure 2-acetamidoethanethiol ester of monic acid A as a colourless oil, (0.310 g; 23%). [α]D20 -7.04° (c, 1.0 CHCl3)νmax (CHBr3) 3350, 1660 and 1625 cm-1, λmax (EtOH) 240 nm (εm 9,630), 267 nm (εm 8,390), δH (CDCl3) 6.67 (1H, broad resonance, NH); 6.02 (1H, s, CH=C); 2.17 (3H, s, CH3 --15); 1.94 (3H, s, COCH3); 1.19 (3H, d, J=6.0 Hz, CH3 --14); 0.92 (3H, d, J=6.5 Hz, CH3 --17), δc (CDCl3), 189.3, 171.0, 155.7, 124.2, 75.0, 71.1, 70.4, 68.9, 65.5, 61.1, 55.7, 42.8, 39.9, 31.7, 28.5, 23.1, 20.8, 20.3, and 12.6. m/e 327.1799 (3% C17H27O6 requires 327.1808).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35]Br)[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13].CN(C=O)C>CC(C)=O>[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35][O:8][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13]
Reactant: O=C(O)C1CCCCC1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C1CCCCC1
Yield: 88.2 %

Procedure:
In 20 ml of acetone is dissolved 0.64 g of cyclohexanecarboxylic acid, and 2.5 ml of 2N-NaOH and then 1.0 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 20 ml of DMF are serially added to the above solution. The mixture is refluxed for 5 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is then chromatographed on a silica gel column. Following passage of 200 ml of n-hexane-diisopropyl ether (6:4), elution is carried out with 600 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.98 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1)[CH:2]=[CH2:3].CN(C)C=[O:20]>O.C(OCC)(=O)C.[Pd](Cl)Cl>[O:20]=[C:2]([CH3:3])[CH2:1][C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[CH2:5]1
Reactant: CN(C)C=O
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(=C(C)C)N1C(=O)C[C@H]1CC(C)=O
Reaction time: 3.5 h

Procedure:
A mixture of methyl 2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (100 mg), palladium chloride (16 mg) and cuprous chloride (44 mg) in a mixture of dimethylformamide (1 ml) and water (0.12 ml) was stirred under an oxygen atmosphere for 3.5 hours. The reaction mixture was diluted with ethyl acetate (20 ml), and filtered. The filtrate was washed with water and brine. The combined aqueous layer was extracted with ethyl acetate (10 ml×2) and the extract was washed with brine. The organic layers were combined, and dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed on silica gel (1 g) eluting with methylene chloride and acetone (100:2-100:5) to give methyl 2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (89 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11](Cl)=[C:10]([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:43][C:44]([F:58])([F:57])[C:45]1[CH:46]=[C:47]([Mg]Br)[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1.FC(F)(F)C1C=C(Br)C=C(C(F)(F)F)C=1>O.C1COCC1>[CH3:1][C:2]1[C:11]([C:47]2[CH:48]=[C:49]([C:51]([F:54])([F:52])[F:53])[CH:50]=[C:45]([C:44]([F:43])([F:58])[F:57])[CH:46]=2)=[C:10]([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(C)c1Cl
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Agent: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccccc2c(C)c1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a THF solution of the obtained 2,4-dimethyl-3-chloroquinoline (0.65 g) and Ni(dpp)Cl2 (dpp: 1,3-bis(diphenylphosphino)propane) (0.1 g), 3,5-bis (trifluoromethyl)phenylmagnesium bromide prepared from Mg and 3,5-bis(trifluoromethyl)bromobenzene was dropped and the reaction solution was allowed to react for 24 hours at room temperature. Water was added to the reaction solution and the organic layer was extracted using CHCl3. The solvent was removed under reduced pressure and the residue was purified through column chromatography to obtain 2,4-dimethyl-3-[3,5-bis(trifluoromethyl)phenyl]quinoline.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9].[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: NCCCO
Reactant: Cc1cc[n+]([O-])c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: Cc1cc[n+]([O-])c(NCCCO)c1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A mixture of 2-chloro-4-methylpyridine-N-oxide (12.1 g, 0.068 mole) (Brown, E. V. J. Amer. Chem. Soc. 1957, 79, 3565), 3-amino-1-propanol (10.33 mL, 0.14 mole), NaHCO3 (28 g, 0.34 mole), and tert-amyl alcohol (70 mL) was heated to reflux. After 16 hr, the reaction was cooled, diluted with CH2Cl2 (300 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene to leave a yellow oil. Recrystallization from CH2Cl2/Et2O gave the title compound (10.87 g, 88%) as a yellow solid: TLC (15% MeOH/CH2Cl2) Rf 0.44; 1H NMR (400, CDCl3) δ 7.92 (d, J=6.7, 1 H), 7.28 (br t, 1 H), 6.43 (s, 1 H), 6.33 (dd, J=6.6, 2.1 Hz, 1 H), 3.73 (t, J=5.7 Hz, 2 H), 3.47 (q, H=6.3 Hz, 2 H), 2.29 (s, 3 H), 1.82-1.88 (m, 2 H); MS (ES) m/e 183 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][CH:8]=[CH:7]2.[CH3:14][C@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[N:9]([CH2:14][C@@H:15]([OH:16])[CH3:17])[CH:8]=[CH:7]2
Reactant: Fc1cc2cc[nH]c2cc1F
Reactant: C[C@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C[C@H](O)Cn1ccc2cc(F)c(F)cc21
Reaction time: 1 h
Yield: 74 %

Procedure:
A suspension of 0.12 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 5,6-difluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.46 mlof (S)-methyloxirane the reaction mixture was stirred at room temperature for 60 hours and subsequently treated with water. The mixture was diluted with ether, washed twice with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 35 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.5 g (74%) of (S)-1-(5,6-difluoro-indol-1-yl)-propan-2-ol as yellowish crystals with m.p. 116°-118°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.ClCCl.[N:23]1([C:29]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:30]=2[NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O>[N:23]1([C:29]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][C:30]=2[NH:31][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
4-Nitrobenzoyl chloride (64.2 mg, 0.345 mmol, commercially available product) and triethylamine (120 μl, 0.859 mmol) were sequentially added at 0° C. to a dichloromethane (2 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (51.2 mg, 0.209 mmol), obtained as described in Referential Example 1-2. The resulting mixture was warmed to room temperature and stirred for 60 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=8/1-6/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]-4-nitrobenzamide (GIF-0345) (46.3 mg, 56.3%) was yielded as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:20])[CH3:19])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(4-aminophenyl)ethanone (3.1 g, 22.96 mmol, 1.00 equiv) in dichloromethane (30 mL), triethylamine (4.64 g, 45.94 mmol, 2.00 equiv). This was followed by the addition of acetyl chloride (1.79 g, 22.95 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was washed with 3×50 mL of saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.0 g (74%) of N-(4-acetylphenyl)acetamide as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:8]1[CH2:9][CH2:10][CH:11]([CH3:12])[CH:6]([CH2:4][OH:3])[CH2:7]1)=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCN(C(=O)OC(C)(C)C)CC1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
A flask containing (+/−)-4-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (5.96 g, 21.94 mmol) in dry tetrahydrofuran (40 mL) was cooled to 0° C. (ice bath) under argon atmosphere. A solution of lithium aluminum hydride (19.4 mL, 1M in tetrahydrofuran) was added via slow drop-wise addition. The cooled mixture was stirred for 2 hours. A solution of 1 M hydrochloric acid (23 mL) was added via slow drop-wise addition. After 10 minutes powdered magnesium sulfate was added followed by the addition of ethyl acetate (80 mL). The mixture was filtered through a plug of celite, rinsing well with ethyl acetate. The filtrate was stripped providing 5.08 g of (+/−)-3-hydroxymethyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester as a clear semi-mobile oil. MS (M+Na)+=252.