Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>O.CO.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)c2cccc(N)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution tert-butyl (3-{[(3-nitrophenyl)sulfonyl]amino}phenyl)carbamate (0.51 g, 0.0013 mol) in water (1 mL), methanol (5 mL) and acetic acid (2 mL) was added iron (290 mg, 5.2 mmol) powder in one batch. The mixture was stirred at 0° C. for 0.5 h. The reaction mixture was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated, followed by the addition of EtOAc and NaHCO3/water. The aqueous phase was extracted with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a yellow powder (0.46 g, 98%). LCMS for C17H21N3O4S (M-tBu+H)+: m/z=308.0. 1H NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.31 (s, 1H), 7.33 (br, 1H), 7.10 (t, J=8.0 Hz, 1H), 7.02 (m, 1H), 6.93 (t, J=2.0 Hz, 1H), 6.85 (ddd, J=7.6, 1.8, 1.0 Hz, 1H), 6.67 (m, 1H), 5.53 (s, 1H), 1.43 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH:5]1[C:14]2[S:13][C:12]([C:15](=[O:17])[NH2:16])=[N:11][C:10]=2[C:9]2[CH:18]=[C:19]([C:22]#[C:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH:20]=[CH:21][C:8]=2[O:7][CH2:6]1.[Li+].[OH-]>CO>[C:15]([C:12]1[S:13][C:14]2[CH:5]([CH2:4][C:3]([OH:28])=[O:2])[CH2:6][O:7][C:8]3[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([OH:27])([CH3:26])[CH3:25])=[CH:18][C:9]=3[C:10]=2[N:11]=1)(=[O:17])[NH2:16]
Reactant: COC(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(CC(=O)O)CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2-Carbamoyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-4-yl]-acetic acid methyl ester in MeOH (5 mL) was added 4 mol/L aqueous solution of LiOH (0.2 mL) and the reaction mixture was stirred at room temperature for 2 h. Then the mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and triturated with EtOAc and hexane (1:1) to afford [2-Carbamoyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-4-yl]-acetic acid (20 mg) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.66 (br, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.46 (s, 1H), 7.88 (s, 1H), 7.28 (dd, J1=8.36 Hz, J2=2.2 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.45 (s, 1H), 4.5 (m, 1H), 4.16 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 1.48 (s, 6H); LC-MS (ESI & APCI): 387.6 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:19][NH:20][CH3:21]>C(O)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:15])[CH2:13][N:20]([CH3:21])[CH3:19])=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Reactant: CNC
Solvent: CCO
Product: CCCCc1ccc(NC(=O)CN(C)C)c([N+](=O)[O-])c1

Procedure:
A suspension of N-(4-n-butyl-2-nitrophenyl)-2-bromoacetamide (41 g) in ethanol (200 ml) was treated with a solution of dimethylamine in ethanol (90 ml of 20% w/w). The mixture was refluxed for one hour and the ethanol was evaporated off. Water (100 ml) was added and the mixture extracted with diethyl ether (3 × 200 ml). The extract was dried over magnesium sulphate, filtered and evaporated to give N-(4-n-butyl-2-nitrophenyl)-2-dimethylaminoacetamide as a yellow oil which was used without further purification in the next stage.
Reaction SMILES: [C:1]([C:3]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH:9]1[CH2:8][CH2:7][C:6]2([C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:3]([C:1]#[N:2])=[CH:4][CH2:5]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC=C(C#N)c3ccccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1=CCC2(CCNCC2)c2ccccc21

Procedure:
A solution of the nitrile (A3) (300 mg) in dichloromethane (3 ml) was treated with TFA (1 ml) for 1 hour, concentrated, co-evaporated with acetonitrile and dissolved in dichloromethane (ca. 100 ml). The resulting solution was washed with a mixture of brine (ca. 20 ml) and 6N NaOH (2 ml), dried over Na2SO4, and concentrated to give 2H-spiro[naphthalene-1,4′-piperidine]-4-carbonitrile (A4) as a white solid. LC-MS: m/e=225.2 (M+H). Rt=1.53 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[I:19])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>CCO>[C:4]([C:6]1[C:7]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[I:19])=[N:8][O:9][C:10]=1[CH3:11])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2c(F)cccc2I)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2c(F)cccc2I)c1C(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a solution of 4-ethoxycarbonyl-5-methyl-3-(2-iodo-6-fluoro-phenyl)isoxazole (7.15 g, 19 mmol) in EtOH (100 ml) was added 5N NaOH (7.6 ml, 38 mmol, 2 eq.), and stirred in a 50° C. oil bath for 4 hrs. The reaction was cooled to room temperature, poured into ice H2O and extracted with Et2O. The aqueous layer was then acidified to pH 3 using conc. HCl and extracted with ethyl acetate. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound (6.08 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: Cc1ccccc1-n1ccc2c(NCCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 180 °C

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(600 mg, 1.5 mmol), prepared by the procedures of Step 1 and Step 2 in the Example 34, was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 3 hours. After removing the excess 3-amino-1-propanol by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 522 mg of desired compound as solid in 81% of yield.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.C([Si](C)(C)[O:21][CH2:22][C:23]#[C:24][C:25]([OH:27])=O)(C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1>O1CCCC1.N1C=CC=CC=1.C(OCC)(=O)C>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:25](=[O:27])[C:24]#[C:23][CH2:22][OH:21])[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cnc2ccc(NC(=O)C#CCO)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.214 g, 1.57 mmol) and N-methylmorpholine (0.190 g, 1.88 mmol) were added to an ice cold solution of 0.336 g (1.57 mmol) of 4-(tert-butyl-dimethyl-silanyloxy)-2-butynoic acid in 15 mL of tetrahydrofuran under N2. After stirring for 30 min, it was transferred to an additional funnel plugged with a glass wool and added dropwise to a solution of 0.4 g (1.18 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 3 mL of tetrahydrofuran and 1.5 ml of pyridine. The mixture was stirred at 25° C. for 1 h. The reaction solution was poured into ethyl acetate and washed with saturated sodium bicarbonate and brine. The product was collected and purified by flash column chromatography (60% ethyl acetate in hexane) to give 0.220 g of
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([OH:13])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C@H:6]([OH:13])[CH2:5][CH2:4]1)[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CN[C@@H]1CC[C@@H](O)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CC[C@@H](O)c4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,4R)-1,2,3,4-tetrahydro-4-(methylamino)-1-naphthalenol and its enantiomer (70 mg, 0.39 mmol) (i.e. the product of Example 28, Step A) and triethylamine (0.082 mL, 0.59 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (181 mg, 0.43 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 3 h, diluted with 5 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 0-20% of acetone in ethyl acetate as eluant to give 160 mg of the title compounds, compounds of the present invention as a white foam.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:41][CH3:42])[C:32]1[O:33][CH2:34][C@@H:35]([C:37]([O:39]C)=[O:38])[N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:41][CH3:42])[C:32]1[O:33][CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCN(C1=N[C@H](C(=O)OC)CO1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(C1=N[C@H](C(=O)O)CO1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
Methyl (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylate (190 mg) is dissolved in methanol (4 ml) and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→4:1) to give (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid (130 mg). The resulting (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid (130 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (180 μl) and concentrated under reduced pressure to give (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid sodium salt (120 mg). MS (m/z): 729 [M−Na]−
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[N:5]=[C:4]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([C:22](=[O:27])[NH:23][NH:24]3)=[CH:20][CH:19]=2)[N:3]=1.Cl.[CH3:29][O-:30].[Na+]>CO>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([O:30][CH3:29])[N:3]=[C:4]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22](=[O:27])[NH:23][NH:24]5)=[CH:20][CH:19]=4)[N:5]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: O=c1[nH][nH]c2cc(Nc3nc(Cl)nc(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Nc2ccc3c(=O)[nH][nH]c3c2)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.8 %

Procedure:
(6-[4-Chloro-6-(5-cyclopropyl-2H-pyrazol-3-ylamino)-[1,3,5]triazin-2-ylamino]-1,2-dihydro-indazol-3-one (70 mg, 0.14 mmol) was dissolved in 6 ml of 0.5 M solution of sodium methoxide in methanol and stirred at room temperature for 3 hours. The reaction was neutralized to pH 6–7 with 0.5 N hydrogen chloride. The cloudy solution was concentrated in vacuo. The resulting yellow solid was suspended in water, filtered, then purified by prep HPLC to afford 7.5 mg of the desired product as a white solid (10.8% yield). H-NMR(DMSO-d6, 500 mHz) δ 10.96(s br, 1H), 9.76(s br, 1H), 7.90(s br, 1H), 7.44(d, 1H), 7.18(m, 1H), 6.02(s br, 1H) 3.85(s, 3H), 1.80(s br, 1H), 0.84(m, 2H), 0.61(s br, 2H). MS (ES+): m/e=380.1 (M+H), 378.1 (M−H); LC/Method A/3.543 min, 90.0% purity by area %.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(O)(=O)C.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH:16]=O.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:16][C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[CH:4][CH:3]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: Nc1ccc(Br)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1cccc(F)c1CNc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.1 %

Procedure:
To a solution of 6-bromopyridin-3-amine (500 mg, 2.89 mmol), in MeOH (3 mL), acetic acid (0.165 mL, 2.89 mmol), 2,6-difluorobenzaldehyde (0.31 mL, 2.89 mmol) was added. After stirring the resulting mixture at RT for 12 h, sodium cyanoborohydride (363 mg, 5.78 mmol) was added at 0° C. and resulting mixture was stirred at RT for 6 h. Solvent was evaporated under vacuum. Residue was purified by column chromatography to afford 200 mg (23%) of the title compound as white solid. GC-MS-298, 300 [M+, Br79,81]
Reaction SMILES: C(O[CH2:4][CH2:5]O)C.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24]C=[CH:22][N:21]=2)[CH:15]=1>O>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:4]([CH3:5])=[CH:22][N:21]=2)[CH:15]=1
Reactant: Cc1ccccc1-c1cccc(-c2ccccn2)c1
Reactant: CCOCCO
Solvent: O
Product: Cc1ccc(-c2cccc(-c3ccccc3C)c2)nc1

Procedure:
To a mixture of 2-ethoxyethanol (95 mL) and water (25 mL) were added 11.0 g (42.4 mmol) of 2-(2′-methylbiphenyl-3-yl)pyridine and 7.9 g (21.2 mmol) of IrCl3. The reaction mixture was heated under a nitrogen atmosphere at reflux for 50 h and cooled. The yellow precipitate that formed was collected by vacuum filtration and washed with methanol and ethyl acetate to give 11.0 g (70%) of chloro-bridged dimer
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].Cl.[Cl:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>CN(C=O)C>[ClH:37].[ClH:1].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][N:30]([CH2:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)[C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1
Reactant: ClCc1cccnc1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCN(Cc6cccnc6)C5=O)c4)CC3)cccc2n1

Procedure:
The title compound was prepared according to the procedure described for Example 156 using 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 14 mg) and 3-chloromethylpyridine hydrochloride (20 mg). Yield, 20 mg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)c1cc(Br)ccc1O
Yield: 12 %

Procedure:
Using 5-bromosalicylic acid and 2-aminothiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15](OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([CH3:15])[CH2:9][CH2:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CCN(C)C2
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To 3,4-dihydro(1H)isoquinoline-2,6-dicarboxylic acid 2-(tert-butyl) ester 6-methyl ester (WO00/09480) (344 mg) dissolved in methylene chloride (6 mL), under ice cooling, trifluoroacetic acid (3 mL) was added, followed by stirring for 30 minutes. The reaction mixture was concentrated, and diluted with chloroform. The resultant mixture was neutralized with saturated aqueous sodium hydrogencarbonate, followed by extracting with chloroform/methanol (4/1). The resultant organic layer was dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1→1:1), to thereby give 1, 2, 3, 4-tetrahydroisoquinoline-6-carboxylic acid methyl ester (154 mg). This material was dissolved in methylene chloride (5 mL), and formalin (90.6 μL) was added thereto at room temperate, followed by stirring for 10 minutes. Under ice cooling, acetic acid (46 μL) and sodium triacetoxyborohydride (269 mg) were added thereto. The mixture was stirred at room temperature for 105 minutes, and neutralized with saturated aqueous sodium hydrogencarbonate. The resultant mixture was extracted with chloroform. The organic layer was dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (162 mg).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 3 h
Yield: 102 %

Procedure:
A mixture of tert-butyl 2-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}morpholine-4-carboxylate 157 (0.35 g, 0.71 mmol) and Pd/C (0.12 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 158 (0.29 g, quantitative yield) as a white foam.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]=O.Cl.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CC(O)=O.O1CCOCC1>CCOC(C)=O.CCCCCC>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[N:28]=[CH:13][C:5]3[C:4](=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:15])=[CH:25][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(NN)cc1
Reactant: COC(=O)c1c(C=O)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-n2ncc3cccc([N+](=O)[O-])c3c2=O)cc1
Temperature: 200 °C

Procedure:
A solution of the aldehyde (Step C, 0.58 g, 3.3 mmol), 4-t-butylphenylhydrazine-HCl (0.66 g, 3.3 mmol), AcOH (1 mL), and dioxane (3 mL) in a sealed reaction vial was heated at 200° C. for 20 min in a microwave. Upon cooling, the residue was diluted with EtOAc (10 mL), then hexane (10 mL). The resulting precipitate was filtered to afford the desired compound as a tan solid. MS m/e 324 (M+H)+. Calc'd for C18H17N3O3-323.35.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].F[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:27][C:26]1[CH:28]=[CH:29][C:23]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:19]=[CH:20][CH:21]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[C:24]([N+:30]([O-:32])=[O:31])[CH:25]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3[N+](=O)[O-])c2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxyphenyl)benzamide (20 g, 71.3 mmol) produced in Example 1(i) and 4-fluoro-3-nitroaniline (10.9 g, 69.9 mmol) in N,N-dimethylformamide (150 mL) was added cesium carbonate (33.8 g, 104 mmol), and the mixture was stirred at 80° C. for 16 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off and washed with ethyl acetate. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed successively with water (300 ml) and saturated brine (150 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (23.8 g, 82%) as a red-orange powder.