Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]([CH3:11])[CH:7]1[CH2:10][O:9][CH2:8]1)([CH3:5])[CH:3]=O.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C@@H:36]3[CH2:41][CH2:40][CH2:39][N:38]([C:42](=[O:46])[CH2:43][C:44]#[N:45])[CH2:37]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:24][C:23]=3[F:35])[C:14]=12.N1CCCC1.[Si](Cl)(C)(C)C>>[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([C@@H:36]3[CH2:41][CH2:40][CH2:39][N:38]([C:42]([C:43](=[CH:3][C:2]([CH3:1])([N:6]([CH3:11])[CH:7]4[CH2:10][O:9][CH2:8]4)[CH3:5])[C:44]#[N:45])=[O:46])[CH2:37]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:24][C:23]=3[F:35])[C:14]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CN(C1COC1)C(C)(C)C=O
Agent: C[Si](C)(C)Cl
Solvent: C1CCNC1
Product: CN(C1COC1)C(C)(C)C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
The mixture of 2-methyl-2-[methyl(oxetan-3-yl)amino]propanal (66.69 mg, 0.42 mmol), 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (100 mg, 0.2100 mmol) and pyrrolidine (0.1 mL, 1.27 mmol) was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C., followed by addition of TMS-Cl (0.11 mL, 0.85 mmol). The ice bath was removed and the reaction mixture was stirred for another 1 hour at room temperature, checking process by TLC and LC-MS. The solvent was removed and the resultant residue purified by column chromatography (MeOH, CH2Cl2, MeOH gradient from 0 to 10% to get 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[methyl(oxetan-3-yl)amino]pent-2-enenitrile (118.5 mg) as a white powder. LC-MS (ES, m/z): 612 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:26][OH:27])=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:26][O:27][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:9]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:16][CH2:17]3)[N:10]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: OCc1c(CN2CCN(c3ccc(Cl)cc3Cl)CC2)nc2ccc(Cl)cn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(N2CCN(Cc3nc4ccc(Cl)cn4c3COCc3ccccc3)CC2)c(Cl)c1
Reaction time: 0.12 h

Procedure:
To 6-chloro-2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]imidazo[1,2-a]pyridine-3-methanol (Example 44; 0.0651 g) in THF (1 mL) is added sodium hydride (Aldrich, 60% dispersion in mineral oil; 0.0067 g). After 7 min, benzyl bromide (Aldrich; 0.020 mL) is added and the mixture is stirred for an additional 4.5 h. at which time it is partitioned between dichloromethane and aq. sodium bicarbonate/brine. The organic layers are filtered through sodium sulfate and concentrated, and the residue is chromatographed on silica gel using methanol/dichloromethane (2/98) to give 0.061 g of 6-chloro-2-[[4-(2,4-dichlorophenyl)-1-piperazinyl]methyl]-3-[(phenylmethoxy)methyl]imidazo[1,2-a]pyridine. The methanesulfonic acid salt is prepared by dissolving the product in dichloromethane and adding methanesulfonic acid (1 equivalent) and concentrating the mixture under reduced pressure. Crystallization from ethyl acetate/hexane affords 0.050 g of the title compound; mp 159-160.5° C.; MS m/z 514, 516; IR (mineral oil) 806, 1170, 1042, 1188, 1480 cm-1. 1H NMR (CDCl3) δ2.68, 3.02, 3.75, 4.57, 4.91, 6.92, 7.17, 7.36, 7.53, 8.14.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:41])[C:11]([OH:40])([CH2:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][NH:9][C:10](=[O:41])[C:11]([OH:40])([CH2:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)NOCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-benzyloxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-phenylbenzenesulfonyl)-propionamide (0.152 g), 10% palladium on carbon, and 50 mL of absolute ethanol is placed under 20 psi of hydrogen, and agitated overnight at ambient temperature. The mixture is filtered through a Celite pad, rinsing with ethanol and with ethyl acetate. Concentration of the filtrate affords the title compound.
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.CCN(C(C)C)C(C)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[N:33]1>C(Cl)Cl>[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37]([NH:1][C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([NH:12][C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=5)=[O:14])([CH2:5]4)[CH2:3]2)[CH2:9]3)=[O:38])=[N:33]1
Reactant: Cn1ccc(C(=O)Cl)n1
Reactant: Cc1cccc(C(=O)NC23CC4CC(CC(N)(C4)C2)C3)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2ccn(C)n2)(C4)C3)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a solution of 6-methyl-pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide (Intermediate 1, 20 mg, 0.07 mmol) in DCM (5 mL) was added DIEA (30 mg, 0.2 mmol) and 1-methyl-1H-pyrazole-3-carbonyl chloride (20 mg, 0.1 mmol, Maybridge Chemical Co., Cornwall, UK). After stirring at room temperature for 16 h, the reaction mixture was partitioned into dichloromethane and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient: acetonitrile in water, 25-95%, in 3.9 minutes with a cycle time of 5 min. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium formate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 10 mg (30%) of the title compound, 6-methyl-pyridine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, br, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.26-7.21 (m, 1H), 6.76-6.72 (m, 2H), 3.89 (s, 3H), 2.55 (s, 3H), 2.54-2.52 (m, 2H), 2.35-2.08 (m, 10H), 1.72-1.69 (m, 2H). ESI-MS m/z: 394.1 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Br.C(O)(=O)C>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Yield: 43.7 %

Procedure:
A solution of 1-phenyl-2-(4-methoxyphenyl)benzimidazole (0.60 g, 2.0 mmol) in hydrobromic acid (6 ml) and acetic acid (6 ml) was refluxed for 40 hours. The reaction mixture was extracted with diethyl ether (5×150 ml) at a pH of 3-5. The organic solvents were discarded. The aqueous phase was alkalinized to pH 8-9 and extracted with ethyl acetate (5×150 ml). The organic fractions were combined and dried over potassium carbonate, then filtered and the solvents were removed in vacuo to yield a white solid. The solid was triturated in diethyl ether and filtered to yield 0.25 grams of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(F)cc(Br)c1
Product: COc1ccc(S(=O)(=O)Nc2cc(F)cc(Br)c2)cc1
Yield: 87.8 %

Procedure:
3-Bromo-5-fluoroaniline (500 mg, 2.63 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (572 mg, 2.77 mmol) according to the method described in Preparation 15b to give 832 mg (88% yield) of the title compound as an oil. Purity 70%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]2=3)[CH2:4][CH2:3]1.C1C(=O)N([Br:26])C(=O)C1>CN(C=O)C.O>[Br:26][C:16]1[CH:17]=[CH:18][C:9]2[N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:15]=1
Reactant: CN1CCC(N2CCCCc3ccccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(N2CCCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of compound 3 (0.73 g, 2.99 mmol) in DMF (5 mL) was treated with a solution of NBS (0.53 g, 2.99 mmol) in DMF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and stored at 0° C. overnight. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4) and concentrated. The product was filtered through a short plug of silica gel (2.0 N NH3 in MeOH:CH2Cl2, 2.5:97.5) to give compound 4 (0.915 g, 95.3%) as a yellow oil. 1H-NMR (DMSO-d6) δ 1.56 (m, 4H), 1.72 (m, 4H), 1.96 (td, 2H, J=10.9, 2.2 Hz), 2.15 (s, 3H), 2.65 (m, 2H), 2.76 (m, 2H), 2.93 (m, 2H), 3.14 (m, 1H), 6.83 (d, 1H, J=8.5 Hz), 7.19 (td, 2H, J=8.6, 2.4 Hz); EI-MS (m/z, %) 324 (M+, 14) 322 (M+, 14), 98 (25), 97 (100), 96 (25), 71 (38).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4](=[NH:8])OCC.[C:9]([OH:14])(=[O:13])[C:10]([OH:12])=[O:11].C(O)(=O)/C=C/C(O)=O.[NH2:23][CH2:24][C@@H:25]([O:32][C:33]1[CH:40]=[C:39]([Cl:41])[C:38]([F:42])=[CH:37][C:34]=1[C:35]#[N:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:9]([OH:14])(=[O:13])[C:10]([OH:12])=[O:11].[Cl:41][C:39]1[C:38]([F:42])=[CH:37][C:34]([C:35]#[N:36])=[C:33]([CH:40]=1)[O:32][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH:23][C:4](=[NH:8])[CH2:3][OH:2].[Cl:41][C:39]1[C:38]([F:42])=[CH:37][C:34]([C:35]#[N:36])=[C:33]([CH:40]=1)[O:32][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][NH:23][C:4](=[NH:8])[CH2:3][OH:2]
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CN)c1ccccc1
Reactant: CCOC(=N)CO
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)C(=O)O
Product: N#Cc1cc(F)c(Cl)cc1OC(CNC(=N)CO)c1ccccc1

Procedure:
The title compound was prepared by the method of Example 5 using ethyl 2-hydroxyethanimidate hydrochloride in metianol and the ethanedioic acid salt of the product from Example 1 step (c). M.p. 196° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3cccc(C(=O)c4ccccc4)c3)c2cc1OC
Temperature: 170 °C
Yield: 65.3 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and 3-hydroxybenzophenone (297 mg) were mixed together, and the mixture was heated at 170° C. for 10 min. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane-acetone as a solvent to give the title compound (126 mg, yield 65%).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:15]([C:16]1[CH:17]=[CH:18][C:19]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:21]=1)[CH2:14][CH2:13][CH3:12]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-butylbenzene (0.62 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-n-butylbenzoin was obtained as crystal (362.7 mg, 67.2% yield).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CO>[CH3:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([OH:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: CCCCCC(=O)CCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(O)CCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.55 g, 14.6 mmol) was added to a solution of 6-undecanone (1.66 g, 9.8 mmol) in 50 ml methanol, and the mixture was stirred at room temperature 2 hours. Solvent was evaporated and water was added to the residue which was extracted with CH2Cl2. The extracts were dried over anhydrous potassium carbonate, filtered, and the solvent was evaporated to leave crude 6-undecanol. The procedure of example 13 a. was followed but the crude 6-undecanol was substituted in place of 9-dodecyn-1-ol to obtain crude 6-undecanyl methanesulfonate. The crude 6-undecanyl methanesulfonate was dissolved in 20 ml acetonitrile and 1 g potassium cyanide were added, as well as 50 mg 18-crown-6, and 100 mg Et4NCN. The mixture was stirred and heated at reflux for 4 days. The mixture was cooled, poured into 5% aqueous NaOH, and extracted with CH2Cl2. The extracts were dried over Na 2 SO4. The extracts were filtered, and the solvent was evaporated. The residue was chromatographed on silica gel eluting with EtOAc-hexanes (2:98) to obtain crude 3-pentylheptanenitrile in low yield. This nitrile was dissolved in 30 ml THF, 1 ml 1M BH3 -THF solution was added, and the mixture was stirred at reflux for 4 hours. Water and 1N NaOH were added. The mixture was concentrated and water was added. The mixture was extracted with CH2Cl2. The extracts were dried over Na2SO4, filtered, and the solvent was evaporated to leave the title compound as an oil (57 mg, 3% yield overall): C12H27N (185.36); 1H-NMR (CDCl3) δ2.64 (d,2), 1.28 (m,17), 0.89 (t,6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([C:13](=O)[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Br:20])[CH:15]=2)=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.O.[NH2:23][NH2:24]>CO>[Br:20][C:16]1[CH:15]=[C:14]([C:13]2[C:8]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:6]=[N:24][N:23]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NN
Reactant: COc1cc(C=O)c(C(=O)c2ccnc(Br)c2)cc1OC
Solvent: CO
Solvent: O
Product: COc1cc2cnnc(-c3ccnc(Br)c3)c2cc1OC

Procedure:
To a solution of 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde (4.5 g) in methanol (70 ml) is added dropwise hydrazine monohydrate (0.8 ml). The reaction mixture is cooled with ice, and the precipitates are collected by filtration, and recrystallized from methanol to give 2-bromo-4-(6,7-dimethoxyphthalazin-1-yl)pyridine (4.01 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)[C:5]2=[O:33].[CH3:34]OC1C=C2C(=CC=1OC)N=CN=C2N1CCC(N2C(=O)C3C(=CC=C([N+]([O-])=O)C=3)NC2=O)CC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:34])[C:7](=[O:12])[N:6]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:17][CH2:18]1)[C:5]2=[O:33]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(Cl)cc5c4=O)CC3)c2cc1OC
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(Cl)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 65 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.64 mmol) of 6-chloro-3-[1(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]1,2,3,4-tetrahydro-2,4-dioxoquinazoline (Compound h) obtained according to the method described in the literature [Chem. Pharm. Bull., 38, 1591-1595 (1990)] was used in place of Compound 24. As a result, 199.2 mg (yield: 65%) of Compound 40 was obtained as white crystals.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:9]#[N:10].[Na+]>C(#N)C>[C:2]1([CH2:1][C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: N#CCc1ccccc1

Procedure:
A mixture of 0.635 g. (0.005 mole) benzyl chloride, O.50 g. sodium cyanide (0.010 mole), 0.53 g. (0.0005 mole) compound I (R = --CH2CH2 -O--2CH2CH3), and 15 ml. acetonitrile was stirred at reflux for 3.0 hours, at which time vapor-phase chromatographic analysis of the reaction mixture showed complete consumption of benzyl chloride and formation of phenylacetonitrile as the sole product. The reaction mixture was poured into water and extracted with petroleum ether to afford phenylacetonitrile and recovered catalyst I (82% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:26][C:27]([C@@H:29]3[CH2:31][C@H:30]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])[CH:23]=2)[CH2:18]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:26][C:27]([C@@H:29]4[CH2:31][C@H:30]4[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])[CH:23]=3)[CH2:18]2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)Nc1ccc2c(c1)CC(N)C2
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)Nc1ccc2c(c1)CC(NC(=O)c1nc(Cl)c(CC)[nH]1)C2
Yield: 93.7 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.23 g, 1.32 mmol), thionyl chloride (4 mL), ethyl trans(±)-2-[(2-amino-2,3-dihydro-1H-inden-5-yl)carbamoyl]cyclopropanecarboxylate obtained in Example (98a) (95 mg, 0.24 mmol) and pyridine (5 mL). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/2, 3/2, 1/0) gave 0.10 g of the title compound as a light yellow solid (92%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4](C)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[Br:14][C:15]1[CH:16]=[C:17]([C:21](=[CH:27]O)[C:22](OCC)=[O:23])[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:17]([C:21]2[C:22](=[O:23])[N:2]([CH3:1])[C:3]3[NH:4][C:5]4[C:10]([C:11]=3[CH:27]=2)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=4)[CH:18]=[CH:19][CH:20]=1
Reactant: CNc1cc2cc(C)ccc2n1C
Reactant: CCOC(=O)C(=CO)c1cccc(Br)c1
Product: Cc1ccc2[nH]c3c(cc(-c4cccc(Br)c4)c(=O)n3C)c2c1

Procedure:
This compound is prepared according to the usual methods by reaction of N,1,5-trimethyl-1H-indole-2-amine with ethyl 2-(3-bromophenyl)-3-hydroxy-2-propenoate.
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[ClH:7].[ClH:7].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=3)[C:33]=2[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc(NC2=NCCN2)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC4=NCCN4)cc3)ccc2c1
Reaction time: 2 h

Procedure:
45 Milliliters of 20% hydrous pyridine was added to 2.85 g of 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid.hydrochloride, 3 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.65 g of N,N'-dicyclohexylcarbodiimide (hereinafter referred to as "DCC") and 131 mg of 4-dimethylaminopyridine (hereinafter referred to as "DMAP"), followed by stirring for 2 hours under cooling with ice and 3 days under cooling with water. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of N,N-dimethylformamide (hereinafter referred to as "DMF"), and a small amount of the insoluble matter was filtered off. The filtrate was added dropwise to 500 ml of a mixed liquid of ether and acetone (10:1) and this was stirred for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19].[CH:22]1([NH:25][CH2:26][C@@H:27]2[C@H:31]([F:32])[CH2:30][NH:29][CH2:28]2)[CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:3]([N:29]2[CH2:30][C@@H:31]([F:32])[C@@H:27]([CH2:26][NH:25][CH:22]3[CH2:23][CH2:24]3)[CH2:28]2)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19]
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 20.5 %

Procedure:
Using 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (318 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 8-chloro-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a yellow solid (93.6 mg).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:35][NH2:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: NNc1cccc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=433.2 (M+H)+