Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][N:13]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32].CC(O)=O.C([BH3-])#N.[Na+]>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:36][CH2:35][CH2:34][C@H:30]4[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D31) (99 mg, 0.254 mmol) in Ethanol (15 mL) stirred at room temperature was added L-proline (117 mg, 1.017 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium cyanoborohydride (31.9 mg, 0.508 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water and DCM was evaporated in vacuo. The mixture was extracted by EA/THF for 3 times. The combined organic solution was washed with brine, concentrated and purified by Mass Directed AutoPrep to afford 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-L-proline (E59) (52 mg) as a off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](OCC)=[O:22])=[CH:17][CH:16]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
3.53 g (9.0 mmol) of 4-(3-chloroanilino)-6-(4-ethoxycarbonylphenyl)-7H-pyrrolo[2,3-d]pyrimidine are suspended in 150 ml of THF. At 54° C., a total of 0.845 g (21.6 mmol) of lithium aluminum hydride are introduced in the course of 5 h. For working up, 1 ml of water, 2 ml of 1N sodium hydroxide solution and 1 ml of water, followed by 10 g of sodium sulfate, are added successively. The solid is filtered off and the filtrate is concentrated. The residue obtained is washed with methanol and diethyl ether and then dried. 4-(3-Chloroanilino)-6-(4-hydroxymethlyphenyl)-7H-pyrrolo[2,3-d]pyrimidine is obtained in colorless crystals; m.p.>250° C.; FAB-MS (M+H)+=351.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3].Br.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=1>>[CH2:1]([O:4][C:5](=[O:25])[N:6]([C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([Cl:37])[CH:31]=3)[N:15]=2)[CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(C)(C)C
Reactant: NCCc1ccc(O)c(Cl)c1
Agent: Br
Product: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(C)(C)C
Yield: 79 %

Procedure:
tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-carbamic acid allyl ester was coupled with 4-(2-amino-ethyl)-2-chloro-phenol hydrobromide salt (intermediate 71) following procedure F to give the title product in 79% yield. LC-MS showed the product had the expected M+H+ of 495. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.3 (d, 1H)) 7.9 (m, 2H) 7.4 (m, 1H) 7.3 (m, 1H) 7.2 (s, 1H) 7.0 (d, 1H) 6.9 (m, 2H) 5.9 (m, 1H) 5.2 (m, 2H) 5.1 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 3.7 (m, 2H) 2.9 (m, 2H) 1.41 (s, 9H).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[C:13](=[O:14])[NH:8][N:9]=[CH:10][C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)cnn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1[nH]ncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
The crude 2-benzyl-4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one from the above reaction was dissolved in toluene (350 mL). Aluminum chloride (AlCl3, 46.3 g, 348.0 mmol) was then added to the toluene solution, producing an exotherm. The reaction was then placed in an oil bath preheated at 75° C. for 3 h. After this time, the reaction mixture was poured into ice-water (1000 mL), and the resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water (500 mL), then filtered through a silica gel pad (˜50 g) to remove residual alumina salts. The organic solvents were evaporated under reduced pressure to nearly dryness. Diethyl ether (Et2O, 500 mL) was added with stirring. After stirring for 15 min at RT, hexane (1000 mL) was added subsequently. The resultant beige colored solid was collected by filtration and subsequently washed with a hexane-ether mixture (8:2). The title compound, 4,5-bis(4-chlorophenyl)pyridazin-3(2H)-one, (33.0 g, 92%) was obtained as a solid. MS: M+H=317. 1H NMR (CDCI3, 500 MHz): δ 11.94 (1H, br), 7.89 (1H, s), 7.23–7.32 (4H, m), 7.18 (2H, d, J=10.0 Hz), 7.07 (2H, d, J=10 Hz).
Reaction SMILES: [C:1](=[O:7])=[N:2][S:3]([Cl:6])(=[O:5])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)(=[O:18])=[O:17])=[CH:11][C:10]=1[N+:29]([O-:31])=[O:30]>C1(C)C=CC=CC=1>[Cl:6][S:3]([NH:2][C:1](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)(=[O:17])=[O:18])=[CH:11][C:10]=1[N+:29]([O-:31])=[O:30])(=[O:5])=[O:4]
Reactant: Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-])NS(=O)(=O)Cl
Reaction time: 2 h

Procedure:
30 ml of N-chlorosulfonyl isocyanate are added dropwise, at +10° C., to 108 g of 2-amino-5-(3-trifluoromethylphenylsulfonyloxy)nitrobenzene in 800 ml of toluene. The mixture is stirred for a further two hours while cooling, and 500 ml of petroleum ether are added. The 2-(3-chlorosulfonylureido)-5-(3-trifluoromethylphenylsulfonyloxy)nitrobenzene produced is filtered off with suction, washed with petroleum ether and dried over potassium hydroxide, melting point 137° C., decomposition. 150 g of this sulfochloride are introduced, with stirring and cooling in ice, into 2 liters of 1N HCl. The mixture is stirred for 2 hours while cooling and for 5 hours at room temperature, and next day the precipitate is filtered off with suction, washed with water to neutrality and dried, melting point 152° C.
Reaction SMILES: [C:1]([NH:9][C:10](=[O:30])[NH:11][C:12]1[S:22][C:15]2[CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:14]=2[C:13]=1[C:23]([O:25]C(C)(C)C)=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:9][C:10](=[O:30])[NH:11][C:12]1[S:22][C:15]2[CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:14]=2[C:13]=1[C:23]([OH:25])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)NC(=O)c2ccccc2)sc2c1CC(C)(C)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2c(sc(NC(=O)NC(=O)c3ccccc3)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 6.7 %

Procedure:
To a solution of tert-butyl 2-(3-benzoylureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.105 g, 0.24 mmol, 1 equiv.) in DCM (10 mL) was added TFA (0.5 mL, 6.5 mmol, 27 equiv.), and the reaction was stirred at rt for 5 days. The solvent was removed under reduced pressure and the product was purified by preparatory HPLC (0-5% MeOH/DCM), followed by mass-directed reverse-phase chromatography and isolated as a white solid (6 mg, 7% yield). 1H NMR (400 MHz, DMSO) δ 13.11 (s, 1H), 11.39 (s, 1H), 8.05-7.99 (m, 2H), 7.69-7.63 (m, 1H), 7.55 (t, J=7.7 Hz, 2H), 4.62 (s, 2H), 2.71 (s, 2H), 1.22 (s, 6H). LCMS retention time: 2.872 min; LCMS purity at 215 nm=100%. HRMS m/z calculated for C18H19N2O5S [M++1]: 375.1009. found 375.1013.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH2:26]([NH2:28])[CH3:27].Cl>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([OH:24])[CH2:25][NH:28][CH2:26][CH3:27])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H]2CO2)ccc1Cl
Agent: Cl
Solvent: ClCCl
Product: CCNC[C@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5c) (452mg), ethylamine (70% aqueous solution, 5 mL) and tetrahydrofuiran (15 mL) were heated together at 50° C. under nitrogen for 20 hours, cooled and concentrated to give an oil. This was purified by Waters' MCX resin (mixed-mode cation exchanger) and then by column chromatography eluting with 19:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and one molar (1M) ethereal hydrogen chloride (4 mL) was added. The mixture was concentrated to give the sub-titled compound as a solid (415 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6](/[CH:7]=[N:8]/[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[H][H]>[Pd].CC(=O)OCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(/C=N/NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNNC(=O)OC(C)(C)C)cc1
Yield: 104.3 %

Procedure:
Add 10% palladium on carbon (water wet, 20 g) slurried in EA (100 mL) to a sealed pressure reactor via vacuum transfer. Rinse transfer line with a minimal amount of EA. Charge (E)-tert-butyl 2-(4-methoxybenzylidene)hydrazinecarboxylate (320 g, 1.28 mol) dissolved in tetrahydrofuran (THF, 1000 mL) via vacuum transfer and rinse line with a minimal amount of THF. Pressurize the reactor to 50 PSI with H2 and mix the contents of the reactor at 20±10° C. Continue the reaction, maintaining the hydrogen pressure at 50 PSI, until no further hydrogen uptake is observed. Filter the reaction solution to remove the catalyst and wash the catalyst filter-cake with THF (500 mL). Add the wash to the reaction filtrate. Concentrate the solution in vacuo to obtain the title compound (337 g, 86%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 8.1-8.3 (s, 1H), 7.1-7.3 (d, 2H), 6.8-6.9 (d, 2H), 4.4-4.6 (bs, 1H), 3.7-3.8 (s, 2H), 3.6-3.7 (s, 3H), 1.3-1.5 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C@@H:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH3:20])[C:9](=[O:18])[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.F[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:31]#[N:32].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:31]([C:30]1[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:28]([NH:1][C:2]2[N:7]=[C:6]3[N:8]([C@@H:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH3:20])[C:9](=[O:18])[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:5]3=[CH:4][CH:3]=2)[CH:29]=1)#[N:32]
Reactant: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(N)nc21
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](c1cccnc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Nc3cc(C#N)ccc3[N+](=O)[O-])nc21
Temperature: -15 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
A solution of (R)-tert-butyl 5-amino-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (94 mg) and 3-fluoro-4-nitrobenzonitrile (225 mg) in DMF (6 mL) was cooled to −25° C. and treated with NaH (60% w/w in mineral oil, 75 mg) and slowly allowed to warm to −15° C. The mixture was stirred for four hours between −20° C. and −15° C., then diluted with EtOAc and quenched with saturated ammonium chloride solution. The organic phase was washed three times with brine, separated, dried over sodium sulfate, filtered, and concentrated. Column chromatography (2% MeOH in methylene chloride) provided 100 mg (R)-tert-Butyl 5-(5-cyano-2-nitrophenylamino)-2-oxo-3-(1-(pyridin-3-yl)ethyl)-2,3-dihydroimidazo[4,5-b]pyridine-1-carboxylate (70).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:34])[C:17]([C:18]3[S:19][C:20]([C:29]4[NH:33][CH:32]=[N:31][N:30]=4)=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:34])[C:17]([C:18]3[S:19][C:20]([C:29]4[N:33]=[CH:32][N:31]([CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][O:35]5)[N:30]=4)=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:22]=3)=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn2ccc(OCc3ccccc3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 60 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A mixture of 5-(benzyloxy)-2-methyl-3-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridine (440 mg, 0.94 mmol) produced in Example 30-B(x), 3,4-dihydro-2H-pyran (0.17 mL, 1.9 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) and tetrahydrofuran (10 mL) was stirred at 60° C. for 1 day. The reaction mixture was concentrated under reduced pressure, aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0). The obtained solution was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give 5-(benzyloxy)-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridine (430 mg, 84%) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35]1(=O)[CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH:35]5[CH2:38][CH2:37][CH2:36]5)[CH:4]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: O=C1CCC1
Product: Nc1ncnn2c(-c3cccc(CNC4CCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 17 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cyclobutanone as starting materials, 39 mg (17%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.80 (m, 2 H), 2.10 (m, 1 H), 2.00 (m, 2 H), 1.70-1.40 (m, 4 H); ES-MS m/z 500.2 [M+H]+, HPLC RT (min) 2.46.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=S)[NH2:15])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.[CH2:17](N)[CH2:18][NH2:19]>>[NH:19]1[CH2:18][CH2:17][N:15]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: NC(=S)c1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: NCCN
Product: O=C1CCC(c2ccc(C3=NCCN3)cc2)=NN1
Temperature: 0 °C

Procedure:
A slurry of 3 g of 4-(1,6-dihydro-6-oxo-3-pyridazinyl)benzenecarbothioamide in 5 ml of ethylenediamine is heated at 100° C. for 30 minutes when a clear solution is obtained. The solution is poured into 50 ml of ice-water and the solid is filtered, washed with a small volume of ice-water, and air-dried to give 2.5 g of the product, 6-[4-(4,5-dihydro-1H-imidazol-2-yl) phenyl]-4,5-dihydro-3(2H)-pyridazinone, mp 296°-297° dec.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16].CC1(C)C(C)(C)OB([C:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)O1>>[C:14]([NH:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:7][C:2]=1[C:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)C(=O)Nc1ccc(OC(F)(F)F)cc1Br
Product: CC(C)C(=O)Nc1ccc(OC(F)(F)F)cc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared by Procedure W and Scheme AF using N-[2-bromo-4-(trifluoromethoxy)phenyl]-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 329.0 (M−100)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([O-:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1
Reactant: O=C([O-])C1=Cc2cc(OCc3ccc(F)cc3F)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OCc3ccc(F)cc3F)ccc2CCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (477 mg, 1.39 mmol) dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml) was added a 1N aqueous solution of sodium hydroxide (4.2 ml), and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.2 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-(2,4-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (436 mg, 1.32 mmol, 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH:27]=[N:26][N:25]=[CH:24]3)[CH:21]=2)[NH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][N:10]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH:27]=[N:26][N:25]=[CH:24]3)[CH:21]=2)[NH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNCCCc1c[nH]c2ccc(-n3cnnc3)cc12
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(CCCc1c[nH]c2ccc(-n3cnnc3)cc12)Cc1ccccc1
Reaction time: 4 h
Yield: 77.3 %

Procedure:
To a solution of 2-[(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl)amino]ethyl carbamic acid tert-butyl ester (0.42 g, 1.2 mmol) in methanol (10 ml) at 0° C. was added benzaldehyde (133 μl, 1.3 mmol), acetic acid (189 μl, 3.3 mmol) and sodium cyanoborohydride (137 mg, 2.2 mmol). After addition the cooling bath was removed and the mixture stirred for 4 h. After this time more benzaldehyde (110 μl, 1.1 mmol) was added and the mixture stirred for 18 h. More benzaldehyde (110 μl, 1.1 mmol) was added and the mixture stirred for a further 10 min. The solvents were evaporated and the residue partitioned between EtOAc (2×50 ml) and water (50 ml). The combined organic layers were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (95:5:1), to give the desired product (0.44 g, 85%) as a pale yellow foam. 1H NMR (360 MHz, CDCl3) δ1.41 (9H, s), 1.84-1.96 (2H, m), 2.52-2.58 (4H, m), 2.75 (2H, t, J=7.5 Hz), 3.12-3.20 (2H, m), 3.58 (2H, s), 4.78 (1H, br s), 7.03 (1H, s), 7.14 (1H, dd, J=8.5 and 2.0 Hz), 7.21-7.36 (5H, m), 7.45 (1H, d, J=8.5 Hz), 7.51 (1H, d, J=2.0 Hz), 8.29 (1H, br s), 8.45 (2H, s). MS (ES+) (475, M+1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=[C:14](CO)[N:15]=1)[CH3:10].C(O)C>O1CCOCC1>[CH2:9]([C:11]1[NH:12][C:13]([CH2:18][OH:19])=[C:14]([Cl:1])[N:15]=1)[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1nc(CO)c(CO)[nH]1
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 0.18 h

Procedure:
1.76 Grams (13.2 mmol) of the N-chlorosuccinimide was added little by little to a solution consisting of 2.06 g (13.2 mmol) of an ethyl-4,5-bis(hydroxymethyl) imidazole, 100 ml of ethanol and 40 ml of 1,4-dioxane maintained at room temperature with stirring over a period of about 11 minutes. The mixture was then stirred at the same temperature for three hours and for another 30 minutes at a temperature of 50° C. After the reaction, the solvent was distilled off under reduced pressure and the resulting yellowish oily product was subjected to the column chromatography (silica gel-acetone), and the obtained effluent was evaporated to dryness under reduced pressure. By using acetonitrile, the resulting solid product was recrystallized three times to obtain a colorless crystalline 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 0.82 g (yield, 39.0%). The TLC and spectra of this compound were the same as the properties exhibited by the above-mentioned 2-ethyl-4-chloro-5-(hydroxymethyl) imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9](=O)/[CH:10]=[CH:11]/[CH3:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:11]([CH3:12])[CH:10]=[CH:9]2
Reactant: Nc1ccccc1Cl
Reactant: C/C=C/C=O
Product: Cc1ccc2cccc(Cl)c2n1
Yield: 57 %

Procedure:
The procedure described in Example 1 was followed, except that 130 g/hour of 2-chloroaniline and 84 g/hour of crotonaldehyde were employed. Distillation from the oil bed under 5 mbar until the bottom temperature reached 250° C., and crystallization of the distillate with xylene, gave 101 g (57% of theory) of 8-chloro-2-methylquinoline of melting point 64° C.