Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=O>O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:11])[CH:12]=[CH:18][C:14]2[NH:13][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc[nH]1
Reactant: CC(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(=O)C=Cc2ccc[nH]2)cc1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a solution of 10.1 g (0.18 mole) of potassium hydroxide in 2.18 L of water was added 176.4 g (1.32 mole) of 4-methylacetophenone and 50 g (0.53 mole) of pyrrole-2-carboxaldehyde. The mixture was heated to 40°-45° C. with mechanical stirring under a nitrogen atmosphere overnight. The solid precipitate was filtered, washed with water and 2-propanol, and air dried to give 42.1 g (38% yield) of the title compound as a solid, mp 158.5°-159.5° C.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH2:27][CH:28]1[CH2:30][CH2:29]1>>[CH:28]1([CH2:27][NH:26][C:3](=[O:25])[C:4]2[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:30][CH2:29]1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NCC2CC2)cn1
Yield: 83 %

Procedure:
As described for example 173, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (70 mg, 0.2 mmol) was converted, using aminomethylcyclopropane instead of 2,2,2-trifluoroethylamine, to the title compound (80 mg, 83%) which was obtained as an off white foam. MS: m/e=381.4 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[SH:18][CH2:19][CH2:20][CH2:21][SiH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]>C1(C)C=CC=CC=1>[C:8]([S:18][CH2:19][CH2:20][CH2:21][SiH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCC(=O)Cl
Reactant: COC(OC)[SiH2]CCCS
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)SCCC[SiH2]C(OC)OC
Reaction time: 2 h
Yield: 95 %

Procedure:
In a four-necked flask of 1 L, 18.0 g of 3-mercaptopropyl dimethoxymethyl silane and 11.1 g of triethylamine are dissolved in 300 mL of toluene under a nitrogen atmosphere. To this solution is added 16.2 g of octanoic acid chloride dropwise over 30 minutes, which is stirred for 2 hours. Thereafter, the precipitates are filtered off and the solvent is removed by a rotary evaporator at 20 hPa/40° C. to obtain 29.0 g of 3-octanoylthio-propyl dimethoxymethyl silane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:65][C:66](O)([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68]>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][CH2:26][O:27][C:66]([CH3:65])([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68])[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCO)CC4)cc3)oc12
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCOC(C)(C(F)(F)F)C(F)(F)F)CC4)cc3)oc12
Reaction time: 0.17 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-hydroxyethyl)cyclohexyl]methyl}benzamide (50 mg, 0.112 mmol, EXAMPLE 43, Step A) and 1,1′-(azodicarbonyl)dipiperidine (57 mg, 0.226 mmol) in toluene (2 ml) was added tri-n-butylphosphine (0.06 ml, 0.241 mmol). After stirring for 10 min, hexafluoro-2-methylisopropanol (0.03 ml, 0.245 mmol) was added. Tetrahydrofuran (2 ml) was added to solubilize starting material, and the mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (8.7 mg, 0.014 mmol, 12.72% yield). Mass spectrum (ESI) 610.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.94 (d, J=8.5 Hz, 2H), 7.94 (d, J=1.5 Hz, 1H); 7.51 (s, 1H), 6.27 (br s, 1H), 3.72 (t, J=6.5 Hz, 2H), 3.46 (septet, J=6.5 Hz, 1H), 3.36 (t, J=6.0 Hz, 2H), 1.83 (m, 4H), 1.50-1.65 (m, 5H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.50 (m, 2H), 0.85-1.22, (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:37]=[C:36]3[C:31]([CH:32]=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35]4)=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1ccc2ccc(-c3ccc(O)cc3)cc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.050 g, 0.16 mmol), methyl 7-(4-hydroxyphenyl)-2-naphthalenecarboxylate (0.045 g, 0.16 mmol), triphenyl phosphine (0.042 g, 0.16 mmol) and diisopropyl azodicarboxylate (0.043 mL, 0.16 mmol) in dichloromethane (1.6 mL) was placed in microwave reaction tube and heated to 80° C. for 20 minutes. The solution was concentrated and the residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.059 g, 64%). 1H NMR (DMSO-d6): 8.68 (s, 1H), 8.40 (s, 1H), 8.07-7.93 (m, 4H), 7.80 (d, J=7 Hz, 2H), 7.42 (d, J=8 Hz, 2H), 7.28-7.24 (m, 1H), 7.14 (d, J=7 Hz, 2H), 4.99 (s, 2H), 3.91 (s, 3H), 3.32-3.20 (2m, overlapping H2O, total 3H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 574 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1cccc(Nc2ccccc2)c1N
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(Nc2ccccc2)c1NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of 3-methyl-N1-phenylbenzene-1,2-diamine (381 mg, 1.92 mmol) in anhydrous DCM (10 mL) were added (R)-2-tertbutoxycarbonylaminopropionic acid (399 mg, 2.11 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (404 mg, 2.11 mmol) and the mixture was stirred at RT for 2 h. After this period of time, additional amounts of (R)-2-tertbutoxycarbonylaminopropionic acid (145 mg, 0.77 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol) were added. Stirring was continued for 20 h and then additional amounts (R)-2-tertbutoxycarbonylaminopropionic acid (545 mg, 2.88 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) were added. Stirring was continued for 24 h and then the crude mixture was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording [(R)-1-(2-methyl-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an orange oil (456 mg, 64%). LCMS: RT 3.69 min [M+H]+ 370.2
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([SH:8])[CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14].C(N(CC)CC)C>O1CCCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: Cc1cccc(S)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(SCCCC(=O)c2ccc(F)cc2)c1
Yield: 98.8 %

Procedure:
A solution of 3-thiocresol (25.0 g, 0.2 mole) and 4-chloro-4'-fluorobutyrophenone (40.1 g, 0.2 mole) in tetrahydrofuran (200 ml) was treated with triethylamine (22.3 g, 0.22 mole) and refluxed for six hours under nitrogen. The mixture was concentrated in vacuo, and the residue was partitioned between diethyl ether (200 ml) and water (200 ml). The organic layer was washed three times with sodium hydroxide (1N), water, and brine; dried over anhydrous magnesium sulfate, filtered, and concentrated to a pure oil by tlc (n-butyl chloride) to yield the title compound (57.0 g, 99%); IR(nujol): C=O @ 1686 cm-1 ; NMR(CDCl3, TMS): δ2.08(m,2H,CH2), 2.30(s,3H,ArCH3), 3.00(t,2H,CH2 --CO), 3.10(t,2H,S--CH2), 6.9-7.17(m,4H, 1,3-substituted phenyl), [7.10(d of d, 2H) and 7.97(m,2H) p-F-phenyl]; Anal. Calcd. for C17H17FNOS, MW 288.38: C,70.80; H,7.97; S,11.12. Found: C,70.79; H,6.01; S,11.18. Mass spectrum m/e 288,150.
Reaction SMILES: [C:1]([C:9]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:14](=[O:16])[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>CS(C)=O.O>[C:1]([C:9]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:14](=[O:16])[N:15]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2c(=O)[nH]c3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2c(=O)n(CCN(C)C)c3cc(C(=O)c4ccccc4)ccc32)cc1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of 1.09 g of 5-benzoyl-1-(4-methoxybenzyl)-2H-benzimidazol-2-one in 10 ml of dimethylsulfoxide was added at room temperature 0.27 g of 60% dispersion of sodium hydride in mineral oil. After being stirred for 30 minutes, the reaction mixture was treated with 0.48 g of chloroethyldimethylamine hydrochloride at room temperature for 2 hours and at 55° C for 3 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was extracted with 10% hydrogen chloride. The aqueous layer was alkalized with 20% sodium hydroxide and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine in turn and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was chromatographed on silica gel using chloroform-methanol (15:1) to afford 1.14 g of 5-benzoyl-1,3-dihydro-3-(2-dimethylaminoethyl)-1-(4-methoxybenzyl)-2H-benzimidazol-2-one.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([C:19]2[CH:32]=[CH:31][C:22]3[C@H:23]4[C@H:28]([CH2:29][CH2:30][C:21]=3[CH:20]=2)[NH:27][CH2:26][CH2:25][CH2:24]4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:27]3[C@@H:28]4[C@H:23]([C:22]5[CH:31]=[CH:32][C:19]([C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=6)=[CH:20][C:21]=5[CH2:30][CH2:29]4)[CH2:24][CH2:25][CH2:26]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc(-c2ccc3c(c2)CC[C@@H]2NCCC[C@@H]32)cc1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3ccc(-c4ccccc4)cc3CC[C@@H]21
Yield: 19 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-8-phenyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 19% of theory; TLC: rf=0.43 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[C:22]3[C:17](=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH2:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[C:22]3[C:17](=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(Oc2nccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-3-[4-([2,6]naphthyridin-1-yloxy)phenyl]propionic acid methyl ester (271 mg, 0.64 mmol) in dichloromethane (7.5 ml) was treated with trifluoroacetic acid (7.5 ml) and stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (60 ml) and saturated aqueous NaHCO3 (25 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×25 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford the title compound (206 mg, 100%) as an oil that was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][CH:10]([O:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1>CN(C)C=O.O.[Cu]>[CH3:19][O:18][CH:10]([O:9][CH3:8])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:16]=1
Reactant: c1c[nH]cn1
Reactant: COC(OC)c1cccc(Br)c1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)c1cccc(-n2ccnc2)c1
Temperature: 155 °C
Reaction time: 36 h
Yield: 79.4 %

Procedure:
A solution of 296 mg of imidazole and 131 mg of sodium hydride (80% dispersion in mineral oil) in 2 ml of anhydrous dimethylformamide was stirred at room temperature for 1 hour under nitrogen. 1.0 g of 3-bromobenzaldehyde dimethyl acetal and 30 mg copper powder were then added and the mixture was stirred at 150-160° C. under nitrogen for 36 hours. The cooled mixture was diluted with 20 ml of water and extracted with four 25 ml portions of dichloromethane. The combined extracts were washed with two 25 ml portions of 25% aqueous ammonia, followed by two 25 ml portions of brine and then dried over anhydrous magnesium sulphate. The solution was concentrated under reduced pressure to give 0.75 g of 3-(1-imidazolyl)-benzaldehyde dimethyl acetal as a clear viscous oil.
Reaction SMILES: C[N:2](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][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)N>>[CH3:34][C:30]1[CH:29]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazino-2-methylpyridine according to the method described for example 43. MS: M=414.2 (M+H)+
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([CH3:29])=[CH:24][C:25]([OH:28])=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][N:32]1[C:36]([CH2:37]O)=[CH:35][C:34]([C:39]([F:42])([F:41])[F:40])=[N:33]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([CH3:29])=[CH:24][C:25]([O:28][CH2:37][C:36]3[N:32]([CH3:31])[N:33]=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:35]=3)=[C:26]([F:27])[C:21]=2[S:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)cc1CO
Reactant: COC(=O)Cc1csc2c(F)c(O)cc(C)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(F)c(OCc3cc(C(F)(F)F)nn3C)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a mixture of tri-n-butylphosphine (0.338 mL), methyl(7-fluoro-6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (131.3 mg), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (93 mg) and THF (4.0 mL) was added ADDP (284 mg) at room temperature. The mixture was stirred overnight at room temperature under nitrogen atmosphere. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (205.9 mg). The compound was crystallized from EtOAc-hexane.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(F)c(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 65 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-fluoro-3-(trifluoromethyl)benzoic acid: MS (ESI): m/z 455 (M+1).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH2:44][CH3:45])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:44]([O:43][C:37]1[CH:36]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH3:42])[CH3:45]
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OC
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Temperature: 85 °C
Reaction time: 10 h
Yield: 38.3 %

Procedure:
After adding 230 mg of 2-hydrazinopyrimidine and 293 μl of triethylamine to a 50 ml DMF solution containing 983 mg of {2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester, the mixture was stirred at 85° C. for 10 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 30 ml of a methanol:THF=1:1 mixed solvent. After adding 420 μl of acetic acid and 657 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture which was then filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (400 mg) as a light yellow solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[NH:23][CH:22]=[CH:21]3)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]([CH2:8][CH2:9][N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[NH:23][CH:22]=[CH:21]3)[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2cc(OC3CCN(CCOc4ccccc4)CC3)ccc12
Reaction time: 17 h

Procedure:
2-Phenoxyethyl bromide (1 mol eq) was added to a suspension of 6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol) and potassium carbonate (50 mgs, 3 mol) in N, N-dimethylformamide (1 ml) and shaken for 17 hours. The reactions was quenched with hydrochloric acid (2M) and methanol and passed down an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean product was isolated by evaporation under reduced pressure to afford 6-[1-(2-phenoxyethyl)piperidin-4-yloxy]-2H-isoquinolin-1-one: El-MS: m/z=365.1 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>C(O)C>[CH3:17][N:13]1[C:14]2=[CH:15][N:22]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: CCOC(=O)CCCCN
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (1.38 g, 4.09 mmol), ethyl 5-aminovalerate hydrochloride (1.109 g, 6.14 mmol) and triethylamine (1.711 mL, 12.28 mmol) were combined in ethanol (20 mL) and the mixture heated at reflux for 40 mins. The reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was partitioned between water and DCM and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated onto silica. The silica was deposited onto a 25 g silica cartridge and the system eluted with 20% EtOAc/hexane, 40% EtOAc/hexane, 60% EtOAc/hexane and 80% EtOAc/hexane. The product fractions were combined and concentrated under reduced pressure to afford the title compound;