Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:37])[CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:41]=1[C:42](O)=[O:43]>>[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:41]=1[C:42]([NH:36][CH2:35][CH2:34][CH:33]([N:30]1[CH2:29][CH2:28][CH:27]([N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[C:14]2[CH:13]=[CH:12][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:38])=[CH:9][CH:8]=3)=[CH:16][CH:15]=2)[CH2:32][CH2:31]1)[CH3:37])=[O:43]
Reactant: COC(=O)c1ccc(Oc2ccc(N(Cc3cccc(C#N)c3)C3CCN(C(C)CCN)CC3)cc2)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Product: Cc1cccc(Cl)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1
Yield: 40.3 %

Procedure:
Using general procedure E with 4-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-phenoxy}-benzoic acid methyl ester (see EXAMPLE 162) (80 mg, 0.16 mmol) and 2-chloro-6-methyl benzoic acid (29 mg, 0.17 mmol) followed by general procedure K afforded COMPOUND 163 as a white solid (42 mg, 41% over 2 steps). 1H NMR (CD3OD) δ 1.39 (d, 3H, J=6.6 Hz), 1.79-2.07 (m, 3H), 2.08-2.21 (m, 3H), 2.34 (s, 3H), 3.06-3.26 (m, 2H), 3.34-3.64 (m, 5H), 3.98-4.10 (m, 1H), 4.48 (s, 2H), 6.86 (d, 2H, J=8.4 Hz), 6.92 (s, 4H), 7.19-7.30 (m, 3H), 7.44-7.51 (m, 1H), 7.55-7.65 (m, 3H), 7.91 (d, 2H, J=8.4 Hz). 13C NMR (CD3OD) δ 14.26, 19.87, 28.36, 28.48, 32.53, 37.62, 51.11, 56.02, 61.37, 113.82, 117.65, 119.02, 120.25, 122.79, 128.23, 128.90, 130.28, 131.07, 131.75, 131.85, 131.92, 132.11, 133.03, 133.18, 138.02, 138.59, 143.83, 146.92, 149.84, 163.81, 171.08, 172.17. ES-MS m/z 651 (M+H). Anal. Calcd. for C38H39N4ClO4.0.5CH2Cl2.1.7H2O: C, 63.84; H, 6.04; N, 7.74; Cl, 9.79. Found. C, 63.70; H, 6.08; N, 7.64; Cl, 9.92.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].CCN(CC)CC>C(Cl)Cl.O>[O:24]=[C:18]([NH:2][CH2:3][C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:10][CH:11]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCC(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=O)NCC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a solution of 2-amino-1-(4-(trifluoromethoxy)phenyl)ethanone hydrochloride (9.5 g, 37 mmol) in DCM (150 mL) at 0° C. was added dropwise ethyl 2-chloro-2-oxoacetate (5.6 g, 41 mmol), followed by Et3N (16 mL, 111 mmol). The mixture was stirred at RT for 16 h and then diluted with H2O (200 mL) and extracted with EtOAc (4×80 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1 to 1:1) to give the title compound as a yellow solid (7.8 g, 66%). MS (ES+) C13H12F3NO5 requires: 319. found: 320 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[Cl:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27].O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:22][CH2:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:16]=[C:6]([O:7][C:8]2[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]=1[O:20][CH3:21])=[O:27]
Reactant: O=C(Cl)CCCCl
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(=O)CCCCl
Reaction time: 4.5 h
Yield: 89.8 %

Procedure:
To a solution of 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.400 g, 1.4 mmol) in 15 ml CHCl3 and Na2HPO4 (0.392 g, 2.8 mmol) was added 4-chlorobutyryl chloride (0.194 g, 1.4 mmol) drop-wise. After 4.5 h, H2O and CH2Cl2 were added and the mixture was allowed to stir 15 min. The mixture was neutralized with 2N Na2CO3 and extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 4-chloro-N-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-butyramide (0.495 g, 91%) as brown foam; [MH]+=394.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[OH-].[Li+:17]>O1CCCC1.O>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:2][CH:3]=1.[Li+:17]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 13.23 g (122.4 mmol) of 1,4-phenylenediamine and 225 ml of tetrahydrofuran. A solution prepared by dissolving 8.00 g (81.6 mmol) of maleic anhydride in 24 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of 2 hours, then, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a solution prepared by dissolving 1.99 g (81.6 mmol) of 98% lithium hydroxide in 17.95 g of water was dropped at room temperature over a period of 30 minutes, and the mixture was stirred at room temperature for 1 hour. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue to which 200 ml of 2-propanol was added, and the mixture was stirred at room temperature overnight. Thereafter, the deposited solid was isolated by filtration, and washed with 50 ml of 2-propanol. The resultant solid was dried under reduced pressure at 45° C. for 5 hours, to obtain 13.03 g of lithium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate as a pate brown-white solid. Yield: 75.3%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:14][CH3:15])=[O:13]>C(Cl)Cl>[C:8]([C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:20]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([O:14][CH3:15])=[O:13])(=[O:22])=[O:23])=[O:26])[N:7]=1)#[N:9]
Reactant: COc1cc(C#N)nc(N)n1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C#N)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-cyano-6-methoxypyrimidine, 0.1 g, was mixed with 2-carbomethoxythiophene-3-sulfonyl isocyanate, 0.165 g, in 10 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. The reaction mixture was stripped to yield 0.19 g of the title compound as a solid, m.p. 89°-92° C. (dec). NMR (CDCl3): δ6.89 (s, 3H), 4.20 (s, 3H), 6.83 (s, 1H), 7.59 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: P(OCC)(OCC)OCC.[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-])=O)=[N:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:24]=[N:23][C:22]2[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][C:21]=2[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(OCc2ccccc2)cn1
Agent: CCOP(OCC)OCC
Product: c1ccc(COc2cnc3c(c2)[nH]c2ccccc23)cc1
Temperature: 25 °C
Yield: 33.5 %

Procedure:
Triethyl phosphite (3 ml, 17.15 mmol) and 5-(benzyloxy)-2-(2-nitrophenyl)pyridine (0.3 g, 0.979 mmol) were heated to 125° C. for 4 hours. Let the reaction cool to room temperature. Concentrated and purified with Combiflash column using ethyl acetate followed by 15% methanol in DCM to afford 3-(benzyloxy)-5H-pyrido[3,2-b]indole (0.09 g, 0.328 mmol, 33.5% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:19]([OH:21])=O)[C:6]2[CH:7]=[N:8][N:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10]=2[CH:11]=1)#[N:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([S:70]([NH:73][CH:74]2[CH2:79][CH2:78][N:77]([CH3:80])[CH2:76][CH2:75]2)(=[O:72])=[O:71])=[CH:66][CH:65]=1>CN(C=O)C.O.C(OCC)(=O)C>[CH3:80][N:77]1[CH2:76][CH2:75][CH:74]([NH:73][S:70]([C:67]2[CH:68]=[CH:69][C:64]([CH2:63][NH:62][C:19]([C:5]3[C:6]4[CH:7]=[N:8][N:9]([C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=5)[C:10]=4[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:21])=[CH:65][CH:66]=2)(=[O:72])=[O:71])[CH2:79][CH2:78]1
Reactant: N#Cc1cc(C(=O)O)c2cnn(-c3ccc(F)cc3)c2c1
Reactant: CN1CCC(NS(=O)(=O)c2ccc(CN)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCC(NS(=O)(=O)c2ccc(CNC(=O)c3cc(C#N)cc4c3cnn4-c3ccc(F)cc3)cc2)CC1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.040 g, 0.14 mmol) in DMF (15 mL) was added PyBOP (0.1 g, 0.2 mmol) and triethylamine (0.04 g, 0.3 mmol) at room temperature. After 15 minutes, 4-aminomethyl-N-(1-methyl-piperidin-4-yl)-benzenesulfonamide (0.05 g, 0.16 mmol) was added. After 5 hours, the mixture was diluted with water (30 mL) and ethyl acetate (30 mL). The organic layer separated and washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 30-50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([S:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(C=O)cc(-c2ccccc2)n1S(=O)(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
A solution (15 mL) of ethyl 2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (980 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L solution (5.3 mL) of diisobutylaluminum hydride in toluene was added dropwise over 10 min., and the mixture was warmed to 0° C. over 2 hr. Water (100 mL) and ethyl acetate (20 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite, and the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile solution (25 mL), tetra-n-propylammonium perruthenate (93 mg), N-methylmorpholine N-oxide hydrate (466 mg) and molecular sieves 4A powder (500 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (30 mL) was added to the residue. The mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as a yellow oil (yield 235 mg, 27%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1I.[F:12][C:13]([F:18])([F:17])C([O-])=O.[Na+]>CN1CCCC1=O.O.[Cu]I>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:18])([F:17])[F:12]
Reactant: O=C([O-])C(F)(F)F
Reactant: Cn1c(I)cc2ccccc21
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc2ccccc21
Temperature: 160 °C
Yield: 37 %

Procedure:
A mixture of 1-methyl-2-iodoindole (4.40 g, 17.3 mmole), sodium trifluoroacetate (24.0 g, 176.5 mmole) and copper(I) iodide (17.1 g, 89.8 mmole) in N-methylpyrrolidone is heated at 160° C. for 6 hours, cooled to room temperature, diluted with water and filtered through diatomaceous earth to remove copper salts. The filtrate is extracted with ether. The extracts are combined, washed with water, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and 4:1 hexanes:ethyl acetate as eluent to give the title product as a pale yellow oil which crystallized on standing, 119 g (37% yield), mp 28°-32° C., identified by IR, 1HNMR and 19FNMR analyses.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH2:12][CH2:11]1)=[O:9].[C:32](Cl)(=[O:34])[CH3:33]>CN(C)C=O>[C:32]([N:22]1[C:23]2[C:18](=[CH:17][C:16]([N:13]3[CH2:12][CH2:11][N:10]([C:8](=[O:9])[C:7]4[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:5]([O:4][CH3:3])[CH:6]=4)[CH2:15][CH2:14]3)=[CH:25][CH:24]=2)[CH2:19][CH2:20][C:21]1=[O:26])(=[O:34])[CH3:33]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(C)=O)CC2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 263 mg) was suspended in dimethylformamide (DMF) (30 ml). To the suspension was added 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (2 g) and the mixture was stirred at 70° to 80° C. for 30 minutes. After cooling, to the mixture was added slowly acetyl chloride (0.43 m/g) with stirring and under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. After completion of reaction, the reaction mixture was poured into ice-water and extracted with chloroform. The chloroform layer was washed successively with water and saturated saline solution and dried over magnesium sulfate. The chloroform extract was evaporated under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol=100:1) and recrystallized from a mixture of dichloromethane and diethyl ether to give 1-acetyl-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (700 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15](O)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=S(Cl)Cl
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: ClCCl
Product: CCCCC(Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (1.50 g, 4.85 mmol) in dry DCM was added SOCl2 (3.53 mL, 48.50 mmol), and the resulting solution stirred under nitrogen for 3 hours at rt. The mixture was then reduced under vacuum to afford the title compound as an oily yellow solid (1.65 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(N(CC)CC)C.[NH:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:21](=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:18]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccccc1C(=O)NNc1ccccc1F
Temperature: 21 °C
Reaction time: 0.33 h
Yield: 40.4 %

Procedure:
A stirred suspension of 845 g (5.03 mole) of 97% (2-fluoro-phenyl)-hydrazine, hydrochloride in 7.6 L of ethanol at 21-22° C. was added in a stream 563 g (5.57 mole) of triethylamine over a 20 minute period. A whitish gas formed initially. The resulting dark mixture was stirred at 21° C. for 20 minutes and then 854 g (5.03 mole) of 96% 1H-benzo[d][1,3]oxazine-2,4-dione was added. The resulting mixture was heated up to reflux (78° C.) over the next 1 hour. During this period, vigorous gas evolution was noted. Reflux was maintained for 2 hours and then the suspension was stirred at room temperature for 16 hours. The solid was collected by filtration, rinsed once with 150 mL of ethanol, then once with 150 mL of ethanol: ethyl acetate (1:1), and pressed dry under suction. Further drying in vacuo at 35° C. for 7 hours provided 498 g (40%) of product. A second crop of 51 g (4%) of material was obtained from the mother liquor.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH:31]1[CH:38]=[CH:37][C:35]([NH2:36])=[N:34][C:32]1=[O:33].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:22])[F:23])[CH:12]=2)[C:8]([NH:36][C:35]2[NH:34][C:32](=[O:33])[N:31]=[CH:38][CH:37]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccnc(=O)[nH]2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (183 mg, 0.50 mmol) in methylene chloride (5 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.30 mL, 0.56 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of cytosine (116.7 mg, 1.06 mmol) in tetrahydrofuran (2.0 mL) and N,N-dimethylformamide (2.0 mL) followed by N,N-diisopropylethylamine (0.20 mL, 1.20 mmol). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 90/10 methylene chloride/methanol) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-oxo-2,3-dihydro-pyrimidin-4-yl)-propionamide (100 mg, 53.7%) as a white solid: mp 236-238° C.; EI-HRMS m/e calcd for C20H22F3N3O4S (M+) 457.1283, found 457.1291.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:28][C:25]([F:26])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:11]3[CH2:12][CH2:13][CH2:14][CH:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(C2CCCNCC2)cc1
Agent: Cl
Product: FC(F)(Cl)c1nnc2ccc(N3CCCC(c4ccccc4)CC3)nn12
Yield: 69 %

Procedure:
A mixture of 4-phenylazepane hydrochloride and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 331 to give 3-[chloro(difluoro)methyl]-6-(4-phenylazepan-1-yl)[1,2,4]triazolo[4,3-b]pyridazine in 69% yield.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[C:14]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]4=[N:19][CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:2]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>>[CH3:32][S:33]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[C:14]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]4=[N:19][CH:20]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:2]1)(=[O:35])=[O:34]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3NC3CCCCNC3)cnc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3NC3CCCCN(S(C)(=O)=O)C3)cnc21

Procedure:
(1-Methanesulfonyl-azepan-3-yl)-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from azepan-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methanesulfonyl chloride, using 4 equivalents of DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: Cl.[F:2][CH:3]([F:13])[O:4][C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1.[CH:14]([CH:16]([CH:22]=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O>C(O)C.CCCCC>[F:2][CH:3]([F:13])[O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C=O)C=O
Reactant: NNc1cccc(OC(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: CCCCC
Product: CCOC(=O)c1cnn(-c2cccc(OC(F)F)c2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-(Difluoromethoxy)phenyl)hydrazine hydrochloride (4.2 g, 19.9 mmol; CAS 479581-64-1) was suspended in ethanol (80 ml) and cooled to 0° C. A solution of ethyl 2-formyl-3-oxopropanoate (2.87 g, 19.9 mmol; CAS 80370-42-9) in ethanol (40 ml) was added, and the reaction was stirred overnight. The solvent was removed under reduced pressure and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield an orange solid. The solid was suspended in pentane (50 ml) and stirred at 35° C. for 90 min. The suspension was cooled in an ice bath for one hour and the solid was filtered and washed with pentane. After drying 5.12 g (91%) of a yellow solid was obtained MS (ISP): 283.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH3:13])=[CH:7][C:4]=1[CH:5]=[O:6].C[Si]([C:18]#[N:19])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.[I-].[Zn+2].[I-]>[CH3:1][O:2][C:3]1[C:4]([CH:5]([OH:6])[CH2:18][NH2:19])=[CH:7][C:8]([CH2:12][CH3:13])=[C:9]([CH3:11])[N:10]=1
Reactant: C[Si](C)(C)C#N
Reactant: CCc1cc(C=O)c(OC)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: CCOCC
Product: CCc1cc(C(O)CN)c(OC)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methoxy-5-ethyl-6-methylnicotinaldehyde (1.05 g, 5.86 mmol) and trimethylsilyl cyanide (0.85 mL, 6.37 mmol) containing zinc iodide (10 mg) was stirred, under a nitrogen atmosphere, at ambient temperature for two hours. This liquid was diluted with anhydrous diethyl ether, filtered and then added dropwise to a suspension of lithium aluminum hydride (225 mg, 5.9 mmol) in diethyl ether (15 mL) under nitrogen. After two hours the reaction was quenched with saturated aqueous sodium sulfate, diluted with methylene chloride, filtered and the solvents evaporated to give a semi-solid. This residue was triturated with cold diethyl ether and the crystalline product was collected by filtration to yield 346 mg (28%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:5](=O)[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1.COC(=O)C(C1C=CC(F)=CC=1)C(=O)C1C=C[N:31]=CC=1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[C:3](=[O:22])[O:2][NH:31][C:5]=2[C:6]2[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(F)cc1
Product: CSc1nccc(-c2[nH]oc(=O)c2-c2ccc(F)cc2)n1

Procedure:
Using the procedure from Example 1l set forth above, substitute 2-(4-fluorophenyl)-3-oxo-3-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid methyl ester for 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-propionic acid methyl ester to produce the title compound.