Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:15]([C:13]2[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=2[CH3:18])[C:16]1=[S:17])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(F)cc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cc(F)ccc2C)C1=S
Yield: 41.3 %

Procedure:
A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenylisothiocyanate (10.42 g), triethylamine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98°-100° C. Anal. Calcd. for. C12H13F N2O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C.C(=O)(O)[O-].[Na+]>O>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH:6]([CH2:14][CH3:15])[C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CCC1C(=O)N(CC)CCc2cc(N)c(OC)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCC1C(=O)N(CC)CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc21
Temperature: 120 °C

Procedure:
7-Amino-1,3-diethyl-8-methoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one (85 mg, 0.32 mmol), N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (120 mg, 0.36 mmol), and 10-camphorsulfonic acid (82.5 mg, 0.355 mmol) were charged to isopropyl alcohol (3 ml, 40 mmol) in a microwave reaction tube. The reaction was heated in microwave at 120° C. for 40 minutes. The resulting solution was poured into a mixture of 20 ml saturated sodium bicarbonate solution and 40 ml water and the aqueous solution was extracted with methylene chloride (4×10 ml portions). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield a clear yellow oil. The oil was evaporated onto celite and the celite placed on silica gel (12 g Isco column) and eluted with 0-70% EtOAc in Hexanes to obtain N-{(1R,2R)-2-[5-Chloro-2-(1,3-diethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a beige powder. MP: 126-127° C.; 1H-NMR (CDCl3) δ 8.01 (d, J=7.1 Hz, 1H), 7.35 (s, 1H), 6.72 (s, 1H), 5.35 (d, J=7.8 Hz, 1H), 5.29 (d, J=7.8 Hz, 1H), 4.00-3.82 (m, 5H), 3.57 (p, J=7 Hz, 1H), 3.45 (m, 2H), 3.28-3.07 (m, 3H), 2.80 (d, J=2.8 Hz, 3H), 2.30-2.10 (m, 3H), 1.98-1.80 (m, 3H), 1.47-1.30 (m, 4H), 1.10 (t, J=7 Hz, 3H), 1.03 (t, J=7 Hz, 3H); LC/MS (ESI+): 565 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]#[N:13])=[CH:9][C:8]=2[CH:14]=1)(=O)[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH2:23][CH2:24][CH3:25])[NH2:19].[BH4-].[Na+]>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][CH:1]([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([C:12]#[N:13])=[CH:9][C:8]=3[CH:14]=2)[CH3:2])[CH:20]=[CH:21][C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)c1ccc2oc(C#N)cc2c1
Reactant: CCCc1ccc(N)cc1Cl
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1ccc(NC(C)c2ccc3oc(C#N)cc3c2)cc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of 5-acetylbenzofuran-2-carbonitrile (64 mg, 0.35 mmol), 3-chloro-4-propylaniline (140 mg, 0.82 mmol) and Ti(OiPr)4 (205 μL, 0.69 mmol) was heated to 50° C. for 3 hr, then 60° C. for 2 hr. The reaction mixture was diluted with 10 mL of DCM, and celite was added to the solution (enough to equal the volume of the mixture). The reaction was quenched with 5 mL of sat. NaHCO3:H2O=1:1, and filtered. The separated organic layer was washed with H2O, brine and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 1.4 mL of TFE and NaBH4 (15.69 mg, 0.415 mmol) was added. The reaction was stirred at 40° C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with 50 mL of DCM, which was then washed with H2O, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, 100% Heptane-30% Ethyl Acetate/70% Heptane, to give (±) 5-(1-((3-chloro-4-propylphenyl)amino)ethyl)benzofuran-2-carbonitrile (113 mg). LCMS retention time=1.66 minutes (LC method 1); MS (m+1)=339.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:7]([N:24]=[C:25]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:10]=1)=[O:4]>CO.[OH-].[K+]>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]2[N:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]3[N:7]([N:24]=[C:25]([C:27]4[O:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:8]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)cn2nc(-c3ccco3)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cn3nc(-c4ccco4)nc3c(C(=O)O)n2)CC1
Yield: 69.7 %

Procedure:
A solution of 6-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-8-carboxylic acid methyl ester (4 mg, 0.009 mmol; see Example 16 (g) above) in 1 N potassium hydroxide methanol solution (1 mL) was stirred at room temperature for 2 hours. The solvent was then removed, and the residue was suspended in water. The resulting suspension was acidified with acetic acid until pH 4 and extracted with methylene chloride three times. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to afford 6-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-8-carboxylic acid as a yellow solid (2.6 mg, 68%). 1H NMR (300 MHz, CDCl3) δ1.50 (s, 9H), 3.53-3.58 (m, 4H), 3.63-3.68 (m, 4H), 6.63 (dd, J=1.8, 3.3 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 8.08 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ28.39, 45.90, 80.49, 106.62, 112.27, 113.83, 134.92, 142.08, 144.56, 145.30, 149.18, 154.60, 157.09, 161.49.
Reaction SMILES: [C:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH3:11])[CH2:3][CH:2]=1.C(N(CC)CC)C.Cl.[O:21]([NH2:23])[CH3:22]>CO>[CH3:22][O:21][N:23]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]1[CH2:3][CH:2]=1)[CH3:11]
Reactant: CON
Reactant: CC(=O)CCCCCCC1=CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C)CCCCCCC1=CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
To a solution of 0.15 g (0.9 mmol) of 8-cycloprop-1-enyl-octan-2-one in 10 mL of methanol cooled in an ice bath was added 0.30 g (3 mmol1) of triethylamine and 0.83 g of a 30-35% aqueous solution of methoxylamine hydrochloride (3 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 1.5 hours. Water and ether were added. The phases were separated and the aqueous phase was washed with ether. The combined ether phases were washed with dilute aqueous hydrochloride acid, water (2×), and brine, then dried over magnesium sulfate, filtered and stripped. Column chromatography gave 50 mg of 8-cycloprop-1-enyl-octan-2-one O-methyl oxime (Compound 47) as a 30% solution in ether. The ratio of oxime isomers was 3:1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[N:13]([CH3:15])[NH2:14])([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:44])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](=O)[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:21](=[O:39])[C:20]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:19]12.C(Cl)Cl.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C.CO>[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[N:13]([CH3:15])[NH:14][CH:27]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[C:18](=[O:44])[C:19]2=[CH:43][CH:42]=[CH:41][CH:40]=[C:20]2[C:21]1=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Reactant: CN(N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(NC(CCCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
A solution of carbazide 2 (0.665 g; 2.74 mmol) and benzyl 6-phthalimido-2-oxohexanoate (1.00 g; 2.74 mmol) in THF (5 ml) containing glacial acetic acid (3 drops) was heated at reflux for 3 hours. TLC (silica gel, CH2Cl2 --CH3OH,20:1) showed a single product spot, Rf=0.5. The crude product was treated as for 14 (Example 10) with sodium cyanoborohydride (172 mg; 2.74 mmol), giving pure carbazide 24 (1.18 g; 2.00 mmol; 73%) after flash chromatography on silica gel (hexanes-EtAc, 1:1). TLC (silica gel; hexanes-EtOAc, 1:1) showed a mixture (1:1) of diastereomers, Rf=0.25, 0.30. MS m/e 592 (M+). Analysis: Calculated for C32H40N4O7 : C, 64.85; H, 6.80; N, 9.45. Found: C, 64.24; H, 6.98; N, 8.95. NMR (CDCl3): δ 1.40 (9H,s); 1.5-2.0 (8H,m); 2.88, 2.90 (3H,2 x S); 3.2-3.7 (6H,m); 4.2-4.4 (1H,m); 4.8-5.1 (1H,m); 5.12, 5.15 (2H,2 x S); 7.27 (5H,s); 7.6-7.9 (4H,m). IR (CHCl3): 2980, 1770, 1730, 1720, 1640 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:13][CH:12]=[CH:11][C:10](=[O:14])[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([C:5]1[CH:15]=[C:9]2[C:8](=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)[O:13][CH2:12][CH2:11][C:10]2=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2occc(=O)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OCCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To 1.0 g (3.87 mmol) of 4H-6,8-di-t-butyl-benzopyran-4-one in 8 mL of EtOAc was added 200 mg of 10% Pd/C. The mixture was degassed, followed by addition of H2 gas and stirred under an H2 gas atmosphere for 2 h at RT. After filtration (celite), the product was concentrated and purified (SiO2 chromatography, 5% EtOAc-hexanes) to give 857 mg (3.29 mmol) of 32 as a white solid (85% yield): TLC (5% EtOAc-hex) Rf 0.7; 1H-NMR (CDCl3)δ 1.32 (s, 9H, CH3), 1.42 (s, 9H, CH3), 2.78 (t, J=6.0 Hz, 2H, CH2), 4.52 (t, J=6.0 Hz, 2H, CH2), 7.53 (d, J=2.4 Hz, 1H, Ar--H), 7.81 (d, J=2.4 Hz, 1H, Ar--H)
Reaction SMILES: C(OC1C=NC(C2C=CC=CC=2C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=1)C.Cl.[CH:36]1([C:39]2[C:40]([NH:49][C@H:50]3[CH2:54][CH2:53][CH2:52][C@@H:51]3[NH2:55])=[N:41][CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)[CH2:38][CH2:37]1.[N:56]1[CH:61]=[CH:60][CH:59]=[N:58][C:57]=1[C:62]1[C:63]([C:68](O)=[O:69])=[N:64][CH:65]=[CH:66][CH:67]=1>>[CH:36]1([C:39]2[C:40]([NH:49][C@H:50]3[CH2:54][CH2:53][CH2:52][C@@H:51]3[NH:55][C:68]([C:63]3[C:62]([C:57]4[N:56]=[CH:61][CH:60]=[CH:59][N:58]=4)=[CH:67][CH:66]=[CH:65][N:64]=3)=[O:69])=[N:41][CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[N:44]=2)[CH2:37][CH2:38]1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ncccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(5-Ethoxypyrimidin-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 135) from (1S,2S)-1-N-[3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 48; 105 mg, 0.33 mmol) and 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 79 mg, 0.39 mmol) except after work-up, the organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM, then methanol and 2M ammonia in methanol and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH:13]=[O:14])=[C:11]([CH3:15])[N:10]=[N:9]1.FC1C=CC(N2C(C=O)=C(C)N=N2)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1C=O
Agent: Cc1nnn(-c2ccc(F)cc2)c1C=O
Product: Cc1nnn(-c2ccccc2F)c1CO
Yield: 74.7 %

Procedure:
As described for example 60e, 1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazole-5-carbaldehyde (469 mg, 2.19 mmol), instead of 3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazole-4-carbaldehyde, was converted to the title compound (339 mg, 75%) which was obtained as a white solid. MS: m/e=208.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:10][NH:11][C:12]([NH2:14])=[S:13]>CO>[CH3:10][NH:11][C:12]1[S:13][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[N:14]=1
Reactant: CNC(N)=S
Reactant: COC(=O)CC(=O)CCl
Solvent: CO
Product: CNc1nc(CC(=O)OC)cs1
Temperature: 80 °C

Procedure:
A mixture of methyl 4-chloro-3-oxobutanoate (1 g, 11.1 mmol) and 1-methylthiourea (1.72 g, 11.43 mmol) in MeOH (5 mL) was heated to 80° C. for 3 hours. The mixture was cooled, ethanol evaporated, and diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and the reaction mixture purified by a standard method to provide methyl 2-(2-(methylamino)thiazol-4-yl)acetate. LC-MS: m/z (M+H)=187.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[O:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:37][C@H:34]5[CH2:35][CH2:36][O:32][CH2:33]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: N[C@H]1CCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N[C@H]5CCOC5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), (S)-tetrahydrofuran-3-amine hydrochloride (0.161 g, 1.3 mmol), DIEA (0.26 mL, 1.5 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellow solid, which was washed with methanol to produce a purified product (0.363 g) in 74.1% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2].[CH2:26]([NH:28][CH2:29][CH2:30][OH:31])[CH3:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][OH:31])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCNCCO
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)N(CC)CCO)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 70 mg (0.784 mmol) of 2-(ethylamino)-ethanol, 23 mg (20.1% of theory) of 4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-4-oxo-3,4-dihydroimindazo-[5,1-f][1,2,4]triazin-2-yl)-benzene-sulphonamide are obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[S:20]1[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[N:22]=[CH:21][S:20][CH:24]=3)=[O:26])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cscn1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cscn3)n2)ccc(C#N)c1Cl
Yield: 313.3 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.2 g, 0.728 mmol), 1,3-thiazole-4-carboxylic acid (0.113 g, 0.874 mmol), HOBt (0.118 g, 0.874 mmol), DIPEA (0.152 ml, 0.874 mmol) and EDCI (0.167 g, 0.874 mmol) using DCM as solvent using the method of Example 34(d) affording 0.88 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.16 (d, 3H), 2.51 (s, 3H), 4.37 (m, 2H), 6.61 (d, 1H), 7.67 (d, 1H), 7.83-7.85 (m, 2H), 8.27 (d, 1H), 8.56 (d, 1H), 9.20 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:22])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([OH:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl[Sn]Cl>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:22])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([OH:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccc([N+](=O)[O-])c(O)c1)Nc1cccc(Cl)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(/C=C/C(=O)Nc2cccc(Cl)c2)cc1O
Temperature: 25 °C
Yield: 61.6 %

Procedure:
(E)-N-(3-Chloro-phenyl)-3-(3-hydroxy-4-nitro-phenyl)-acrylamide (159 mg, 0.5 mmol) was suspended in EtOH (10 ml); SnCl2 (562 g, 2.5 mmol) was added and the mixture refluxed for 1.5 hrs. After cooling to RT, the solvent was evaporated. The residue was worked up with 5% sodium bicarbonate and 10% sodium potassium tartrate solutions, extracted with AcOEt, which was separated, dried and evaporated. The residue was triturated with a 1:1 diethyl ether-petroleum ether mixture, giving 89 mg of (E)-N-(3-chloro-phenyl)-3-(4-amino-3-hydroxy-phenyl)-acrylamide as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:43]=[C:23]4[C:24]([C:28]5[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=5[O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:39]([O:38][C:29]1[CH:30]=[CH:31][C:32]([C:34]([F:36])([F:35])[F:37])=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:43]=2)[CH:27]=[CH:26][CH:25]=1)[CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12

Procedure:
[8-(2-Isobutoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine was prepared from 7-[8-(2-isobutoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.263 g, 0.442 mmol) and trifluoroacetic acid (0.5 mL) in a manner analogous to Example 312 to give product (0.190 g, 87%). MP=102-103° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.47 (s, 1H), 8.78 (d, 1H), 7.98 (s, 1H), 7.75 (d, 1H), 7.62 (d, 1H), 7.35 (m, 3H), 7.05 (t, 1H), 6.98 (d, 1H), 3.87 (d, 2H), 2.62-2.75 (br m, 9H), 1.85 (m, 1H), 0.81 (d, 6H). MS=496 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=3)[NH2:24])[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:28](Cl)(=[O:30])[CH3:29]>>[F:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([NH:24][C:28](=[O:30])[CH3:29])[CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)c(F)ccc2n1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cccc(CCN2CCN(c3c(F)ccc4nc(C)ccc34)CC2)c1
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield according to Method B for the preparation of amides starting from 3-{2-[4-(6-fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline and acetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(/[CH:23]=[CH:24]/[CH3:25])[CH2:11][CH2:10][CH:9]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N)(=O)C1C(=CC=CC=1)C(N)=O.NC1CCC(C)(C(N[C@@H](C2C=CC(F)=CC=2)C)=O)CC1>>[NH2:12][CH:9]1[CH2:8][CH2:7][C:6](/[CH:23]=[CH:24]/[CH3:25])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: C/C=C/C1(C(=O)OCC)CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: C[C@@H](NC(=O)C1(C)CCC(N)CC1)c1ccc(F)cc1
Agent: NC(=O)c1ccccc1C(N)=O
Product: C/C=C/C1(C(=O)OCC)CCC(N)CC1

Procedure:
Intermediate 117 was prepared from Intermediate 116 using standard phthalamide deprotection conditions analogous to the conditions used to prepare Intermediate 77.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:22])[N:10]([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(-c3ccnc(Br)c3)n[nH]c(=O)c2cc1OC
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(-c3ccnc(Br)c3)nn(Cc3ccncc3)c(=O)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
2-Bromo-4-(6,7-dimethoxyphthalazin-1(2H)-on-4-yl)pyridine (362 mg), 4-picolyl chloride hydrochloride (180 mg), and potassium carbonate (359 mg) are added to dimethylformamide (10 ml), and the mixture is heated with stirring at 80° C. for three hours under nitrogen atmosphere. Water is added to the reaction mixture, and the mixture is extracted with methylene chloride. The extract is washed, dried, and concentrated to give 2-bromo-4-[6,7-dimethoxy-2-(4-pyridyl)methylphthalazin-1(2H)-on-4-yl]pyridine (355 mg).