Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>CN(C)C=O>[CH:22]1([C:20]([C:19]2[O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[C:9]=2[CH3:10])=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(=O)c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2cccc(F)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution (50 mL) of 1-(2-fluoro-6-hydroxyphenyl)ethanone (2.5 g) in N,N-dimethylformamide were added potassium carbonate (6.7 g) and 2-bromo-1-cyclohexylethanone (4.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was allowed to cool to room temperature and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution, and the mixture was stirred at 110° C. for 1 hr with heating. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the reaction mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (2.6 g, 62%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9](=[O:22])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[F:21])[CH:11]([CH3:12])[C:5]2=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[N:10]1[CH:11]([CH3:12])[C:5]2[C:6](=[N:7][C:2]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:3][CH:4]=2)[N:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]1=[O:22]
Reactant: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Cl)ncc3C2C)c(F)c1
Reactant: Nc1ccccc1
Product: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Temperature: 110 °C

Procedure:
(±)-7-Chloro-3-(2-fluoro-4-methoxy-phenyl)-4-methyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.21 g; 0.53 mmol) (from Example 8c supra) and aniline (450 μL; 4.94 mmol) (Aldrich) were combined and heated at 110° C. for 1 hour. After cooling, the mixture was triturated with hexanes. The solid residue was dissolved in dichloromethane and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 12M; 40:60 to 50:50 ethyl acetate-hexanes gradient) and then crystallization from dichloromethane-ether gave (±)-3-(2-fluoro-4-methoxy-phenyl)-4-methyl-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 0.20 g; 81.4%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[N:12]S(C(C)(C)C)=O.Cl>O1CCOCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[NH:12]
Reactant: CC(C)(C)S(=O)N=C1CCOc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N=C1CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
N-(6-Bromochroman-4-ylidene)-2-methylpropane-2-sulfinamide (2.0 g, 6.0 mmol, Intermediate 1) was dissolved in dry dioxane (2 mL), and 4M HCl in dioxane (15 mL, 60.00 mmol) was added. A white precipitate started to form. The mixture was stirred at r.t. for 12 h. The mixture was diluted with dry Et2O (50 mL) and vacuum filtered. The filter cake was washed with dry Et2O (50 mL), then immediately dissolved by shaking in NaHCO3 (aq) and CH2Cl2. The organic phase was dried (K2CO3) and evaporated to give 6-bromochroman-4-imine (1.3 g, 5.7 mmol). The solid was dissolved together with 2-oxopropanethioamide (Intermediate 2, 1.7 g, 17 mmol, Intermediate 2) in dry methanol (5 mL) and the resulting solution was heated at 60° C. for 12 h. Evaporation onto silica and purification by flash chromatography (EtOAc in heptane) gave the title compound (0.39 g, 21% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 2.18 (m, 1 H), 2.35 (m, 1 H), 2.42 (s, 3 H), 4.35-4.40 (m, 1 H), 4.60 (m, 1 H), 6.81 (d, 1 H), 6.88 (d, 1 H), 7.33 (dd, 1 H); MS (ES+) m/z 311 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=2)[C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.CO>C(Cl)Cl>[Br:5][C:6]1[C:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[CH:12]=[C:11]([OH:17])[CH:10]=[CH:9]2
Reactant: COc1ccc2c(-c3ccc(Cl)cc3)c(Br)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(-c2ccc(Cl)cc2)c1Br
Temperature: -78 °C
Yield: 4664.2 %

Procedure:
A vessel was charged with boron tribromide (1 M in DCM, 0.7 mL, 0.7 mmol) and cooled to −78° C. 2-bromo-1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalene (0.1 g, 0.28 mmol) was added as a solution in DCM (0.5 mL). The reaction was allowed to slowly warm to room temperature over 3.5 h. This procedure was repeated twice on a scale of 1 g and 4.1 g of 2-bromo-1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalene with appropriate adjustments in the scale of other reagents. The three lots were combined, cooled to 0° C. and the volume of the reaction was slowly doubled with MeOH. After warming to room temperature, the mixture was concentrated in vacuo and the residue was taken up in EtOAc (150 mL), treated with saturated NaHCO3 (150 mL) and then small portions of solid NaHCO3 until the solution was pH ˜7. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (5-25% EtOAc/Hex) to afford 4.54 g (91%) of the title compound as a colorless syrup. LCMS-ESI+ (m/z): [M+H]+ calcd for C17H13BrClO: 348.64; found: 348.79.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1C[N:13]([C:33]1[S:34][CH:35]=[CH:36][N:37]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:28]=2)=[CH:19][N:18]=1)(=[O:16])=[O:15].C(Cl)Cl>>[C:29]([C:27]1[N:28]=[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([S:14]([NH:13][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:16])=[O:15])=[N:18][CH:19]=2)[S:25][CH:26]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Nc3nc(C(C)(C)C)cs3)cn2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1csc(Nc2ccc(S(=O)(=O)Nc3nccs3)nc2)n1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic Acid (49.4 uL, 0.641 mmol) was added to a solution of 5-(4-tert-Butyl-thiazol-2-ylamino)-pyridine-2-sulfonic acid (2,4-dimethoxy-benzyl)-thiazol-2-yl-amide (35 mg, 0.064 mmol) in Methylene chloride (0.39 mL, 6.1 mmol). After 30 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in DMSO and purified on Gilson (semi-prep, reverse phase, Phenomenex 100×21.2 mm 10 micron C18 column, 20 mL/min, Gradient 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). Fractions were checked by LC/MS and then dried on a lyophilizer to give the desired product as a pale yellow powder.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[C:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1)#[N:16]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: N#CCc1ccc(C2CCC(=O)CC2)cc1
Product: N#CCc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by the reductive amination of [4-(4-oxo-cyclohexyl)-phenyl]-acetonitrile (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[N:42]=[C:43]=[O:44]>CCCCCC>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[NH:42][C:43](=[O:44])[N:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: COc1ccc(N=C=O)c(OC)c1
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(OC)cc1OC
Yield: 82.4 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.75 g, 0.0017 mol), prepared according to the procedure of Example 1, Part D, in hexane (40 mL) was added, dropwise, a solution of 2,4-dimethoxyphenylisocyanate (0.358 g, 0.002 mol) in hexane (20 mL) and the reaction mixture was stirred at ambient temperature for 4.5 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed with 7:3 hexane-ethyl acetate. The resulting solid was triturated with hexane to give the title compound (0.83 g, 0.0014 mol) as a glassy solid. 1H NMR (CDCl3) δ7.7-7.1(m,10H), 6.8-6.1(m,3H), 3.8(s,3H), 3.7(s,3H), 3.45(s,1H), 3.4-3.3(m,2H), 3.2(t,2H,J=7Hz), 3.0(t,2H,J=7Hz), 1.8-1.1(m,16H), 0.9(t,3H,J=8Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(S[C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>COCCOC.FC(F)(F)C([O-])=O.[Ag+]>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)SC(C)(C)C
Reactant: Nc1cc(O)ccc1Cl
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: COCCOC
Product: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)Nc1cc(O)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.4 %

Procedure:
Silver trifluoroacetate (1.5 g) was added, over a period of 1 hour, to a stirred solution of 3-amino-4-chlorophenol (0.67 g) and 3-oxo-2-(4-pyrazol-1-ylbenzyl)thiobutyric acid S-tert-butyl ester (1.7 g) in 1,2-dimethoxyethane (10 mL) at room temperature, and the resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 3:1 by volume) to afford title compound as a brown solid (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.[CH2:16]([O:18][C:19]([C@H:21]1[CH2:23][O:22]1)=[O:20])[CH3:17].[O-]S(C(F)(F)F)(=O)=O.[Li+]>C(#N)C>[CH2:16]([O:18][C:19](=[O:20])[C@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:9]=[CH:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[C:4]([F:15])[CH:3]=1)[CH3:17]
Reactant: Nc1ccc(N2C=CC(=O)CC2)c(F)c1
Reactant: CCOC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)[C@H](O)CNc1ccc(N2C=CC(=O)CC2)c(F)c1
Yield: 45 %

Procedure:
A solution of 1-(4-amino-2-fluorophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 4, 0.412 g, 2.0 mmol) and oxirane-2(R)-carboxylic acid ethyl ester (0.394 g, 3.4 mmol) with lithium triflate (0.360 g, 3.0 mmol) in dry acetonitrile (5.0 mL) is heated at 50-60° C. for 24 h. Volatiles are removed under vacuum, and the crude material purified by silica gel flash chromatography (eluent: 5% acetone in CH2Cl2) to afford the title compound (290 mg, 45%) as a viscous yellow oil, MS (m/z): 323 [M +H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)[CH:35]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J36) (361 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light red foam (490 mg, 85%).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]2)=[N:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:21][CH2:20]2)=[N:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
To a solution of 1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole (2.0 g, 5.93 mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.9 ml, 29.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, refluxed for an additional 0.5 hours and subsequently concentrated. The remaining residue was dissolved into dichloromethane and washed with 10% HCl (aq.). The organic phase was dried (MgSO4), filtered, and concentrated to give an oil which was purified via flash column chromatography (silica gel, 20% DCM/EtOAc). Concentration of the product-containing fractions gave an oil which solidified on standing. The white solid was washed with EtOAc, leaving 0.47 g of the desired product, m.p. 137-139° C.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19](S(C)=O)=[N:20]2)=[CH:15][CH:14]=1)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[NH:29][C:30](=[O:32])[CH3:31].C(O)(C(F)(F)F)=O>>[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19]([NH:25][C:26]3[CH:27]=[C:28]([NH:29][C:30](=[O:32])[CH3:31])[CH:33]=[CH:34][CH:35]=3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CS(=O)c1ncc2ccc(-c3cccn3C(=O)OC(C)(C)C)n2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(Nc2ncc3ccc(-c4ccc[nH]4)n3n2)c1

Procedure:
Following the synthetic and purification procedures described in Example 1291c, 2-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyrrole-1-carboxylic acid tert-butyl ester (80 mg, 0.2 mmol) was coupled with 3′-aminoacetanilide (77.0 mg, 0.513 mmol). Yield of TFA salt: 6 mg (7%); LC/MS: 333 (M+H); HPLC: 97% pure, RT=2.32 min; 1H NMR (DMSO, δ): 11.35 (s, 1H), 9.90 (s, 1H), 9.34 (s, 1H), 8.85 (s, 1H), 7.89 (s, 1H), 7.51 (d, J=8.5, 1H), 7.25 (t, J=8.2, 1H), 7.17 (s, 1H), 7.14 (d, J=4.7, 1H), 7.07 (s, 1H), 6.96 (m, 1H), 6.92 (d, J=4.7, 1H), 6.22 (m, 1H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH3:13].C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH3:13])[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:45])([F:47])[F:46])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: CNC1c2ccccc2CCC1C
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3c4ccccc4CCC3C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-N,2-dimethyl-1-naphthalenamine (115 mg, 0.66 mmol) and triethylamine (0.12 mL, 0.825 mmol) in 2 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (231 mg, 0.55 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo to give 270 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[C:1]1([C:7](=[N:14][C:15]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)([CH3:29])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cncnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(N=C(c1ccccc1)c1ccccc1)c1cncnc1
Reaction time: 0.5 h

Procedure:
To a solution of 456 mg of ethyl [(diphenylmethylene)amino](pyrimidin-5-yl)acetate in 4.5 ml of DMF was added 69 mg of sodium hydride (55% mineral oil included) under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added 0.1 ml of methyl iodide, followed by stirring at room temperature for 1.5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 224 mg of ethyl 2-[(diphenylmethylene)amino]-2-(pyrimidin-5-yl)propanoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1.[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:8]=3)=[O:11])[CH3:29])[N:16]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: COCc1cc(C(=O)O)[nH]n1
Product: COCc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 5.07 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-(methoxymethyl)-1H-pyrazole-5-carboxylic acid (0.119 g, 0.759 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.165 g, 0.633 mmol). The product was purified with flash-chromatography. Yield 5.07%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 3.42 (s, 3H), 4.27 (dd, 1H), 4.43 (dd, 1H), 4.54-4.62 (m, 3H), 6.62 (d, 1H), 6.69 (s, 1H), 7.49 (d, 1H), 7.67 (d, 1H), 7.75 (dd, 1H), 7.83 (m, 1H), 8.17 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[Cl-].[Na+]>C(OCC)C>[CH3:9][C:5]1[N:6]=[CH:7][O:8][C:4]=1[C:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:3])[CH3:2]
Reactant: CC(=O)c1ocnc1C
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ncoc1C(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5-Acetyl-4-methyloxazole (5g) in dry diethylether (25ml) at -70° C. under a nitrogen atmosphere was treated dropwise with phenyllithium (1.8M solution in cyclohexane-diethylether, 27ml). After 45 minutes the mixture was allowed to warm to room temperature and water (10 ml) was added. The mixture was poured into saturated aqueous sodium chloride and extracted with dichloromethane. The product thus obtained was crystallised from diethylether to give 1-(4-methyl-5-oxazolyl)-1-phenylethanol, m.p. 102-104° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:42][C:43]([NH:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[S:36]1[CH:37]=[C:33]([CH2:32][N:22]([C@@H:23]([CH3:31])[CH:24]([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:12]([CH3:13])[NH:11][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:42][C:43](=[O:44])[NH:45][C:46]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 55 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:6]([C:10]1[CH:15]=[C:14]([NH:16][C:1](=[O:4])[CH:2]=[CH2:3])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CC(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.42 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)acrylamide was prepared by adding a solution of 10 grams of acryloyl chloride in 50 milliliters of benzene to a mixture of 22.1 grams of 2,6-di tert.butyl-4-aminophenol, 6 grams of sodium carbonate, and 100 milliliters of benzene. The addition was accomplished in 25 minutes at 19° C. to 38° C. The mixture was stirred for 21/2 hours and the precipitate which had formed was filtered off, washed thoroughly with water, and dried. The yield was 12.5 grams and the product melted at 204° C. to 206° C.