Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:38]=[CH:37][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:36]=[S:32]1(=[O:35])[CH2:33][CH2:34][N:29]([CH2:28][C:27]2[CH:37]=[CH:38][C:24]([NH:1][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:11]=[CH:12][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:25][CH:26]=2)[CH2:30][CH2:31]1
Reactant: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ccc(-c2cccn3nc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nc23)cc1)S(C)(=O)=O

Procedure:
N-{4-[2-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}amino)[1,2,4]triazolo[1,5-a]pyridin-8-yl]phenyl}-N-methylmethanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (80.0 mg, 0.263 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as an orange solid (0.083 g, 65%). MP=177-180° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (dd, J=6.7, 1.1 Hz, 1H), 8.04 (d, J=8.6 Hz, 2H), 7.60-7.52 (m, 5H), 7.28 (d, J=8.5 Hz, 2H), 7.00 (t, J=6.9 Hz, 1H), 6.89 (s, 1H), 3.62 (s, 2H), 3.39 (s, 3H), 3.08-2.96 (m, 8H), 2.90 (s, 3H). MS=541 (MH)+.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[H][H]>[Pd]>[CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CC=CCC1
Reactant: [H][H]
Agent: [Pd]
Product: O=C(O)C1CCCCC1

Procedure:
3.2 g (2.5 wt. % of 3-cyclohexene-1-carboxylic acid) 3% Pd/C was added to the 3-cyclohexene-1-carboxylic acid solution and the reaction was activated at the temperature of 100° C. with a hydrogen pressure of 120 psi to yield cyclohexanecarboxylic acid with a conversion rate of more than 99%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[CH3:31][O:32][C:33](=[O:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:38](=[O:39])[C:37]3[CH:36]=[CH:35][C:34]([C:33]([O:32][CH3:31])=[O:43])=[CH:42][CH:41]=3)=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cn3c(C(=O)OC)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.9 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in dichloromethane (5 ml) were added terephthalic acid monomethyl ester (65 mg), 1-hydroxy-1H-benzotriazole (64 mg) and dimethylpyridin-4-yl-amine (51 mg), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (103 mg) was added at room temperature. The mixture was stirred at room temperature for 15 hrs. Dichloromethane was added, and the mixture was washed with 1N hydrochloric acid and saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=1/0-+9/1) to give the title compound (103 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1.I[CH3:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:30])=[CH:24][N:23]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(O)cn2)c1
Reactant: CI
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1

Procedure:
N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.12 mmol) was used in Procedure L with excess iodomethane. Purified by silica gel chromatography (0-100% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-methoxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.57 (50% ethyl acetate/hexanes); MS (Q1) 423 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)[CH:9]=1)([O-:3])=[O:2].[NH2:16][C@@H:17]([CH3:34])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:13]([C:11]3[N:12]=[C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]4[CH:10]=3)=[O:15])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2cc([N+](=O)[O-])ccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cc([N+](=O)[O-])ccc2n1
Yield: 18.9 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 6-nitroimidazo[1,2-a]pyridine-2-carboxylic acid (0.551 mmol, 0.114 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.459 mmol, 0.128 g). DMF (4 ml) was used as the solvent and HBTU (0.046 mmol, 0.017 g) was used instead of HOBt. The crude product was purified by preparative HPLC. 0.0405 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.37 (d, 3H), 4.30-4.37 (m, 1H), 4.38-4.46 (m, 1H), 4.59-4.72 (m, 1H), 6.72 (d, 1H), 7.54 (d, 1H), 7.68 (d, 1H), 7.72 (s, 1H), 7.78 (d, 1H), 8.15-8.21 (m, 1H), 8.38 (s, 1H), 10.40-10.44 (m, 1H).
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([C:5](=S)[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:3][CH2:2]1.[NH3:15]>>[NH2:15][C:5]1[CH:4]2[CH2:3][CH2:2][CH2:1][CH:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: S=C1Nc2ccccc2C2CCCC12
Reactant: N
Product: NC1=Nc2ccccc2C2CCCC12

Procedure:
1,2,3,3a,5,9b-Hexahydrocyclopenta[c]quinoline-4-thione (110 mg, 0.54 mmol) is stirred in 7 M methanolic ammonia solution (50 ml) for 15 hours at room temperature. The batch is concentrated by evaporation in a vacuum. The residue is purified by column chromatography on silica gel with dichloromethane-methanol-concentrated NH4OH as an eluant.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]2[C:14]3[C:3]=1[CH2:4][CH2:5][C:6]=3[CH:7]=[CH:8][C:9]=2[Cl:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([NH:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]2[C:14]3[C:3]=1[CH2:4][CH2:5][C:6]=3[CH:7]=[CH:8][C:9]=2[Cl:15])(=[O:18])[CH3:17]
Reactant: Nc1cc(Cl)c2c(Cl)ccc3c2c1CC3
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c2c(Cl)ccc3c2c1CC3
Temperature: 10 °C

Procedure:
A suspension of 3-amino-5,6-dichloroacenaphthene (3.3 g 13.8 mmol, from Example D4) in 10 mL of acetic acid was treated with 10 mL of acetic anhydride and heated on a steam bath for 1 hour. The reaction was cooled to 10° C., and the solid was removed by filtration, washed with petroleum ether, and dried in vacuo to give 3.5 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[OH:16])=[CH:5][CH:4]=[N:3]1.Br.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1O
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCc1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 110.7 %

Procedure:
A mixture of 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (100 mg, 0.46 mmol), 2-bromomethylpyridine hydrobromide salt (140 mg, 0.55 mmol) and potassium carbonate (158 mg, 1.15 mmol) in DMSO (4 mL) was stirred at 100° C. overnight. The crude was purified by HPLC to provide the title compound as a brown solid (158 mg, 81%). Exact mass calculated for C16H14N4O3 310.1. found 311.2 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[S:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:15]=1Br)=[O:10].[C:23]([O:27][C:28]([N:30]1[CH2:35][C:34](=[O:36])[NH:33][C@H:32]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].O1CCOCC1>CCOC(C)=O.[Cu]I>[C:23]([O:27][C:28]([N:30]1[CH2:35][C:34](=[O:36])[N:33]([C:15]2[CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][C:11]=2[C:9]([O:8][CH3:7])=[O:10])[C@H:32]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N[C@H](C2CCCCC2)C1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CN(C(=O)OC(C)(C)C)C[C@H]1C1CCCCC1
Temperature: 110 °C
Yield: 29.4 %

Procedure:
A tube was charged with trans-cyclohexanediamine (162 mg, 1.42 mmol, 0.5 equiv), K2CO3 (783 mg, 5.67 mmol, 2.0 equiv), 3-bromo-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.01 g, 3.40 mmol, 1.2 equiv), CuI (270 mg, 1.42 mmol, 0.5 equiv), (R)-3-Cyclohexyl-5-oxo-piperazine-1-carboxylic acid tert-butyl ester (800 mg, 2.83 mmol, 1.0 equiv) and 1,4-dioxane (3.0 mL). The tube was then flushed with N2 and sealed. The reaction mixtures were heated at 110° C. for 72 hours after which it was diluted with EtOAc and filtered. The filtrate was washed with 1.0 N HCl aq. solution, brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane, 50%) to give product (R)-3-Cyclohexyl-4-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-5-oxo-piperazine-1-carboxylic acid tert-butyl ester 415 mg.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[OH:24][CH2:25][CH2:26][NH2:27]>>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:27][CH2:26][CH2:25][OH:24])[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Reactant: NCCO
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccc(OC)cc23)cc1

Procedure:
A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.2 g, 0.60 mmol), and 2-hydroxylethylamine (1.5ml) was microwaved at 120° C. for 20 min. The excess of 2-hydroxylamine evaporated under reduced pressure. The product was isolated by preparative TLC (CH2CL2/MeOH=5/3 as eluent) yielded 35 mg (18%). 1H NMR (DMSO): δ 7.2 (d, 2H), 7.1 (d, 2H), 7.05 (d, 1H), 6.9 (d, 2H), 6.2 (s, 1H), 3.75 (s, 3H), 3.5 (t, 2H), 3.4 (t, 2H), 3.41 (s, 3H), 3.2 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:17][CH3:16])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccccc2Cl)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2ccccc2Cl)C1
Reaction time: 16 h

Procedure:
A stirred solution of 4.5 g (0.018 mol) of 3-(2-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mol) of 40% aqueous monomethylamine and stirred for 16 h. The reaction mixture was diluted with 200 ml of water and the precipitated product collected by filtration (4.3 g). The crude product was recrystallized from benzene/ligroin yielding 3.9 g (90.0%) of fine white crystals, mp 129.5°-131.5° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=[O:5].[Li+].CC([N-]C(C)C)C.[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.S(=O)(=O)(O)O>CCOCC>[I:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](=[O:21])[CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 47 %

Procedure:
A solution of EtOAc (6 mL) in Et2O (15 mL) was added to a solution of LDA (2 M in THF, 60 mL, 120 mmol) in Et2O (80 mL) at −78° C. The resulting solution was stirred at −78° C. for 45 minutes. To this solution, a solution of 4-iodobenzoyl chloride (16 g, 60.5 mmol) in Et2O (30 mL) was added at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was poured into iced-sulfuric acid (300 g, 10%), stirred for 15 minutes, and extracted with Et2O (3×80 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound as light orange oil (9 g, 47%). Compound exists as a mixture of ketone and enol forms (3:1). 1H NMR (CDCl3, 400 MHz): (ketone form) δ 7.87 (d, 2H), 7.67 (d, 2H), 4.26 (q, 2H), 3.95 (s, 2H), 1.24 (t, 3H); (enol form) δ 12.55 (s, 1H), 7.78 (d, 2H), 7.50 (q, 2H), 5.65 (s, 1H), 4.59 (q, 2H), 1.34 (t, 3H).
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:19]1[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Product: c1ccc2c(c1)OCCc1cc(-c3ccncc3)sc1-2

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine from Example 73 was reacted with 4-pyridine boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on silica gave 153. 1H NMR (400 MHz, CDCl3): 3.29 (2H, t), 4.39 (2H, t), 7.06-7.11 (2H, m), 7.22 (1H, dt), 7.28 (1H, s), 7.49 (2H, dd), 7.75 (1H, dd), 8.62 (2H, dd). MS: (ESI+) 280
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[S:30]([C:34]1[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=1)(=[O:33])(=[O:32])[NH2:31]>>[S:30]([C:34]1[CH:35]=[C:36]([NH:40][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:13])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:28])[CH:37]=[CH:38][CH:39]=1)(=[O:32])(=[O:33])[NH2:31]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 572.1 [(M−H)−]; mp 253° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:23]2[C:19]3[N:20]=[CH:21][N:22]=[C:17]([C:8]4[CH:9]=[C:10]([C:13]([F:15])([F:14])[F:16])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:3][CH2:4]4)[C:18]=3[NH:25][C:24]=2[CH3:26])=[O:28])[CH2:35][CH2:34]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f31) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:50][CH2:51][CH2:52][C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:50][CH2:51][CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: NCCc1cccnc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCc4cccnc4)cc3)cn2)cc1
Yield: 103.7 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (60.0 mg, 0.0909 mmol) obtained in Step A in Example 1-D-19 and 3-(2-aminoethyl)pyridine (21.4 μl, 0.182 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-pyridin-3-yl-ethyl)-benzamide as a brown solid (72.0 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-279) as a yellow powder (40.4 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.[H-].[Na+].Cl[CH2:26][O:27][CH3:28]>CN(C=O)C>[F:21][C:19]1[CH:18]=[C:15]([CH:14]=[C:13]([C:11]2[CH:10]=[CH:9][C:4]3[N:5]([CH2:26][O:27][CH3:28])[C:6](=[O:8])[O:7][C:2]([CH3:22])([CH3:1])[C:3]=3[CH:12]=2)[CH:20]=1)[C:16]#[N:17]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile (0.150 g, 0.51 mmol) in DMF (5 mL) was treated at rt with sodium hydride (0.061 g, 1.53 mmol). The mixture was stirred for 30 minutes and treated with chloromethyl methylether (0.062 g, 7.7 mmol). Upon completion of the reaction, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3×30 mL), dried over MgSO4, and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 3-fluoro-5-(1-methoxymethyl4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile as a white solid (0.11 g, 65%): mp 169-171° C.; 1H-NMR (DMSO-d6) δ8.17 (bs, 1H), 8.03 (dt, 1H, J=10.4, 2.13 Hz), 7.85-7.77 (m, 3H), 7.31 (d, 1H, J=8.49 Hz), 5.33 (s, 2H), 3.35 (s, 3H), 1.7 (s, 6H); MS (APCI) m/z 341 ([M+H]+, 50%); Anal. Calc. For C19H17FN2O3: C, 65.32, H, 5.19, N, 8.02. Found: C, 64.92, H, 4.96, N, 7.73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C([Li])CCC.[O:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1.O>C1COCC1>[Cl:1][C:2]1[C:3]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[C:4]([C:25]2([OH:28])[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: COc1ccc(Cl)c(NC(=O)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(NC(=O)C(C)(C)C)c1C1(O)CCOCC1
Temperature: -10 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a stirred solution of intermediate 12 (1 g, 4.13 mmol) in THF (25 mL) under nitrogen at −20° C. was added dropwise n-butyllithium (2.5M in hexane, 4.13 mL, 10.34 mmol). The reaction mixture was stirred at −10° C. for 4 h and n-butyllithium (2.5M in hexane, 4.13 mL, 10.34 mmol) was added dropwise at −10° C. The mixture was further stirred for 7 h and tetrahydropyran-4-one was added dropwise at 0° C. The mixture was stirred overnight at room temperature, poured into water and extracted with EtOAc. The organic extracts were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated. The crude material was purified by precipitation in EtOAc to afford intermediate 13 as a white powder (0.25 g, 18%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][C:27]1[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:31]=[C:32]([NH:33][C:34](=[O:36])[CH3:35])[C:27]([O:26][CH2:24][CH3:25])=[N:28][CH:29]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(C)=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCOc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1NC(C)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (synthesized in a similar manner as Stage 64.1.1, (HPLC: tR 1.84 min (Method A); M+H=293 MS-ES)) to give the title compound as a white solid. (HPLC: tR 2.64 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.37 (s, 1H), 8.96 (s, 1H), 8.45-8.43 (m, 1H), 8.12-8.08 (m, 2H), 8.01-8.00 (m, 1H), 7.85-7.82 (m, 1H), 7.52-7.50 (m, 1H), 4.44 (q, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 2.15 (s, 31-1), 1.92 (s, 3H), 1.37 (t, 3H))
Reaction SMILES: [CH:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=3)=[O:17])=[C:11]([N:25]3[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]3)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:31][CH:28]1[CH2:27][CH2:26][N:25]([C:11]2[CH:10]=[C:9]([C:3]3([CH2:1][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]3)[CH:14]=[CH:13][C:12]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])[CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: CC1CCN(c2cc(C3(C=O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1CCN(c2cc(C3(CN4CCCC4)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound is prepared by the procedure of Example 26, step (b) using 4-cyano-1H-imidazole-2-carboxylic acid [4-(4-formyl-tetrahydro-pyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide (as prepared in the previous step) and pyrrolidine.