Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:21](=[O:22])[N:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25][CH:24]=1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:8][CH2:7][N:6]3[C:21](=[O:22])[C:2]([NH:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][N:25]=4)=[CH:3][CH:4]=[C:5]3[C:10]2=[O:11])=[CH:14][CH:15]=1
Reactant: COc1ccc(CN2CCn3c(ccc(Cl)c3=O)C2=O)cc1
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1ccc(CN2CCn3c(ccc(Nc4ccncn4)c3=O)C2=O)cc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H)-dione (3, 0.45 g, 1.41 mmol) in dioxane (10 mL), pyrimidin-4-amine (4, 0.13 g, 1.41 mmol), sodium tert-butoxide (0.41 g, 4.2 mmol) followed by X-Phos (0.14 g, 0.28 mmol) were added and the reaction mixture was degassed with argon for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (0.13 g, 0.14 mmol) was added and the reaction mixture was degassed with argon for another 5 min and stirred at 110° C. for 16 h. The reaction mixture was diluted with water and the compound was extracted in ethyl acetate. The organic layer was washed with brine, separated, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified via column chromatography (silica, methanol/dichloromethane=5%) to afford 2-(4-methoxybenzyl)-7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-c]pyrazine-1,6(2H)-dione (5) as a yellow solid. Yield: 0.42 g, 79%; MS (ESI) m/z 378 [M+1]+.
Reaction SMILES: C(N[C@H](C(O)=O)C)(=O)C.C(N1CCOCC1)C.ClC(OCC(C)C)=O.O1CCCCC1ONC([C@H]([C@@H:46]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:47]([NH:49][NH:50][CH2:51][CH:52]([CH3:54])[CH3:53])=[O:48])C/C=C/C1C=CC=CC=1)=O>O1CCCC1.C(OCC)(=O)C>[CH2:51]([NH:50][NH:49][C:47](=[O:48])[CH2:46][CH2:55][CH:56]([CH3:58])[CH3:57])[CH:52]([CH3:54])[CH3:53]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CC(=O)N[C@@H](C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCC(=O)NNCC(C)C
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.144 g of N-acetyl-L-alanine in 10 ml tetrahydrofuran was cooled to −10° C. and treated with 0.140 ml of N-ethylmorpholine and 0.143 ml of isobutyl chloroformate. The mixture was stirred for a further 10 minutes at 10° C. and then treated with 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide. The mixture was allowed to warm to 0° C. and stirring was continued for 1.5 hours. The mixture was then diluted with ethyl acetate and washed in sequence with 5% aqueous citric acid, 5% aqueous sodium hydrogen carbonate and brine. Drying over magnesium sulphate and evaporation gave 0.601 g of (E)-2′-(N-acetyl-L-alanyl)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: C(OC([C:8]1(C(OC(C)(C)C)=O)[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:30])(=[O:29])[N:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:9]1=[O:31])=O)(C)(C)C>FC(F)(F)C(O)=O>[Br:17][C:13]1[CH:12]=[C:11]2[C:16]([CH2:8][C:9](=[O:31])[N:10]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([N:26]([CH3:27])[CH3:28])(=[O:30])=[O:29])=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)c3ccc(Br)cc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)Cc3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
6-Bromo-1-(4-dimethylsulfamoyl-benzyl)-2-oxo-1,2-dihydro-indole-3,3-dicarboxylic acid di-tert-butyl ester (10.0 g, 16.4 mmol) was dissolved in 50 ml of trifluoroacetic acid (TFA) under an atmosphere of dry N2 and stirred overnight at ambient temperature. The reaction mixture was then concentrated under vacuum and partitioned between DCM and saturated aqueous sodium bicarbonate (NaHCO3). The DCM layer was then dried over MgSO4, filtered and concentrated under vacuum to give 6.05 g of the titled compound as a white solid.
Reaction SMILES: N1(C2C=CC(NC3C4N(C=CN=4)C(C4C=CNC(=O)C=4)=CN=3)=CC=2)CCOCC1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][C:41]([C:42]([NH2:44])=[O:43])=[CH:40][CH:39]=2)O1.Br[C:49]1[N:54]2[CH:55]=[CH:56][N:57]=[C:53]2[C:52]([NH:58][C:59]2[CH:64]=[CH:63][C:62]([S:65]([CH3:68])(=[O:67])=[O:66])=[CH:61][CH:60]=2)=[N:51][CH:50]=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:68][S:65]([C:62]1[CH:63]=[CH:64][C:59]([NH:58][C:52]2[C:53]3[N:54]([CH:55]=[CH:56][N:57]=3)[C:49]([C:38]3[CH:39]=[CH:40][C:41]([C:42]([NH2:44])=[O:43])=[CH:45][CH:46]=3)=[CH:50][N:51]=2)=[CH:60][CH:61]=1)(=[O:66])=[O:67]
Reactant: CS(=O)(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncc(-c3ccc(C(N)=O)cc3)n3ccnc23)cc1

Procedure:
In the same way as described for Compound 85, step 1, using 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.0 g, 6.11 mmol), (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(4-methanesulfonyl-phenyl)-amine (1.49 g, 4.07 mmol), Pd(PPh3)4 (471 mg, 0.41 mmol) and NaOtBu (1.57 g, 0.82 mmol) in DMF (18 mL) and water (6 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated to afford a solid, crystallised in ethyl acetate (566 mg, 34%). LCMS: Rt 2.53 min (99%), m/z (APCI) 408 (M+H)+; 1H-NMR (400 MHz, d6-DMSO δ(ppm) 3.21 (3H, s), 7.54 (1H, br s), 7.67 (1H, s), 7.81 (1H, s), 7.86-7.92 (4H, m), 8.09-8.17 (3H, m), 8.21 (1H, br s), 8.41 (2H, d), 10.32 (1H, s).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.[OH:13][C:14]1[CH:15]=[C:16]([S:20][CH2:21][CH2:22][N:23]([N:32]2[CH:36]=[N:35][N:34]=[CH:33]2)[C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1>O.C(OCC)(=O)C.CN(C)C(=O)C>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:23]([N:32]2[CH:36]=[N:35][N:34]=[CH:33]2)[CH2:22][CH2:21][S:20][C:16]2[CH:15]=[C:14]([O:13][S:1](=[O:4])(=[O:3])[NH2:2])[CH:19]=[CH:18][CH:17]=2)=[CH:25][CH:26]=1)#[N:29]
Reactant: N#Cc1ccc(N(CCSc2cccc(O)c2)n2cnnc2)cc1
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N(CCSc2cccc(OS(N)(=O)=O)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sulphamoyl chloride solution in toluene (1.5 ml, 0.7 M, 1.05 mmol) was concentrated under reduced pressure (30° C. water bath temperature) to ca. 0.5 ml volume. The residue was cooled to 0° C. (ice bath) and N,N-dimethyl acetamide (5 ml) was added. 4-{[2-(3-Hydroxy-phenylsulfanyl)-ethyl]-[1,2,4]triazol-4-yl-amino}-benzonitrile (CAB02149, 75 mg, 0.22 mmol) was added to the colourless solution and the mixture was stirred for 18 hours at room temperature. Ethyl acetate (50 ml) and water (50 mL) were added to the solution, the organic layer was separated, washed with water (2×30 ml) and brine (1×20 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in a small amount of acetone and precipitated by addition of hexane. The precipitate (STX1014) was filtered off and dried under high vacuum. Yield: 79 mg (85%) light yellow powder. 1H-NMR (400 MHz, DMSO-d6) δ3.23 (t, J=7.0 Hz, 2H), 4.07 (t, J=7.0 Hz, 2H), 6.54 (d, J=8.9 Hz, 2H), 7.08-7.12 (m, 1H), 7.20-7.26 (m, 1H), 7.39 (dd, J=9.2, 9.2 Hz, 1H), 7.69 (d, J=8.9 Hz, 2H), 8.03 (s, 2H, —NH2), 8.94 (s, 2H); MS (FAB+): m/z 85.1.1 (28%), 417.0 (100%, [C17H16N6O3S2+H]+); HRMS (FAB+) for C17H17N6O3S2: 417.08036; Found, 417.08067; HPLC tR=1.53 min (99.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:15]=2[S:14][CH:13]=1.ClCCl.C(N(CC)CC)C.Br[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O>[CH2:39]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:20]2[C:15]3[S:14][CH:13]=[C:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:27][CH2:26]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCNCC4)ncnc23)c(F)c1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(Cc5ccccc5)CC4)ncnc23)c(F)c1
Reaction time: 1 h

Procedure:
50 mg of 7-(2-fluoro-4-methanesulfonyl-phenyl)-4-[piperidin-4-yloxy]thieno[3,2-d]pyrimidin was added to 1 ml of dichloromethane, and 32 μl of triethylamine was added thereto. 16 μl of (bromomethyl)benzene was added to the mixture, and after 1 hr, water was added thereto for terminating the reaction. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to obtain a bubble residue. The resulting residue was purified by column chromatography to obtain 30 mg of the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:24][CH2:23][C:11]2([CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:2]1([C:1]([N:9]2[CH2:24][CH2:23][C:11]3([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(C(=O)c3ccccc3)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)N1CCC2(CCNC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 7-benzoyl-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg) was dissolved in 10% TFA solution in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 24 hours. After removal of solvents, the residue, phenyl(2,7-diazaspiro[4.4]nonan-2-yl)methanone, was used in the further reactions without purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C1COCC1.O>[O:11]=[CH:12][CH2:13][N:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(CCO)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC=O)c1ccccc1
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
A solution of oxalyl chloride (0.37 mL) in THF (5.0 mL) was cooled to −78° C., and DMSO (0.39 mL) and THF (2.0 mL) were slowly added dropwise. The reaction mixture was stirred for 5 min, and a solution of the compound (0.50 g) obtained in step 1 in THF (3.0 mL) was added dropwise. The reaction mixture was stirred at −78° C. to −20° C. for 1 hr, and triethylamine (2.0 mL) was added. The reaction mixture was stirred at room temperature for 30 min, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (0.38 g, 77%) as a colorless oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25]/[C:26](=[CH:32]\[C:33]1[CH:34]=[N:35][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([NH:45][CH3:46])[CH:40]=2)=[CH:37][CH:38]=1)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24].O>ClCCl>[CH2:23]([O:25]/[C:26](=[CH:32]\[C:33]1[CH:34]=[N:35][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([N:45]([CH3:46])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH:40]=2)=[CH:37][CH:38]=1)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)nc1)OCC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)nc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 118.4 %

Procedure:
0.17 g (0.83 mmol) of 4-nitrophenyl chloroformate and then 0.14 mL (0.83 mmol) of diisopropylethylamine are added to a solution of 0.18 g (0.55 mmol) of ethyl (Z)-2-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]acrylate in 5 mL of dichloromethane. The reaction mixture is stirred for 1 hour 30 minutes at room temperature. The reaction is stopped by addition of 5 mL of water and extraction with dichloromethane. The organic phases are combined and then dried over magnesium sulfate. The solvents are evaporated off. 0.32 g (100%) of ethyl (Z)-2-ethoxy-3-(6-{3-[methyl-(4-nitrophenoxycarbonyl)amino]phenyl}pyrid-3-yl)acrylate is obtained in the form of a yellow oil. The crude product obtained is used directly in the following step.
Reaction SMILES: [Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:8]=3[C@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:8]=3[C@H:9]3[C@H:14]([NH:15][C:31](=[O:33])[CH3:32])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CC(=O)Cl
Reactant: N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cccc(F)c3[C@@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCCN2c3cc(Br)c(F)cc3Oc3cccc(F)c3[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.4 g (1.05 mmol) (−)-(cis)-7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine in a mixture of CH2Cl2 (10 mL) and triethylamine (0.44 mL, 3.15 mmol), acetyl chloride (0.187 mL, 2.62 mmol) in CH2Cl2 (5 mL) was added and it was stirred at ambient temperature for 1 h. Saturated (aq) NaHCO3 was added and the organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude compound which was used without further purification (0.44 g, 100%).
Reaction SMILES: [I-].[K+].[N+](C1C=C[C:9]2[N:15]3C(CCl)=NN=C3CN=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3Cl)[C:10]=2C=1)([O-])=O.C[NH:30]C1CC1>O1CCCC1>[NH:30]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:11]=[CH:10][CH:9]=[N:15]1
Reactant: CNC1CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=Cc2ccccc2NN=C1

Procedure:
In the manner given in Example 2, potassium iodide and 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran are treated with methylcyclopropylamine to give 8-nitro-1-[(cyclopropylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-]1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([F:18])[CH:17]=1.[OH-].[Na+]>C1COCC1.[Pd]>[F:11][C:12]1[CH:13]=[C:14]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1cc(F)cc(-c2cccc3[nH]ccc23)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-bromoindole (12.42 g, 63.3 mmol), and 3,5-difluorophenylboronic acid (10.0 g, 63.3 mmol) in THF (108 mL) were added Palladium catalyst Pd(PPh3)4 (2.2 g, 1.9 mmol) and the freshly prepared sodium hydroxide solution (7.6 g, 190 mmol in 89 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 85° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, filtered through celite, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column to provide 4-(3,5-difluoro-phenyl)-1H-indole.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:30][C:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:32][OH:33])=[CH:25][CH:24]=1.[CH3:47][O:48][CH2:49][CH2:50][NH:51][CH3:52].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:47][O:48][CH2:49][CH2:50][N:51]([CH3:52])[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:30]/[C:31](/[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:32]\[OH:33])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(Br)cc1
Reactant: CNCCOC
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COCCN(C)c1ccc(C(C/C(=N\O)c2ccncc2)c2ccccc2C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a suspension of tris(dibenzylideneacetone)dipalladium (23 mg), sodium tert-butylate (83 mg), 2(di-tertbutylphosphino)biphenyl (15 mg) and 3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31, 200 mg) in toluene (10 mL) was added a solution of N (2-methoxyethyl)methylamine (158 mg) in toluene (10 mL). The reaction mixture was stirred at 80° C. overnight, cooled to room temperature and a saturated aqueous solution of NH4Cl was added. The phases were separated and the inorganic layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography on silica gel (EtOAc/n-heptane 2:1 to EtOAc) yielded (E)-3-{4-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime containing less than 10% of the Z isomer (88 mg, 43%) as a yellow foam, MS (ESI+): m/z=404.3 ([M+H]+).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.CC1(C)C(C)(C)OB(/[CH:46]=[CH:47]/[C:48]2[CH:49]=[C:50]([CH:55]=[CH:56][N:57]=2)[C:51]([O:53][CH3:54])=[O:52])O1.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8](/[CH:46]=[CH:47]/[C:48]4[CH:49]=[C:50]([CH:55]=[CH:56][N:57]=4)[C:51]([O:53][CH3:54])=[O:52])[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccnc(/C=C/B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)c1ccnc(/C=C/c2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
An aqueous 2.0 M solution of Na2CO3 (0.3 mL) was added to a solution of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (100 mg, 0.103 mmol), (E)-methyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)isonicotinate (1127) (76 mg, 0.26 mmol), Pd(PPh3)4 (75 mg, 0.66 mmol), LiCl (28 mg, 0.66 mmol) in 1,4-dioxane (5 mL) and the resulting mixture was stirred under nitrogen at 90° C. for 16 hours. The crude mixture was evaporated under reduced pressure and adsorbed onto silica gel. Chromatography (SiO2, 0-50% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I128) (110 mg, 86%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=4.9 Hz, 1H), 8.64 (s, 1H), 8.14 (d, J=15.1 Hz, 1H), 8.02 (s, 1H), 7.88 (dd, J=15.1, 1.6 Hz, 1H), 7.80 (dd, J=4.9, 1.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.36 (s, 1H), 7.25 (m, 1H), 4.33-4.19 (m, 2H), 4.00 (s, 3H), 2.82 (m, 2H), 2.67 (m, 1H), 1.85 (d, J=12.7 Hz, 2H), 1.64 (dd, J=12.5, 4.0 Hz, 2H), 1.59 (s, 9H). LCMS Method C: rt 6.93 min; m/z 584.21 [M+1]+, 582.1 [M−1]−, 528.1 [M-tBu+2]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.C1C[O:20][CH2:19]C1.CN(C=O)C.Cl>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH:19]=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(I)ccc(C#N)c1Cl
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1c(C=O)ccc(C#N)c1Cl
Temperature: -32 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-4-iodo-3-methylbenzonitrile (150 g, 0.54 mol) and THF (1200 ml) was cooled down to −32° C. A 2 M i-PrMgCl-THF-solution (541 ml, 1.08 mol) was added slowly during 1 h and the mixture was stirred at −32° C. for 2 h. DMF (83 ml, 1.08 mol) was added at −32° C. and the reaction mixture was allowed to warm to RT. After stirring overnight 10% HCl solution (1000 ml) was added at 0° C. The layers were separated and the aqueous layer was extracted with diethyl ether (2×900 ml). The combined organic layers were washed with saturated NaHCO3 solution (900 ml) and brine (750 ml). The organic layer was dried with Na2CO4, filtered and evaporated. The dried crude product (95 g) was treated with hot n-heptane and activated carbon. The title compound was obtained as a yellow solid and used without further purification. 1H-NMR (400 MHz; CDCl3): δ 2.78 (s, 3H), 7.71 (d, 1H), 7.84 (d, 1H), 10.36 (s, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccn1
Reactant: CS(=O)c1ncc2ccc(=O)n(C3CCCC3)c2n1
Product: O=c1ccc2cnc(Nc3ccccn3)nc2n1C1CCCC1
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 7 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.7 mmol) prepared as in Example 107 of WO 98/33798 (incorporated herein by reference) and 2-aminopyridine (130 mg, 1.4 mmol) were combined in a 10 mL round-bottomed flask. The flask was purged with nitrogen (10 min), then heated in a 160° C. oil bath (30 min). After cooling, the orange residue was triturated with water to afford an orange solid, which was further purified by reversed-phase HPLC purification. [Vydac C18 TP254 (30 mm×100 mm); A: ACN (acetonitrile)+0.1% TFA (trifluor acetic acid); B; H2O+0.1% TFA; 10%-76% B over 40 min]. 15 mg of 8-cyclopentyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one was isolated as a yellow solid. Mp: >250° C., Anal. HPLC [Vydac C18 TP254 (4.6×150 mm); A: ACN+0.1% TFA; B; H2O+0.1% TFA; 10%-76% B over 20 min]: >98% Rt=13.9 min.