Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:27][C:28](=[O:43])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])=[C:31]([CH3:42])[CH:30]=1)[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[N:18]=1)=O)C1C=CC=CC=1.I[Si](C)(C)C.CO>ClCCl>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:27][C:28](=[O:43])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:36])=[C:31]([CH3:42])[CH:30]=1)[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[N:18]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.3 g (0.49 mmol) of N-[(1S)-5-(benzyloxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is dissolved in 15 mL of dichloromethane and, after the addition of 0.25 mL (0.76 mmol) of iodotrimethylsilane, stirred for 3 hours at ambient temperature. Then 10 mL of methanol is added and the mixture is stirred for a further 30 minutes. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with dichloromethane/methanol (80:20). Yield: 0.22 g (96%); Rf value: 0.15 (silica gel; dichloromethane/methanol=9:1); C25H30ClN5O2 (468.00); mass spectrum: (M+H)+=468/470 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:19])[CH:17]=2)[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:19])[CH:17]=2)[N:12]=[C:11]([N:24]2[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:21][CH2:22][CH2:23]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Clc1nc(OCc2ccccc2)c2cc(Br)ccc2n1
Product: Brc1ccc2nc(N3CCSc4ccccc4C3)nc(OCc3ccccc3)c2c1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of 4-(benzyloxy)-6-bromo-2-chloroquinazoline (700 mg, 2.0 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (990 mg, 6.0 mmol) was heated at 80° C. for 10 minutes. The resulting reaction mixture was cooled to room temperature and purified by silica gel column chromatography (eluting with dichloromethane) to afford 600 mg of the desired product as a white solid (yield was 62.7%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]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.[NH2:66][C:67]1([C:72]([NH:74][C:75]2[CH:80]=[CH:79][C:78](/[CH:81]=[CH:82]/[C:83]([O:85]CC)=[O:84])=[CH:77][CH:76]=2)=[O:73])[CH2:71][CH2:70][CH2:69][CH2:68]1>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:66][C:67]4([C:72]([NH:74][C:75]5[CH:76]=[CH:77][C:78](/[CH:81]=[CH:82]/[C:83]([OH:85])=[O:84])=[CH:79][CH:80]=5)=[O:73])[CH2:68][CH2:69][CH2:70][CH2:71]4)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC(=O)N(C)C)cc1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)C2(N)CCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)NC4(C(=O)Nc5ccc(/C=C/C(=O)O)cc5)CCCC4)cc3n2CC(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11 %

Procedure:
A solution (0.04 M) of 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(4 methoxyphenyl)-1H-indole-6-carboxylic acid (from Step 4) in DMF was treated with DIPEA (3 eq.), HATU (2 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (1.1 eq.). The solution was stirred at 25° C. for 12 h. The mixture was diluted with EtOAc then washed sequentially with aqueous HCl (1N), NaOH (2 N) and brine. The dried organic layer was concentrated and the residue dissolved in a solution 1:1 of THF/H2O. The resulting solution was treated with LiOH monohydrate (3 eq.) and stirred at 50° C. for 5 h. The mixture was concentrated under reduced pressure and the residue was treated with aqueous HCl (1 N). Purification by HPLC (stationary phase: Water Symmetry C18 19×300 mm) gave the title compound (11%) as a solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 1.11-1.40 (m, 3H), 1.62-1.91 (m, 11H), 2.05-2.16 (m, 2H), 2.28-2.44 (m, 2H), 2.50-2.62 (m, 1H), 2.80 (s, 3H), 2.92 (s, 3H), 3.85 (s, 3H), 4.83 (s, 2H), 6.40 (d, J 16.0, 1H), 7.08 (d, J 8.6, 2H), 7.24 (d, J 8.6, 2H), 7.52 (d, J 16.0, 1H), 7.60 (d, J 8.3, 2H), 7.66 (d, J 8.3, 2H), 7.71 (d, J 8.3, 1H), 7.78 (d, J 8.3, 1H), 7.83 (s, 1H), 8.26 (s, 1H), 9.67 (s, 1H), 12.40 (br s, 1H); MS (ES+) m/z 691 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@H:15]([CH2:16][O:17][Si](C)(C)C)[CH2:14][CH2:13][C@@H:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C@H:12]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:13][CH2:14][C@@H:15]2[CH2:16][OH:17])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)OC[C@@H]1CC[C@H](c2ccccc2)N1S(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)N1[C@@H](CO)CC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of (2R,5S)-1-(4-chloro-benzenesulfonyl)-2-phenyl-5-trimethylsilanyloxymethyl-pyrrolidine (0.76 g, 1.8 mmol) in 15 mL of MeOH at 0° C. was added K2CO3 (15 mg, 0.11 mmol, catalyst). After stirring at 0° C. for 30 min, the reaction mixture was partitioned between EtOAc (50 mL) and saturated brine (50 mL). The organic phase was separated, dried (Na2SO4) and concentrated under vacuum to give 0.63 g (100%) of (2R,5S)-[1-(4-chloro-benzenesulfonyl)-5-phenyl-pyrrolidin-2-yl]-methanol as a yellow gum. 1H NMR (CDCl3, 300 MHz) δ 7.90 (1H, d), 7.60 (1H, d), 7.40 (5H, m), 4.87 (1H, t), 4.10–3.90 (3H, m), 2.90 (1H, m), 2.05 (2H, m), 1.85 (2H, m). HPLC analysis using an analytical chiracel OD column (hexane/isopropanol) showed an e.e. >99% for this compound (r.t. for (2R,5S)-eantiomer=9.9 min, r.t. for (2S,5R)-enantiomer=12.3 min).
Reaction SMILES: C(C=CC(OCC)=O)(=O)C1C=CC=CC=1.N[C@H]1CCC2C=CC=CC=2N(CC(OC(C)(C)C)=O)C1=O.[C:37]([O:41][C:42](=[O:69])[CH2:43][N:44]1[C:50](=[O:51])[CH:49]([NH:52][CH:53]2[CH2:57][CH:56]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[O:55][C:54]2=[O:64])[CH2:48][CH2:47][C:46]2[CH:65]=[CH:66][CH:67]=[CH:68][C:45]1=2)([CH3:40])([CH3:39])[CH3:38].C([O-])=O.[NH4+]>C1(C)C=CC=CC=1.[Pd]>[C:54]([CH:53]([NH:52][CH:49]1[CH2:48][CH2:47][C:46]2[CH:65]=[CH:66][CH:67]=[CH:68][C:45]=2[N:44]([CH2:43][C:42]([O:41][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:69])[C:50]1=[O:51])[CH2:57][CH2:56][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)([OH:64])=[O:55]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(NC2CC(c3ccccc3)OC2=O)CCc2ccccc21
Agent: [Pd]
Agent: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: CCOC(=O)C=CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21
Temperature: 40 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. After completion of the reaction the catalyst is filtered off through Celite, 100 ml of acetic acid are added and the solvent mixture is reacted at 20–30° C. for 18 h. After lactonization to compound (17), ammonium formate (51.4 g, 816 mmoles) and 10% Pd—C (26 g, 22 mmoles) are added. The reaction mixture is heated to 40° C. for 3 h, after that the catalyst is filtered off through Celite and solvents are evaporated off. The residue is taken up with acetone (600 ml) and acetic acid (200 ml), heated to dissolution and cooled. The resulting precipitate is filtered, washed with 80 ml of acetone1 and dried to give 3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (15) (60.7 g, yield: 54%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:3]=1.O=C1CCC(=O)N1[O:23][C:24](=O)[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:25][C:24]([N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=2)[CH2:11][CH2:12]1)=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: Cc1cc(NCC2CCNCC2)ncn1
Solvent: CN(C)C=O
Product: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine (0.15 g, 0.73 mmol), in DMF (1 mL) was added carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.18 g, 0.73 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (90:10:1 DCM MeOH NH4OH ) to give 4-[(6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 341.37
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:13]2[C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH3:26])[C:17]=3[N:16]=[C:15]([CH3:27])[C:14]=2[C:28](OCC)=[O:29])[C:5]([CH3:12])=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCN(CC)CC.C(O)=O>O1CCCC1.CO.[Pd]>[CH3:27][C:15]1[C:14]([CH2:28][OH:29])=[C:13]([C:4]2[C:5]([CH3:12])=[C:6]3[C:11](=[CH:2][CH:3]=2)[O:10][CH2:9][CH2:8][CH2:7]3)[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:26])[C:17]=2[N:16]=1
Reactant: CCOC(=O)c1c(C)nc2c(c1-c1cc(Cl)c3c(c1C)CCCO3)c1ccccc1n2C
Agent: [Pd]
Agent: [Al+3]
Agent: [H-]
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(c(-c3ccc4c(c3C)CCCO4)c1CO)c1ccccc1n2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
An ice cold solution of ethyl 4-(8-chloro-5-methylchroman-6-yl)-2,9-dimethyl-9H-pyrido[2,3-b]indole-3-carboxylate (262 mg, 0.584 mmol) in tetrahydrofuran (THF) (5 mL) was treated slowly with LAH (1M in THF) (1.751 mL, 1.751 mmol), and then stirred at rt for 18 hours. The reaction was treated with additional LAH (2×1 mL every two hours), cooled to 0° C., quenched slowly with 163 uL H2O, followed by 163 uL 15% aq. NaOH and 3×163 uL H2O. The mixture was stirred at rt for 2 hours, filtered, washed with EtOAc, and then concentrated to afford mixture of chlorinated and dechlorinated alcohol. The intermediate was dissolved in methanol (5.8 mL), treated with Et3N (0.325 mL, 2.334 mmol), formic acid (0.090 mL, 2.334 mmol), Pd/C (62.1 mg, 0.058 mmol), and stirred at 60° C. for 1 hour. The reaction was treated with additional Pd/C (small scoop) and heated overnight at 60° C. Added MeOH (2 mL), Et3N (330 uL), Pd/C (69 mg), formic acid (100 uL), stirred for 1 hour, added Pd/C (70 mg), and stirred for another hour until no starting material remained. The mixture was filtered through Celite™, washed with EtOAc, DCM, and MeOH, and then concentrated. Purification with column chromatography (0-100% EtOAc/hexane) gave (2,9-dimethyl-4-(5-methylchroman-6-yl)-9H-pyrido[2,3-b]indol-3-yl)methanol (170 mg, 0.456 mmol, 78% yield) as pale yellow oil. The intermediate was suspended in dichloromethane (DCM) (5.00 mL), treated with PCC (189 mg, 0.875 mmol), and stirred at rt for 2 hours. The mixture was diluted with DCM, filtered through Celite™, washed with EtOAc, and then concentrated. Purification by column chromatography (0-100% EtOAc/hexane) gave 2,9-dimethyl-4-(5-methylchroman-6-yl)-9H-pyrido[2,3-b]indole-3-carbaldehyde (122.5 mg, 0.331 mmol, 56.7% yield) as pale yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.01 (s, 1 H), 7.50-7.40 (m, 2 H), 7.06 (ddd, J=2.2, 6.0, 8.0 Hz, 1H), 7.01 (d, J=8.3 Hz, 1 H), 6.85 (t, J=8.4 Hz, 2 H), 4.36-4.21 (m, 2 H), 4.01 (s, 3 H), 3.05 (s, 3 H), 2.81-2.69 (m, 2 H), 2.27-2.07 (m, 2 H), 1.89 (s, 3 H); LCMS (m/z) ES+=371 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][N:26]1[C:30]([NH2:31])=[CH:29][C:28]([CH3:32])=[N:27]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][N:26]1[C:30]([NH:31][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:10]=3[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[CH:29][C:28]([CH3:32])=[N:27]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CNC(=O)c1c(Nc2cc(Cl)ncc2C(F)(F)F)cccc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1c(Nc2cc(Nc3cc(C)nn3C)ncc2C(F)(F)F)cccc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
2-(2-Chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (1.66 g, 4.61 mmol), 1,3-dimethylpyrazol-5-amine (0.523 g, 4.71 mmol), palladium(II) acetate (0.083 g, 0.37 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.427 g, 0.74 mmol) and cesium carbonate (1.804 g, 5.54 mmol) were mixed together in dioxane (30 mL). The reaction was degassed with argon and was stirred at 90° C. for 3 hours under argon. The mixture was filtered, the filtrate concentrated and purified twice by flash chromatography on silica gel eluting with 0 to 4% MeOH in DCM/EtOAc (60:40). The solvent was evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (0.882 g, 44.0%) as a beige solid. 150 mg of this material was dissolved in acetonitrile, concentrated and diluted with DCM. Crystals appeared slowly. The resulting crystalline solid was collected by filtration, washed with DCM and dried to a constant weight to afford 2-[[2-[(2,5-dimethylpyrazol-3-yl)amino]-5-(trifluoromethyl)-4-pyridyl]amino]-6-methoxy-N-methyl-benzamide (110 mg, 32.3%) as a white crystalline solid. Melting onset of 163° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.C(S)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:11][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: SCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-c2nc(N)nc(SCc3ccccc3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, benzyl mercaptan and DBU in DME. ES-MS m/e (%): 409 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:30]([C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:35]2[CH:36]=[N:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: O=Cc1ccc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.4 g, 0.86 mmol) and (6-formylpyridin-3-yl)boronic acid (0.3 g, 1.29 mmol) in dioxane/water mixture (10 mL+2 mL), Na2CO3 (0.32 g, 3.09 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.092 g, 0.086 mmol) was added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 6 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.28 g, 66%).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[CH2:11][CH:10]([C:13]([O:15]C)=[O:14])[CH2:9][CH2:8][C:7]=3[NH:6][N:5]=2)[CH2:3][CH2:2]1.O[Li].O>CO.O>[CH:1]1([C:4]2[C:12]3[CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8][C:7]=3[NH:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C1CCc2[nH]nc(C3CC3)c2C1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)C1CCc2[nH]nc(C3CC3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
To a solution methyl 3-cyclopropyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (35.0 g) in MeOH (300 mL) was added a solution of LiOH.H2O (10.8 g, 0.26 mol) in H2O (200 mL) at 0° C. After stirring 18 h at rt the solvent was removed in vacuum. To the residue water (200 mL) was added and aqueous solution was acidified to pH=4-5 with 10% HCl. The precipitate was collected by filtration to give 3-cyclopropyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid (25.0 g, 80% yield for 2 steps).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([O:30][CH3:31])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2].[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:28]([O:30][CH3:31])=[O:29])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(C)=O)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 6,9-diacetoxy-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylate (5 mg) in pyridine (1.0 ml) was added acetic anhydride (0.5 ml), and the solution was stirred for 5 hours at room temperature. The reaction mixture was evaporated to dryness in vacuo and the residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (30:1 v/v) to afford methyl 6,9-diacetoxy-11-acetyl-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carboxylate (5 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](N)=[O:5].C(OC(=O)C)(=[O:15])C.C(O)(=O)C.N([O-])=O.[Na+]>C(OCC)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:15])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Cl)nc(Cl)c1C(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reaction time: 18 h

Procedure:
A solution of 2,6-dichloro-4-methyl-nicotinamide (6.40 g) in 2:1 acetic anhydride/acetic acid (156 mL) was treated with sodium nitrite (21.5 g), stirred for 18 hours, poured into diethyl ether (600 mL) and filtered. The filtrate was concentrated with a toluene azeotrope, and the concentrate was treated with brine and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated; and this concentrate was suspended in hexane, sonicated and filtered.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([O:24][CH3:23])[CH2:26]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: COC1CCCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC1CCCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Temperature: 65 °C
Yield: 34.4 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 3-methoxypiperidine (0.047 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give the desired product (37.3 mg, 34%). LCMS calculated for C17H20ClN2O2 (M+H)+: m/z=319.1; Found: 319.1.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[N:8]=1)#[N:2].[C:17](=O)([O:20]C)[O:18][CH3:19].C[O-].[Na+].Cl>C1(C)C=CC=CC=1>[C:1]([CH:3]([C:4]1[S:5][CH:6]=[C:7]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[N:8]=1)[C:17]([O:18][CH3:19])=[O:20])#[N:2]
Reactant: N#CCc1nc(-c2c(F)cccc2F)cs1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)c1nc(-c2c(F)cccc2F)cs1
Temperature: 0 °C
Yield: 67 %

Procedure:
To 2 g of 2-cyanomethyl-4-(2,6-difluorophenyl)thiazole and 4.8 g of dimethyl carbonate was added 30 ml of toluene, 0.6 g of sodium methoxide was added, and the resulting mixture was stirred and heated to the reflux temperature for 4 hours. After cooling, the reaction mixture was poured into 100 ml of ice-cold water, 1N-HCl was added to acidify the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue obtained was purified by column chromatography (ethyl acetate/n-hexane=2/1) to give 1.67 g of methyl 2-cyano-2-{4-(2,6-difluorophenyl)thiazol-2-yl}acetate.