Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:7]2=[N:6][N:5]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1C=CC=CC=1>[NH2:1][C:2]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C:7]2=[N:6][N:5]=1)=[S:29]
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2C(N)=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2C(N)=S)C1
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethylethyl 3-(aminocarbonyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I111) (0.2 g, 0.748 mmol) and Lawesson's reagent (0.151 g, 0.374 mmol) in benzene (7.48 ml) was heated at 80° C. for 2 h, left to stand over the weekend at RT and then heated for a further 6 h at 80° C. The mixture was cooled, concentrated and then chromatographed (0-5% MeOH in DCM) to give the desired product as a yellow solid in 99 mg.
Reaction SMILES: C(CN)O.C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[C:20]([F:21])=[C:19]2[C:15]([C:16]([NH:30]C(=O)CCC)=[N:17][N:18]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:14][C:13]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[F:11][C:12]1[C:20]([F:21])=[C:19]2[C:15]([C:16]([NH2:30])=[N:17][N:18]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:14][C:13]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: NCCO
Product: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(F)c(F)c21
Yield: 23.7 %

Procedure:
1.1 cm3 of ethanolamine and then 1.50 g of potassium carbonate are added to 1.6 g of N-[6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]-butanamide described above, in 50 cm3 of dimethylformamide, and the mixture is refluxed for one week. The reaction medium is concentrated to dryness under reduced pressure and taken up in 150 cm3 of ethyl acetate and 75 cm3 of water. The organic phase is separated out after settling of the phases and washed successively with twice 75 cm3 of water and 50 cm3 of brine. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude oil obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40–60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 0.32 g of 6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-amine is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[C:15]([CH3:24])=[CH:16][C:17]([NH2:23])=[C:18]3[C:22]=2[CH2:21][CH2:20][CH2:19]3)=[CH:11][C:10]=1[I:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([N:23]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17]1[CH:16]=[C:15]([CH3:24])[C:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([I:27])[CH:11]=2)=[C:22]2[C:18]=1[CH2:19][CH2:20][CH2:21]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(N)c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7-(4-benzyloxy-3-iodophenoxy)-6-methylindan-4-ylamine (3.80 g) in N,N-dimethylformamide (15 mL) were added benzyl bromide (2.30 mL) and potassium carbonate (2.67 g), and the mixture was stirred under an argon atmosphere at room temperature for 2 days. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) to give the title compound (4.50 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[CH:5]2.Cl[CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=23)[S:22]1(=[O:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=45)[S:22]3(=[O:34])=[O:33])[CH2:16][CH2:17]1)=[CH:5]2
Reactant: Fc1ccc2[nH]c(CC3CCNCC3)cc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCC(Cc2cc3cc(F)ccc3[nH]2)CC1
Yield: 39.7 %

Procedure:
A mixture of 4-[(5-fluoro-2-indolyl)methyl]piperidine (2.9 g), 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.5 g) and sodium hydrogen carbonate (1.1 g) in tetrahydrofuran (30 cc) and dimethylformamide (30 cc) is brought to reflux for 12 hours. After evaporation to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa), the residue is taken up with water (150 cc) and extracted with ethyl acetate (2×75 cc). The combined organic phases are dried over magnesium sulphate and taken to dryness at 80° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with a cyclohexane/ethyl acetate mixture (50:50 by volume) as eluent. 2-{2-[4-((5-Fluoro-2-indolyl)methyl)piperidino]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g), m.p. 154° C., is obtained.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][NH:14][C:15]1[N:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][N:16]=1.Cl[C:31]1[N:39]=[C:38]2[C:34]([N:35]=[CH:36][N:37]2[CH2:40][CH:41]2[CH2:45][CH2:44][O:43][CH2:42]2)=[C:33]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[N:32]=1>O>[CH3:13][NH:14][C:15]1[N:16]=[CH:17][C:18]([C:31]2[N:39]=[C:38]3[C:34]([N:35]=[CH:36][N:37]3[CH2:40][CH:41]3[CH2:45][CH2:44][O:43][CH2:42]3)=[C:33]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[N:32]=2)=[CH:19][N:20]=1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CCOC3)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CCOC4)c3n2)cn1
Yield: 40.8 %

Procedure:
1,4-Dioxane (40 ml), water (20 ml), and sodium carbonate (2 g, 19 mmol) were added to N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.45 g, 6.18 mmol) and 2-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purine (2.0 g, 6.18 mmol) and the atmosphere in the reaction vessel was substituted with nitrogen. Tetrakis triphenylphosphine palladium (0.36 g, 0.31 mmol) was added, then the atmosphere in the reaction vessel was substituted with nitrogen again, and the resulting mixture was heated to reflux for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Methylene chloride-ether was added to the residue and the insoluble matter was collected by filtration and dried to give the title compound (1.0 g, 41%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][C@H:15]1[CH2:20][N:19]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 97.8 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (19.4 mg, 0.10 mmol), tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate (22.0 mg, 0.10 mmol) and triethylamine (40.9 μL, 0.29 mmol) in isopropyl alcohol (0.224 mL) was stirred at 100° C. for 40 min. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography using CombiFlash® (0 to 50% EtOAc in hexanes) to give the sub-title compound as pale yellow powder (36.8 mg, 100%). LCMS calc. for C19H29N4O4 (M+H)+: m/z=377.1. Found: 377.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[C:5]([C:12]#[N:13])=[CH:4][N:3]=1.[CH3:14][O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CC(O)CC>[C:12]([C:5]1[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([S:19](=[O:21])(=[O:20])[NH:18][CH2:17][CH2:16][O:15][CH3:14])=[CH:23][CH:24]=2)=[N:3][CH:4]=1)#[N:13]
Reactant: COCCNS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1cnc(Cl)nc1NC1CC1
Solvent: CCC(C)O
Product: COCCNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(NC3CC3)n2)cc1
Temperature: 90 °C
Yield: 77.2 %

Procedure:
2-Chloro-5-cyano-4-cyclopropylaminopyrimidine (Method 96; 295 mg, 1.28 mmol) was dissolved in hot 2-butanol (3 ml). A hot solution of 4-[N-(2-methoxyethyl)sulphamoyl]aniline (Method 5; 207 mg, 0.90 mmol) in 2-butanol (3 ml) was added and the reaction was stirred and heated at 90° C. for 1 hour. The reaction mixture was cooled and the volatiles evaporated to give a solid. The solid residue was triturated with hot ethyl acetate, cooled, and the resultant solid collected by filtration to give the title compound (270 mg, 77%). NMR: 0.68 (m, 2H), 0.80 (m, 2H), 2.88 (m, 3H), 3.14 (s, 3H), 3.28 (m, 2H), 7.48 (brs, 1H), 7.70 (d, 2H), 8.05 (d, 2H), 8.12 (brs, 1H) 8.41 (s, 1H), 10.31 (s, 1H); m/z: 389.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][OH:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>ClCCl.CN(C)C1C=CN=CC=1>[CH:27]([NH:30][C:31](=[O:32])[O:19][CH2:18][C:4]1([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])([CH3:29])[CH3:28]
Reactant: COC1=CCc2ccccc2C1(CO)CCC(C)C
Reactant: CC(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=CCc2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of Example 179A (50 mg, 0.2 mmol) in dichloromethane (1 mL) was added triethylamine (0.13 mL, 1 mmol), 4-dimethylaminopyridine (9 mg, 0.08 mmol), and isopropyl isocyanate (0.1 mL, 1 mmol). The solution was stirred at room temperature for 18 h. After which, additional 5.0 equivalents (0.1 mL) of isopropyl isocyanate were added, and the solution was stirred for another 18 h. The solution was diluted with dichloromethane (2 mL), washed with water (2×1 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (0-5% ethyl acetate/hexane) afforded product (39 mg, 59%). 1H NMR (300 MHz, CDCl3) δ ppm 0.70 (m, 7 H), 0.91 (m, 8 H), 1.37 (m, 1 H), 1.60 (m, 1 H), 1.93 (m, 1 H), 3.49 (d, J=3.68 Hz, 2 H), 3.58 (s, 3 H), 4.21 (d, J=10.30 Hz, 1 H), 4.45 (d, J=10.30 Hz, 1 H), 5.00 (t, J=3.68 Hz, 1 H), 7.17 (m, 3 H), 7.30 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC=CC=1.P(=O)(O)(O)O.[CH3:44][S:45]([CH3:47])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10](=[S:45]([CH3:47])[CH3:44])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Reactant: CS(C)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)=S(C)C
Temperature: 25 °C

Procedure:
A mixture of 30.0 grams (0.10 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate, 51.58 grams (0.25 mole) of 1,3-dicyclohexylcarbodiimide, 100 milliliters of benzene and 100 milliliters of dimethyl sulfoxide was stirred at ambient temperature and a solution of 4.9 grams (0.05 mole) of anhydrous phosphoric acid in 10 milliliters of dimethyl sulfoxide added dropwise. After a few minutes an exothermic reaction occurred with separation of a white solid and an increase in temperature from 25° C. to 35° C. The reaction mixture was then stirred for an approximate 16-hour period at ambient temperature. The mixture was then diluted with 500 milliliters of ethyl acetate and by-product 1,3-dicyclohexylurea removed by filtration. The filtrate was washed with several portions of water, dried over MgSO4, filtered and freed of solvent under reduced pressure to give a yellow solid. This was crystallized from ethyl acetate-hexane (1:1) to give 15.8 grams (0.04 mole) of ethyl 3 -[(4-bromo-2-methylphenyl)amino]-2-(dimethylsulfuranylidene)-3-oxopropanoate having a melting point of 143° C.-150° C. Recrystallization of a small sample gave a white solid of melting point 146° C.-149° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.FC1C=CC=C(F)C=1C(NC1C=NC(N2C3C=CC(OC)=CC=3N=C2C(F)(F)F)=CN=1)=O.[CH3:55][C:56]1[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=1[CH2:58][NH2:59].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I.CCOC(C)=O>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:5]3[N:6]=[CH:7][C:2]([NH:59][CH2:58][C:57]4[CH:60]=[CH:61][CH:62]=[CH:63][C:56]=4[CH3:55])=[N:3][CH:4]=3)[C:9]([C:19]([F:22])([F:21])[F:20])=[N:10][C:11]=2[CH:16]=1
Reactant: Cc1ccccc1CN
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Agent: [Cu]I
Agent: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2c(F)cccc2F)cn1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NCc2ccccc2C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Into a 50 mL roundbottom flask, was placed a solution of 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (50 mg, 0.13 mmol) in DMSO (5 mL) (1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) was prepared as described for Compound 1 above). To this was added 2-methyl-benzylamine (40 mg, 0.33 mmol) followed by CuI (10 mg, 0.05 mmol). To the mixture was added L-proline (20 mg, 0.17 mmol). The resulting solution was held at 50° C. for 1 hr while the reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the reaction mixture was allowed to cool to room temperature, then washed twice with H2O (30 mL each). After removal of the volatile components under vacuum, the residue was purified by eluting through a silica gel column with a 1:10 EtOAc/PE solvent system. This resulted in 25 mg (44%) of the product [5-(5-Methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-(2-methyl-benzyl)-amine (Compound 46) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C(OCC)(=O)C.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:12][N:13]([CH3:18])[S:14]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)(=[O:16])=[O:15]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Yield: 32.3 %

Procedure:
To 5-aminoindolin-2-one (100 mg, 0.68 mmol) in ethyl acetate/DMF 1:1 (2 mL) was added dimethylsulfamoyl chloride (290 mg, 2.04 mmol) and DMAP (1 mg). After 72 h the product was precipitated with ether, filtered and dried to give 56 mg, 32% of a white solid. 1H NMR (400 MHz, CD3OD) δ 7.21 (s, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.53 (s, 2H), 2.77 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3([O:3][CH2:1][CH3:2])[CH2:6][CH2:5]3)=[C:8]([CH:15]([CH3:16])[CH3:17])[CH:9]=2)=[CH:26][CH:27]=1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)C)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#Cc3ccc(CC(=O)OC)cc3)cc2C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103, 120.0 mg, 0.52 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 150.0 mg, 0.52 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (32.0 mg, 0.17 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (121 mg, 0.17 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 140.0 mg (71%) of the title compound as a pale-yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:24]=2[Cl:23])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1cccc(Cl)c1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(Cl)c2Cl)[nH]1
Reaction time: 8 h

Procedure:
16.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid were dissolved in 100 ml of ethanol and 20.2 g of 2,3-dichlorobenzylhydrazine were added. After standing overnight at room temperature, the precipitate which had formed was filtered off and dissolved in 2 N sodium hydroxide solution. The alkaline solution was again extracted with ether and subsequently slightly acidified with dilute acetic acid. Hereupon the compound identified above precipitated and after recrystallisation from ethanol the melting point was 161°-162° C. Yield: 11 g (40%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([NH:19][CH3:20])[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21](OCC)=[O:22].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:21]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:8][C:7]=3[NH:19][CH3:20])=[O:22])=[CH:29][CH:28]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(NC)cc(CN3CCOCC3)cc2c1O
Product: CNc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 200 °C

Procedure:
A mixture of ethyl 4-hydroxy-8-(methylamino)-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (280 mg) and 4-chlorobenzylamine (1.5 mL) is heated under nitrogen at 200° C. for 30 min. The bulk of the 4-chlorobenzylamine is removed under reduced pressure, and the product is purified by chromatography on silica gel to give 169 mg of the title compound as an oil.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][CH:40]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH2:29][CH3:30])[N:17]=3)[CH2:11]2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(CC)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 67, Step A) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH2:9]([N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]1[SH:23])[CH:10]=[CH2:11]>CN(C=O)C>[CH2:9]([N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]=[C:13]1[S:23][CH3:1])[CH:10]=[CH2:11]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1c(S)nc(C(F)(F)F)cc1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCn1c(SC)nc(C(F)(F)F)cc1=O
Yield: 79 %

Procedure:
Next, potassium carbonate (22.5 g, 163 mmol) and methyl iodide (10.2 ml, 164 mmol) were added to DMF (110 ml) solution of 3-allyl-2-mercapto-6-trifluoromethyl-4(3H)-pyrimidinone (32.1 g, 136 mmol) with stirring under ice-cooling, followed by stirring for 23 hours while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, saturated brine (100 ml), water (100 ml) and ethyl acetate (300 ml) were added to the thus obtained residue to separate the organic layer and then the aqueous layer was extracted with ethyl acetate (100 ml×2). The organic layers were combined, washed with saturated brine (50 ml×2) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. The thus obtained crude product was purified, by a silica gel column chromatography (hexane˜hexane:ethyl acetate=9:1) to obtain white solid of 3-allyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (26.9 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C=O)c(N)c1O
Solvent: c1ccncc1
Product: COc1ccc(C=O)c(NC(C)=O)c1O
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
2-Amino-3-hydroxy-4-methoxybenzaldehyde (20.0 g, 0.12 mol) [M. Grossa, F. Wessely Monatsh. Chem. 1966, 97, 1384-1390] is dissolved at RT in a mixture of pyridine (250 ml) and acetic anhydride (250 ml). The solution is warmed to 60° C. and stirred for 1.5 h. The reaction solution is then poured onto a mixture of ice and half-concentrated aqueous NaCI solution (1:1), extracted with ethyl acetate (5 times), dried over MgSO4, filtered off and concentrated in vacuo. The title compound is obtained as a slightly yellow solid (12.5 g) after silica gel chromatography [petroleum ether/ethyl acetate (7:3)]. TLC, silica gel (glass plates), petroleum ether/ethyl acetate (7:3), Rf=0.23.