Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([OH:22])=[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]4=[C:15]([OH:27])[C:14]=3[C:13]2=[O:28])=[C:8]([Cl:29])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.O>CN(C=O)C>[Cl:29][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[CH:11]=[CH:10][C:9]=1[N:12]1[C:20](=[O:21])[C:19]2[C:18]([O:22][CH2:43][C:44]([F:47])([F:46])[F:45])=[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]3=[C:15]([O:27][CH2:43][C:44]([F:45])([F:46])[F:47])[C:14]=2[C:13]1=[O:28]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(O)c4ccccc4c3O)C2=O)c(Cl)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.1 %

Procedure:
To a solution of ethyl[3-chloro-4-(4,9-dihydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (0.30 g, 0.71 mmol) in DMF (3 ml), was added sodium carbonate (0.299 g, 2.82 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.490 g, 2.12 mmol). This was stirred at room temperature for 21 hours. Further sodium carbonate (0.11 g, 1.06 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.246 g, 1.06 mmol) was added to the reaction to drive it to completion. This was then heated to 50° C. for 2.5 hours. Water was added to the reaction mixture with rapid stirring. The resulting tan coloured solid was collected by filtration, washed with water and dried in the vacuum oven to give the title compound (0.377 g, 0.64 mmol). LC/MS: Rt=3.98, [MH]+ 590.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1>C(NCC)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: Clc1ccc(Cl)nc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CCCCC#Cc1ccc(Cl)cn1
Yield: 87.8 %

Procedure:
9.0 ml (80 mmol) of 1-hexyne and 6.0 g (40 mmol) of 2,5-dichloropyridine in 80 ml of diethylamine are placed under argon, whereby a pale yellow solution results. Thereto there are added 0.40 g (1.5 mmol) of triphenylphosphine, 0.04 g (0.02 mmol) of copper-(I) iodide as well as 0.24 g (0.9 mmol) of palladium-dichloro-bis(triphenylphospine). The orange solution obtained is subsequently heated to reflux for 24 hours while stirring. Thereafter, the reaction mixture is cooled to 25° and evaporated at 40° under reduced pressure. The brown residue is then treated with 50 ml of ethanol and again evaporated. The crude product is filtered over 50 g of silica gel with 700 ml of hexane/toluene (1:1) and the eluate is evaporated at 50° under reduced pressure. The residue is subsequently distilled in a bulb tube at 190°/2600 Pa. There are obtained 6.8 g of 2-hexynyl-5-chloropyridine as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)(C)[CH3:12].ICC>C1COCC1>[CH2:11]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH3:12]
Reactant: [Li]C(C)(C)C
Reactant: c1ccc2sccc2c1
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2ccccc2s1

Procedure:
2-Ethylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 8.9 mmoles, 5.3 ml), iodoethane (8.9 mmoles, 0.72 ml) and THF (20 ml). 1.2 g (99%) of a yellow liquid was isolated.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([C:29]4[CH:30]=[CH:31][N:32]=[C:27]([CH3:26])[N:28]=4)[CH2:24][CH2:25]3)=[O:19])[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(C1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCNCC1
Reactant: Cc1nccc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nccc(N2CCN(C(=O)C3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1

Procedure:
The crude 1-(4-chlorophenylsulphonyl)-4-(piperazin-4-ylcarbonyl)piperidine hydrochloride, 2-methyl-4-chloro-pyrimidine (299 mg) and triethylamine (1.47 ml) were heated under reflux in ethanol (12 ml) for 5 hours. The solvent was removed by evaporation. Purification by filtration column chromatography (silica) eluting with 2% methanol/dichloromethane increasing to 10% methanol/dichloromethane gave 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl]piperidine as a solid (0.87 g); NMR (CDCl3): 1.7-2.0 (m, 5H), 2.5 (m, 5H), 3.5-3.8 (m, 10H), 6.3 (m, 1H), 7.5 (m, 2H), 7.7 (m, 2H), 8.2 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[N:7]([CH:13]3[CH2:15][CH2:14]3)[C:6]=2[N:16]=1.[H-].[Na+].[N+:20](C1C=C([N+]([O-])=O)C=CC=1NO)([O-])=O>CN(C)C=O.O1CCOCC1>[NH2:20][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([F:17])[C:2]([Cl:1])=[N:16][C:6]=2[N:7]([CH:13]2[CH2:15][CH2:14]2)[C:8]1=[O:12]
Reactant: O=[N+]([O-])c1ccc(NO)c([N+](=O)[O-])c1
Reactant: O=c1[nH]c(=O)n(C2CC2)c2nc(Cl)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Nn1c(=O)c2cc(F)c(Cl)nc2n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A solution of 3.83 g (15 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example 23i) in 50 mL of dimethylformamide-dioxane (1:1) is cooled to 0° C. and treated portionwise with 0.8 g (20 mmol) of 60% sodium hydride/mineral oil. The reaction is stirred to room temperature for 30 minutes, re-cooled to 0° C. and 3.2 g (16 mmol) of 2,4-dinitrophenylhydroxylamine is added all at once. After stirring at room temperature overnight, the dioxane is removed in vacuo and the residue is diluted to 300 mL with ice and water and stirred at 5° C. for 1 hour. The precipitate is removed by filtration, washed with water, ether and dried in vacuo to give 2.65 g of the title compound, mp 192-194° C. A second crop, (0.6 g) could be isolated by evaporating the filtrate and triturating the residue with petroleum ether.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH:10]([CH3:12])[CH3:11].FC(F)(F)C(O)=O.[N:20]1([CH2:24][CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=3)[N:28]=[C:27]2[CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:20]1([CH2:24][CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=3)[N:28]=[C:27]2[CH:42]2[CH2:43][CH2:44][N:45]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH:10]([CH3:12])[CH3:11])[CH2:46][CH2:47]2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)Oc1c(N)ncnc1Cl
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 55.7 %

Procedure:
A reaction mixture of 6-Chloro-5-isopropoxy-pyrimidin-4-ylamine (40.00 mg; 0.21 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (133.13 mg; 0.21 mmol; 1.00 eq.), and Cs2CO3 (277.84 mg; 0.85 mmol; 4.00 eq.) in DMSO 5.0 ml was stirred at 120° C. for 2 days, purified the product by HPLC, collected title compound 64 mg, yield 45.5%. LC-MS: (M+1=548, obsd.=548).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH2:11]([CH:16]([CH2:19]O)[CH2:17][OH:18])[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C@@H:16]1[CH2:17][O:18][C@@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[O:10][CH2:19]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(CO)CO
Reactant: N#C[C@H]1CC[C@H](C=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCCCC[C@H]1CO[C@H]([C@H]2CC[C@H](C#N)CC2)OC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.00 g of trans-4-cyanocyclohexanecarboxaldehyde, 2.13 g of 2-pentyl-1,3-propanediol and 65 mg of p-toluenesulphonic acid in 100 ml of benzene was heated to reflux for 3 hours while gassing with argon and with separation of water in a round flask provided with a water separator and a reflux condenser. The mixture was subsequently treated with 3.0 g of potassium carbonate, stirred at room temperature for 16 hours, then filtered and the filtrate was concentrated. Recrystallization of the crystalline residue (4.1 g) from hexane at 0° C. gave 1.47 g (38%) of trans-4-(trans-5-pentyl-m-dioxan-2-yl)cyclohexanecarbonitrile as colourless crystals in a purity of 99.1%. After a further recrystallization from hexane at 0° C., the purity increased to 99.9%; m.p. (C-N) 45.6° C., cl.p. (N-I) 46.7° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10]2[S:11][CH:12]=[C:13]([Br:15])[CH:14]=2)[CH2:8][N:7]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:6]1)=[O:4].C1NCC2C1CC1C(C#N)=CSC=12>>[Br:15][C:13]1[CH:14]=[C:10]([CH:9]2[CH2:8][N:7]([CH:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[CH2:6][CH:5]2[C:3]([OH:4])=[O:2])[S:11][CH:12]=1
Reactant: COC(=O)C1CN(C(C)c2ccccc2)CC1c1cc(Br)cs1
Agent: N#Cc1csc2c1CC1CNCC21
Product: CC(c1ccccc1)N1CC(C(=O)O)C(c2cc(Br)cs2)C1
Yield: 100 %

Procedure:
The product of step b), diastereomer 1 (15 g, 0.038 mol) was treated by the method outlined in Example 34, step c) to afford the subtitle compound (14.7 g, yield: 100%). MS calculated for C17H18BrNO2S +H: 380, observed 380 and 383.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26]>CN(C)C=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH:26][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reactant: COc1ccc(CN)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)O)cc1Cl
Reaction time: 4 h

Procedure:
To a mixture of 4,6-dichloro-5-carboxy-2-methylthiopyrimidine (prepared in the above (1)) 500 mg and triethylamine 0.58 ml in dimethylformamide 3 ml is added 3-chloro-4-methoxybenzylamine 359 mg in dimethylformamide 3 ml at room temperature over a period of 15 minutes, and the mixture is stirred for 4 hour. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-chloro-2-methylthiopyrimidine as a slightly brown powder.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10]2.[C:19](=[O:21])=[O:20]>CCCCCC.C1COCC1>[CH3:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:19]([OH:21])=[O:20])[CH:8]=2)[N:13]=1
Reactant: O=C=O
Reactant: COc1ccc2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (63 cm3 of a 1.6M solution in hexane) was added dropwise to a stirred solution of 6-bromo-2-methoxyquinoline (20 g) in THF (250 cm3) at -70° under nitrogen. After 0.5 hours, solid carbon dioxide (50 g) was added, the solution was allowed to warm to room temperature, and volatile material was removed in vacuo. The residue was partitioned between dichloromethane (100 cm3) and water (100 cm3), the aqueous phase was separated and acidified to pH 3.5 with 5M hydrochloric acid. The precipitated solid was filtered and dried (14.2 g). Recrystallisation of a small portion from isopropanol afforded 2-methoxyquinoline-6-carboxylic acid, m.p. 220°-222°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].[N:20]([CH:23]1[CH2:28][CH:27]([CH3:29])[CH2:26][CH2:25][CH:24]1[C:30](Cl)=[O:31])=[N+:21]=[N-:22].CC1CCC(C(Cl)=O)=CC1.C([O-])(O)=O.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([C:30]([CH:24]1[CH2:25][CH2:26][CH:27]([CH3:29])[CH2:28][CH:23]1[N:20]=[N+:21]=[N-:22])=[O:31])[CH:11]([CH3:13])[CH3:12])=[O:4]
Reactant: CC1CCC(C(=O)Cl)C(N=[N+]=[N-])C1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Agent: CC1CC=C(C(=O)Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1N=[N+]=[N-])C(C)C
Temperature: 90 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (227 mg, 0.824 mmol) in 1,2-dichloroethane (2.5 ml) was added the 2:1 mixture of 2-Azido-4-methyl-cyclohexanecarboxylic acid chloride and 4-Methyl-cyclohex-1-enecarboxylic acid chloride (182 mg, 0.906 mmol) dissolved in 1,2-dichloroethane (0.5 ml). The resulting solution was stirred for 18 h at 90° C. and then cooled to room temperature. It was then diluted with ethyl acetate (10 ml) and a solution of saturated NaHCO3 (10 ml). The aqueous phase was separated and washed with ethyl acetate (2×10 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0% to 20% EtOAc/Hexane) to obtain 178 mg (49%) of 3-[(2-Azido-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH2:19]([O:26][C:27](=[O:31])[C@H:28](O)[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:19]([O:26][C:27](=[O:31])[C@@H:28]([O:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][N:7]=2)=[CH:15][CH:14]=1)[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](O)C(=O)OCc1ccccc1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol (2.90 g, 11.4 mmol) and (R)-2-hydroxypropionic acid benzyl ester (2.25 g, 12.5 mmol) in dry THF (100 mls) at 0° C. under nitrogen is added triphenylphosphine followed by dropwise addition of diisopropylazodicarboxylate (3.36 mls, 17 mmol). The resulting yellow mixture is stirred for 1 hr then left the stand for 16 hours. The reaction mixture is partitioned between water and ethyl acetate and the layers separated. The aqueous is further extracted with ethyl acetate and the combined organic layers dried over magnesium sulphate, filtered and the solvent removed under reduced pressure. Column chromatography on silica gel using 10% ethyl acetate/hexane as eluent yielded (S)-2-[4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenoxy]-propionic acid benzyl ester as a colourless oil. In one example 3.25 g are made representing 69% yield and in >99% ee (as determined by nmr).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:13]([C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[F:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1cc(C)cc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(C)=O)c(F)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A dry CS2 solution (42 mL) containing N-(3-fluoro-5-methylphenyl)acetamide (30-1, 5.00 g, 29.9 mmol) and acetyl chloride (3.2 mL, 45 mmol) was slowly added with aluminum chloride (10 g, 74.8 mmol). The reaction mixture was heated at reflux for 2.0 h. The solution was cooled to room temperature and CS2 was decanted. The remaining syrup was poured into icy HCl, and the resultant solids were collected, re-dissolved in EtOH, and decolorized by charcoal. The solution was filtered and the filtrate was concentrated under vacuum to give N-(4-acetyl-3-fluoro-5-methyl-phenyl)acetamide (30-2, 6.10 g, 29.2 mmol) as light yellow solids in 97% yield: 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J=12.4 Hz, 1 H), 6.93 (s, 1 H), 2.53 (d, J=3.8 Hz, 3 H), 2.31 (s, 3 H), 2.18 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>O1CCCC1>[CH:8]([N:4]1[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cn[nH]c1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1cnn(C(c2ccccc2)c2ccccc2)c1

Procedure:
A solution of 4-bromo-1H-pyrazole (0.294 g), (bromomethylene)dibenzene (0.494 g) and triethylamine (0.418 mL) in tetrahydrofuran (5 mL) was stirred at 60° C. for 24 hours. The reaction mixture was concentrated and purified by chromatography on silica gel using 0-20% ethyl acetate/hexanes as eluent to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[O:11]=[C:12]1[N:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[N:1][CH:19]=[C:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NC1=NCCCCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnc2n(c1=O)CCCCC2
Reaction time: 1 h
Yield: 80.5 %

Procedure:
67.2 g of 7-amino-3,4,5,6-tetrahydro-2H-azepine are dissolved in 600 ml. of ethanol and the solution is cooled to -10° C. and to the reaction mixture a solution of 127.8 g. of diethyl ethoxy-methylene-malonate in 600 ml. of ethanol is added dropwise under stirring within 1 hour. The reaction mixture is stirred for a further hour at a temperature of -10° C. to -5° C. whereafter it is boiled for 1 hour. Ethanol is distilled off at reduced pressure. The residual yellow oil containing an about 10:1 mixture of ethyl 4-oxo-4,6,7,8-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate and ethyl-2-oxo-2,6,7,8,9,10-hexadhydro-pyrimido[1,2-a]azepine-3-carboxylate is dissolved in 600 ml. of benzene and shaken out twice subsequently with 60 ml of water. The benzene soltuion is dried over anhydrous sodium sulphate and evaporated at reduced pressure. 114 g. (80.5%) ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate are obtained melting at 82°-84° C. after recrystallization from ethyl acetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(S(C)(=O)=O)C1
Reaction time: 18 h

Procedure:
The solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (1-piperidin-3-yl-propyl)-amide (0.10 g, 0.26 mmol) and Et3N (58 μL, 0.42 mmol) in dichloromethane (3 mL) was added methanesulfonyl chloride (31 μL, 0.39 mmol). After 18 hours, the cloudy mixture was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-95% EtOAc in hexanes to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.78 (s, 3H), 6.83 (d, 2H, J=9.2 Hz), 7.39 (b, 1H), 7.49 (d, 2H, J=6.4 Hz), 7.68 (m, 4H), 8.85 (d, 2H, J=6.0 Hz), 9.96 (b, 1H). MS: m/z 447.0 (M++1).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][C:17]=3[CH3:25])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[C:17]([CH3:25])[CH:18]=2)[CH2:24][CH2:23]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(C2CC2)ccc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)ccc1N1CCN(C(=O)c2ccc(N3CCOC3=O)nc2)CC1
Yield: 77.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(4-cyclopropyl-2-methylphenyl)piperazin-1-yl]methanone (260 mg) described in Preparation Example 140 and oxazolidin-2-one (66 mg), the title compound (205 mg) was obtained.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:45]([O:47][C:48](=[O:53])[CH2:49][N:50]=[C:51]=[O:52])[CH3:46].[Cl-].[NH4+]>C(N(CC)CC)C>[CH2:45]([O:47][C:48](=[O:53])[CH2:49][NH:50][C:51]([N:31]1[C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([C:16]3[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]4[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=4)[CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[N:18][CH:17]=3)[C:20]=2[CH2:33][CH2:32]1)=[O:52])[CH3:46]
Reactant: CCOC(=O)CN=C=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCOC(=O)CNC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Temperature: 25 °C

Procedure:
To a dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg), triethylamine (260 μl) and isocyanato-acetic acid ethyl ester (208 μl) were added, followed by refluxing for 3 hours. After this was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and passed through Whatman tube. The resulting organic layer was concentrated under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=/) column chromatography (dichloromethane/methanol=1/0 to 100/1), to obtain a crude product of the desired compound (127 mg, quant.).