Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:32][C:28]=1[C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:29]([C:28]4[CH:32]=[C:33]([O:36][CH2:37][O:38][CH3:39])[CH:34]=[CH:35][C:27]=4[F:26])=[O:30])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COCOc1ccc(F)c(C(=O)O)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCOc1ccc(F)c(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1
Reaction time: 1.5 h

Procedure:
To a solution of 4.5 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) in 60 ml of DCM a solution of 2.4 g 2-fluoro-5-(methoxymethoxy)benzoic acid 20 ml of DCM, 1.7 ml TEA, 1.7 g HOBt and 2.4 g EDCi*HCl are added. The reaction mixture is stirred for 90 min until the reaction is complete according to TLC analysis. The reaction mixture is quenched with 1 M aqueous hydrochloric acid, the phases are separated and the organic phase is washed with 1 M aqueous hydrochloric acid again, with water, twice with 1M aqueous sodium carbonate solution and with brine. The organic phase is dried over MgSO4, and the solvent is removed under reduced pressure resulting in a crude product, which is purified by crystallization from diethyl ether to yield 5-(3,4-dimethoxyphenyl)-2-(1-{[2-fluoro-5-(methoxymethoxy)phenyl]carbonyl}piperidin-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one as the product.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:18][C:14]1[C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 464 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.75-6.75 (m, 8H), 4.80-2.70 (m, 5H), 1.65-0.70 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][CH3:10])[NH:5][C:4](=O)[C:3]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:3]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([CH3:1])[N:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=1
Reactant: CCOC(=O)CCc1c(C)nc(COC)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCc1c(C)nc(COC)nc1Cl
Yield: 84 %

Procedure:
A mixture of ethyl 3-(6-methyl-2-methoxymethyl-3H-pyrimidin-4-on-5yl)propionate (4.00 g, 15.6 mmol) and phosphorus oxychloride (25 mL) was heated under reflux for 2 h. The mixture was concentrated, cooled, and poured onto ice. 1N NaOH was added to bring the pH to 6 and the mixture was extracted with EtOAc. The extracts were dried (MgSO4) and concentrated to give 3.6 g (84%) of product as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][C:17]([I:21])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH2:24]>C(O)(C)(C)C>[F:1][C:2]1[C:19]([F:20])=[CH:18][C:17]([I:21])=[CH:16][C:3]=1[C:4]([C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][NH:24][N:23]([CH3:22])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(I)cc(F)c1F
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=CNN(C)C(=O)OC(C)(C)C)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
A solution of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-2-propenoate (Preparation 21, 7.80 g) in tert-butanol (40 mL) is cooled with a cold water bath and a solution of tert-butyl 1-methylhydrazinecarboxylate (2.92 g) in tert-butanol (4 mL) is added. The cooling bath is removed, the mixture is stirred for 5 min at ambient temperature, and then is heated in an oil bath at 45° C. for 40 min. The reaction mixture is poured into 100 mL of crushed ice/water and extracted two times with ethyl acetate. The combined organic layers are dried (Na2SO4) and concentrated in vacuo. The crude product is purified by chromatography, using 300 g of silica gel, packed and eluted with EtOAc/heptane (1/3), to afford 8.95 g (92%) of the title compound as a yellow oily foam. Physical characteristics: 1H NMR (CDCl3) δ8.14, 8.07, 7.59-7.49, 7.46-7.41, 4.07, 3.30, 3.26, 1.50, 1.09, 0.97; MS (ESI+) m/z 511 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[OH-].[K+]>O.C(O)C>[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][N:26]([CH2:3][C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:25][CH2:24]1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC1(c2ccccc2)CCN(Cc2cccc(OCc3ccc4ccccc4n3)c2)CC1
Yield: 47.1 %

Procedure:
A mixture of 3.2 g (0.01 mol) 2-(3-chloromethyl-phenoxymethyl)quinoline hydrochloride, 1.7 g (0.01 mol) 4-hydroxy-4-phenylpiperidine and 1.2 g (0.02 mol) KOH in 5 ml of H2O and 50 ml ethanol was heated over steam bath for a period of 3 hours. Reaction mixture was concentrated to dryness and slurried into water, and extracted with methylene chloride. The methylene chloride extract dried over MgSO4 and concentrated to dryness under reduced pressure to obtain solid. Repeated recrystallization from isopropanol and acetronitrite gave desired product 2 g, m.p. 123°-225° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.P(=O)(O)(O)O.[CH2:18]=[CH:19][CH:20]=[CH2:21]>C1C=CC=CC=1>[CH3:18][CH:19]1[O:1][C:2]2[C:3](=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:21][CH2:20]1
Reactant: C=CC=C
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CC1CCc2c(ccc3[nH]c(=O)ccc23)O1
Temperature: 80 °C
Yield: 34.9 %

Procedure:
6-hydroxyquinoline-2-one (481 mg) and orthophosphoric acid (0.55 ml) were dissolved in 5 ml of benzene, and thereto was added dropwise with stirring 297 mg of butadiene dissolved in 5 ml of benzene. The resulting mixture was heated under reflux at 80° C. for 12 hours. The reaction liquid was poured into ice-cold water and extracted with 100 ml of ethyl acetate. The extracted liquor was washed with water and the ethyl acetate solution was dehydrated by addition of anhydrous sodium sulfate and filtered. The solvent in the filtrate was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to give 224 mg of white needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[C:5]([CH3:19])=[N:4][C:3]=1I.N.[CH3:22][N:23]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=2)[NH:13][C:12](=[O:18])[CH:11]=[CH:10]3)[C:5]([CH3:19])=[N:4][C:3]=1[C:22]#[N:23]
Reactant: Cc1cc(-n2c(C)nc(I)c2Cl)cc2ccc(=O)[nH]c12
Reactant: CN1CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Product: Cc1cc(-n2c(C)nc(C#N)c2Cl)cc2ccc(=O)[nH]c12

Procedure:
A mixture of 6-(5-chloro-4-iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)quinolone (1.0 g), cuprous cyanide (0.45 g) and palladium acetate (0.09 g) in 1-methyl-2-pyrrolidone (5 cm3) was stirred and heated at 160° for 4 hours. The cooled mixture was poured into aqueous ammonia solution (30 cm3 ; S.G. 0.880) and extracted with ethyl acetate (3×150 cm3). The combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:200 by volume. Combination and evaporation of the appropriate fractions afforded the title compound as a solid (0.54 g) which was characterised spectroscopically and used directly without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Br:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([CH2:38][C:39](Cl)=[O:40])=[C:33]([F:42])[CH:32]=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:39](=[O:40])[CH2:38][C:34]2[C:33]([F:42])=[CH:32][C:31]([Br:30])=[CH:36][C:35]=2[F:37])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1c(F)cc(Br)cc1F
Reactant: Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1c(F)cc(Br)cc1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 1.195 mmol) in sulfurous dichloride (5 mL, 1.195 mmol) was added DMF (9.25 μL, 0.120 mmol). The resulting mixture was stirred at 60° C. After 2 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo to give 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.35 g, 0.832 mmol, 69.6% yield). To a solution of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (0.347 g, 1.113 mmol) and Et3N (0.225 g, 2.227 mmol) in DCM (30 mL) was added 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.3 g, 1.113 mmol). The resulting mixture was stirred at 25° C. After LCMS analysis showed the starting material had disappeared, the mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC (PE/EA=3/1) to give N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluoro phenyl)acetamide (110 mg, 0.196 mmol, 17.6% yield): 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=2.8 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.32-7.25 (m, 7H), 7.15 (d, J=8.8 Hz, 1H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.84 (t, J=4.6 Hz, 2H), 3.77 (s, 2H); ES-LCMS m/z 546.0 (M+H).
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH3:12][NH:13][CH3:14]>>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([N:13]([CH3:14])[CH3:12])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CNC
Product: C=CCC1=C(C)C(N(C)C)CC1=O
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
2-Allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added to a 40% aqueous solution of dimethylamine (60 g) in the same flask as used in Example 1 at a temperature of 10° to 20° C. for 30 minutes. At the same temperature, the reaction mixture was kept for 1 hour. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 1 to obtain 2-allyl-3-methyl-4-dimethylamino-2-cyclopentenone (17.3 g). Yield, 96.5%. nD20 1.4997.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9].[F:22][C:23]([F:45])([F:44])C1C=C(S(N2C3C(=C(C=C)C=CC=3)C=C2)(=O)=O)C=CC=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O>[F:22][C:23]([F:45])([F:44])[C:5]1[CH:4]=[C:3]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=3[CH:13]=[CH:12]2)(=[O:9])=[O:10])[CH:2]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
The experimental for Intermediate 16 was followed using 1-{[3-(trifluoromethyl)phenyl]sulfonyl}-4-vinyl-1H-indole (348 mg, 0.99 mmol; Intermediate 18), OsO4 (13 mg, 0.05 mmol), 2,6-lutidine (230 μL, 2.0 mmol) and sodium periodate (0.848 g, 3.96 mmol). The title compound was obtained (368 mg, 105%, still some dioxane according to HNMR) as a black gum. MS (ESI+) for C16H10F3NO3S m/z 354 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(CCl)n1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: Cc1cccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)n1
Yield: 84.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chloromethyl-6-methylpyridine (0.43 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]([C:14](O)=[O:15])[CH:12]3[CH2:17][CH2:18][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1.Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]([C:14]([NH:24][C@H:25]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)[CH3:26])=[O:15])[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:18][CH2:17]3)=[CH:5][CH:4]=1
Reactant: O=C(O)C1C2CCC(CC2)N1Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2C3CCC(CC3)N2Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 35.2 %

Procedure:
The title compound (D155) (12 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (D111) (22.5 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (17 mg). (Reaction time: 2 hrs; 60° C.)
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Mg].[Cl:12][Si:13](Cl)([CH3:15])[CH3:14]>O1CCCC1>[Cl:12][Si:13]([C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:15])[CH3:14]
Reactant: C[Si](C)(Cl)Cl
Reactant: BrC1=Cc2ccccc2C1
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(Cl)C1=Cc2ccccc2C1
Reaction time: 15 h
Yield: 110.2 %

Procedure:
2-Bromoindene (4.0 g, 0.02 mol.) was dissolved in 4 ml of tetrahydrofuran and added dropwise to a mixture consisting of magnesium (0.73 g, 0.03 mol.) and dichlorodimethylsilane (5.0 g, 0.04 mol.) in 4 ml of tetrahydrofuran. During the addition, the solution boiled slightly. After 15 hours' stirring, the volatile constituents were removed under an oil pump vacuum, and 40 ml of n-pentane were added to the residue. The resulting magnesium salt was filtered off with suction. The solvent was removed under an oil pump vacuum to yield 4.6 g (95%) of chloro-2-indenyl-dimethylsilane in the form of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11]([O:13][C:14](=O)[C:15]=1[Cl:16])=[O:12]>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:11](=[O:12])[C:10]([Cl:9])=[C:15]([Cl:16])[C:14]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1ccc(F)cc1
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1
Yield: 99.1 %

Procedure:
5.55g (0.05 mol) of 4-fluoroaniline was emulsified in 150 ml of water. Then to the resulting emulsion 10g (0.06 mol) of 2,3-dichloromaleic anhydride in 50 ml of water was added dropwise over a period of 30 min. at room temperatures under agitation. The mixture was then allowed to react at reflux temperatures. Upon cooling the reaction mixture, a crystal was removed out, which was separated by filtration to obtain 12.9g of N-(4-fluorophenyl)-2,3-dichloromaleimide melting at 240°-243° C (not corrected) at a yield of 99.1%. An analysis by gas chromatography showed the product had a purity of 98.6%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[O:25])[CH:23]=2)=[O:16])=[CH:10][CH:9]=1.[CH3:35][S:36][CH2:37]Cl.O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[N:28]([CH2:35][S:36][CH3:37])[CH:27]=3)=[O:25])[CH:23]=2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Reactant: CSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Potassium carbonate (38 mg, 0.275 mmol) was added to a stirring solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 60.0 mg, 0.153 mmol) in DMF (1.0 mL) at room temperature. After 10 min, chloromethyl methyl sulfide (19 μL, 0.23 mmol) was added to the mixture and the reaction was stirred for 24 hours at room temperature. Water (3 mL) was added to the mixture and it was extracted with EtOAc (3×5 mL). The combined organic fractions were washed with water (5 mL), brine (5 mL), dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow oil. The crude material was purified by column chromatography on silica gel (gradient of 100% DCM to 90:10:1 DCM/MeOH/NH3) to give the title compound as a pale yellow solid in 36% yield, 25 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([C:14]#[C:15][C:16](=[O:33])[NH:17][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:19]([F:22])([F:21])[F:20])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd]>[Cl:1][C:2]1[CH:13]=[C:12](/[CH:14]=[CH:15]\[C:16](=[O:33])[NH:17][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)[C:19]([F:22])([F:20])[F:21])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:8][CH2:9]1)=[O:5]
Reactant: O=C(C#Cc1ccc(C(=O)NC2CC2)c(Cl)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: O=C(/C=C\c1ccc(C(=O)NC2CC2)c(Cl)c1)NC(c1cccc(C(F)(F)F)c1)C(F)(F)F

Procedure:
2-Chloro-N-cyclopropyl-4-[3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-prop-1-yn-1-yl]benzamide (110 mg, 0.20 mmol), quinoline (10 mg, 0.07 mmol) and palladium on calcium carbonate (5% Pd; 10 mg) were suspended in methanol and stirred for 4 days, in the course of which palladium on calcium carbonate (3×10 mg) was added again every 24 h. Then the reaction mixture was filtered through kieselguhr, and the filtrate concentrated to dryness under reduced pressure. The residue was purified by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 50% EA).
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[N+:16]([O-])=O)[C:12](=[O:19])[CH2:11][CH2:10]2)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:16][C:15]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][C:12]2=[O:19])=[CH:8][C:7]=1[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCCCC#Cc1cc2c(cc1N)C(=O)CC2

Procedure:
A mixture of 5-hex-1-ynyl-6-nitroindan-1-one (8.2 g, 31.8 mmol), NH4Cl (0.84 g) and Fe (8.88 g, 0.159 mol) in ethanol (97 ml) and water (32 ml) is heated at reflux for 45 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][NH:53][C:54]1[C:55]([NH2:60])=[CH:56][CH:57]=[CH:58][CH:59]=1>CN(C=O)C>[NH2:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[N:53]([CH3:52])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[N:13][C:5]=1[O:4][C:3]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=1[Cl:1]
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: CNc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)c1cccnc1Oc1cc(Cl)ccc1Cl)c1ccccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (50 mg, 0.18 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (2 mL) was added N-ethyldiisopropylamine (116 mg, 154 μL, 0.90 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (82 mg, 0.22 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at rt for 30 min. After addition of N-methyl-benzene-1,2-diamine (26.9 mg, 0.22 mmol, 1.2 equiv; [CAS RN 4760-34-3]) stirring was continued at rt for 90 min. Removal of the solvent under reduced pressure and purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate afforded 33 mg (47%) of the title compound as a white solid. MS (ISP): 388.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl>>[ClH:1].[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: CNS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: Cl
Product: CNS(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1

Procedure:
250 Grams of 4-chloro-3-methylsulfamoylbenzoic acid (1.0 mole) were stirred with 0.3 l of N-methylpiperazine for 4 hours at 130° C. When the hot reaction solution was introduced into 2 l of 2N HCl, the final product precipitated immediately in a crystalline form. The crude product was purified by recrystallization from a 2:2:1 mixture of ethanol/water/dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH3:33])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: CCc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) in xylene (7.5 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light red solid (236 mg, 77%).