Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])=O.B(F)(F)F.CCOCC>C(Cl)Cl>[SH:6][CH2:5][CH:2]1[CH2:3][O:4][C:10]([CH3:12])([CH2:9][CH2:8][C:7]([O:14][CH2:15][CH3:16])=[O:13])[S:1]1
Reactant: CCOC(=O)CCC(C)=O
Reactant: OCC(S)CS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCC1(C)OCC(CS)S1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
A stirred solution of 2,3-dimercapto-1-propanol (20.0 g, 0.161 mol) and ethyl levulinate (22 g, 0.161 mol) in methylene chloride (600 ml) under a nitrogen atmosphere was treated with boron trifluoride etherate (5 ml). After stirring for 3 days at room temperature, the reaction was quenched by addition of 250 ml of 5% potassium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 6% ethyl acetate/hexane as eluent to give 17 g (43%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]#[N:22])=[CH:15][CH:14]=1.C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:19]([C:16]3[CH:17]=[CH:18][C:13]([S:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:21]([NH2:22])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NN)c1
Reactant: CSc1ccc(C=CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-n2nc(N)cc2-c2ccc(SC)cc2)c1
Temperature: 140 °C
Yield: 51.3 %

Procedure:
To a mixture of (3-methoxyphenyl)hydrazine (6 g) and 3-[4-(methylthio)phenyl]acrylonitrile (5.7 g) in methanol (100 ml) was added sodium methoxide (28 wt. % solution in methanol) (18 ml) at ambient temperature. The mixture was heated to dryness under nitrogen at 140° C. for 30 minutes. The resultant orange mass was partitioned between dichloromethane and ice water. The organic layer was dried over magnesium sulfate, and then filtered. This filtrate was evaporated in vacuo. The resultant mass was dissolved in ethyl acetate (150 ml) and refluxed for 1 hour in the presence of magnesium (IV) oxide (20 g). This mixture was cooled, and filtered. The filtrate was evaporated in vacuo. The resultant mass was purified by column chromatography on silica gel using dichloromethane as eluent to give {1-(3-methoxyphenyl)-5-[4-(methylthio)-phenyl]pyrazol-3-yl}amine (5.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:24]2[C:33]3[C:32](=[O:34])[CH2:31][C@@H:30]([CH2:35][CH2:36][CH3:37])[CH2:29][C:28]=3[NH:27][C:26]([CH3:38])=[C:25]2[C:39]#[N:40])[CH:5]=[C:6]([O:21][CH2:22][CH3:23])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[N+:18]([O-])=O.C(O)(=O)C>C1COCC1.[Zn]>[NH2:18][C:11]1[CH:12]=[C:13]([F:17])[C:14]([F:16])=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:6]([O:21][CH2:22][CH3:23])=[CH:5][C:4]([C@H:24]2[C:33]3[C:32](=[O:34])[CH2:31][C@@H:30]([CH2:35][CH2:36][CH3:37])[CH2:29][C:28]=3[NH:27][C:26]([CH3:38])=[C:25]2[C:39]#[N:40])=[CH:3][C:2]=1[Br:1]
Reactant: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(OCc2cc(F)c(F)cc2[N+](=O)[O-])c(OCC)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC[C@@H]1CC(=O)C2=C(C1)NC(C)=C(C#N)[C@H]2c1cc(Br)c(OCc2cc(F)c(F)cc2N)c(OCC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (4R,7S)-4-[3-Bromo-4-(4,5-difluoro-2-nitro-benzyloxy)-5-ethoxy-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (Example 72 g, 10.6 g) and acetic acid (19.6 ml) in THF (400 ml) was cooled to 0° C. Zinc dust (27.6 g) was added in portions under vigorous stirring. The mixture was stirred for 2 h at 0° C. and then filtered. The solids were washed with dichloromethane and the combined filtrates were washed with sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>>[ClH:40].[CH2:7]([O:6][C:4]([C:3]1[C:2]([CH2:1][Br:13])=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:8]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccnc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1cccnc1CBr
Product: Cl

Procedure:
A mixture of ethyl 2-methylnicotinate (5.0 g, 30.3 mmol), N-bromosuccinimide (7.5 g, 42.1 mmol) and benzoyl peroxide (0.5 g) in carbon tetrachloride (100 ml) was heated under reflux for 6 hours, then allowed to cool. The resulting mixture was filtered, the filtered solid washed with carbon tetrachloride, and the combined filtrate washed with 4% sodium hydroxide solution, water and 2% hydrochloric acid, then dried over sodium sulphate. The solution was then treated with ethereal hydrochloric acid, and the resulting precipitate was filtered off, washed with ether and dried to afford the title compound as a pale yellow solid (4.5 g).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([OH:12])=O)[N:8]=1)=[O:2].N1C(C)=CC=CC=1C.C(Cl)(=O)C(C)(C)C.[NH2:28][CH:29]1[C:64](=[O:65])[N:31]2[C:32]([C:48]([O:50][CH:51]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:49])=[C:33]([CH2:37][O:38][C:39]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[O:40])[CH2:34][S:35](=[O:36])[C@H:30]12>C(Cl)Cl.C(N(CC)CC)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:28][CH:29]2[C:64](=[O:65])[N:31]3[C:32]([C:48]([O:50][CH:51]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)=[O:49])=[C:33]([CH2:37][O:38][C:39]([N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]4)=[O:40])[CH2:34][S:35](=[O:36])[C@H:30]23)=[O:12])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(CC(=O)O)cs1
Reactant: CN1CCN(C(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3S(=O)C2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CN1CCN(C(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4csc(NC=O)n4)[C@H]3S(=O)C2)CC1
Temperature: 22 °C
Reaction time: 0.67 h
Yield: 78.4 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)acetic acid (0.70 g), 2,6-lutidine (0.44 ml), triethylamine (0.05 ml) and pivaloyl chloride (457 mg) in dry methylene chloride (10 ml) was stirred at -15° C. for 20 minutes, at 12° C. for 20 minutes and at 22° C. for a further 40 minutes. A mixture of benzhydryl 7-amino-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (1.7 g) in methylene chloride (20 ml) was cooled to -30° C. and thereto was added the acid anhydride solution obtained above followed by stirring at -20° to -10° C. for an hour and at -10° C. to ambient temperature for a further one hour. The reaction mixture was evaporated and to the residue was added ethyl acetate (20 ml) and water (10 ml) followed by stirring. Insoluble substances were collected by filtration, washed with water and ethyl acetate and then dried under reduced pressure to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylate-1-oxide (1.75 g).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:23]([C:20]1[CH:21]=[N:22][C:17]([C:16]#[C:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:18][CH:19]=1)[S:32]([CH3:31])(=[O:34])=[O:33])(=[O:34])=[O:33]
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 13) (0.89 g, 2.9 mmol), triethylamine (0.61 mL, 4.4 mmol) and N,N-dimethylaminopyridine (catalytic amount) in 20 mL of dichloromethane is cooled to 0° C. and methanesulfonyl chloride (0.30 mL, 3.5 mmol) is added dropwise under nitrogen. The cold bath is removed and the solution is stirred at room temperature for 18 hours. The solution is diluted with dichloromethane and washed with 30 mL of saturated aqueous sodium bicarbonate solution and 30 mL of water, and the organic layer is dried (sodium sulfate). The solvent is removed under reduced pressure and the residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound as a white solid; mp 168°-169.5° C.
Reaction SMILES: [OH:1][CH:2]([CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH:9]=[CH:8]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O>[CH:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([O:1][CH2:18][C:17]([SiH:14]([CH3:16])[CH3:15])([CH3:20])[CH3:19])[CH2:12][CH3:13])[CH2:11][CH2:10][CH:9]=[CH:8]1.[CH3:18][C:17]([Si:14]([CH3:16])([CH3:15])[O:1][CH:2]([CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH:9]=[CH:8]1)([CH3:20])[CH3:19]
Reactant: CCC(O)CCCCC1C=CCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC(CCCCC1C=CCC1)OCC(C)(C)[SiH](C)C
Product: CCC(CCCCC1C=CCC1)O[Si](C)(C)C(C)(C)C

Procedure:
The procedure followed is the same as that described in Examples 7 and 8 using 3-(5-hydroxyhept-1-yl)cyclopentene {alpha-ethyl-2-cyclopenten-1-pentanol} (32.5 g, 0.177 moles), t-butyldimethylsilylchloride (29.3 g, 0.194 moles), imidazole (13.3 g, 0.194 moles), and dimethylformamide (163 ml). The crude product is fractionally distilled under reduced pressure leaving a clear, colorless oil (48 g, 0.162 moles), BP 103° C./0.15 mm.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>CCOCC>[Cl:9][CH2:10][C:11]([N:4]1[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]1)=[O:12]
Reactant: CC1CNCC(C)O1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Product: CC1CN(C(=O)CCl)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.5 %

Procedure:
2,6-Dimethylmorpholine (a mixture of trans- and cis-isomers (1.0 g, 8.7 mmol) and TEA (1.34 ml, 9.6 mmol) were dissolved in anhydrous ether (50 ml) and cooled in ice bath. To the above mixture was added dropwise a solution of chloroacetyl chloride (0.69 ml, 8.7 mmol). Then the mixture was warmed to room temperature and stirred for 3 hours. The mixture was washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography (EA/PE=1/1) to afford the title compound (0.79 g, yield 47.5%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.CC(O)CC>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: O
Solvent: CCC(C)O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 118 °C
Yield: 84 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (100 g, 0.38 mol), N-methylpiperazine (250 mL, 2.5 vol) and 2-butanol (200 mL, 2 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated to reflux at 118° C. under a nitrogen atmosphere and refluxed overnight. The reaction mixture was allowed to cool to below 55° C. whereupon water (300 mL, 3 volumes) was added to precipitate out the solid. It was isolated by Buchner filtration and the light yellow solid was washed twice with 25% aqueous 2-butanol (100 mL) and then once with 2-butanol (100 mL) and dried to provide olanzapine in 84% yield (98.7 g).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CSc1ccc(C2=C(c3ccc(Cl)cc3)CCC2)cc1
Yield: 103.7 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Example 1, Step 2) was reacted with 300 mg (1.9 mmol) of 4-chlorophenylboronic acid (Lancaster). Purification by silica gel chromatography (MPLC) with hexane gave 290 mg of 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 72°-74° C.; NMR (CDCl3) δ 2.04 (m, J=7 Hz, 2H), 2.46 (s, 3H), 2.86 (t, J=7 Hz, 4H), 7.07-7.21 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([NH2:9])[CH3:8])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([C:19](O)=[O:20])=[CH:17][CH:18]=1)=[O:13]>>[CH3:10][O:11][C:12]([C:14]1[S:15][C:16]([C:19](=[O:20])[NH:9][CH:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:8])=[CH:17][CH:18]=1)=[O:13]
Reactant: CC(N)c1ccc(Br)s1
Reactant: COC(=O)c1ccc(C(=O)O)s1
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(Br)s2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 1 from 1-(5-bromo-thiophen-2-yl)-ethylamine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: CC1C(C2CCCC(C3C(C)=CC=CN=3)N2)=NC=CC=1.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27](CBr)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.485 g, 1.81 mmol), 4-bromomethyl-benzoic acid methyl ester (0.642 g, 2.80 mmol), KI (64 mg, 0.38 mmol), and DIPEA (0.65 mL, 3.73 mmol) in DMF (9 mL) was heated at 60° C. for 23 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.67 g (89%) of 4-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester as a white solid. 1H NMR (CDCl3) δ 1.54-1.72 (m, 3H), 2.02-2.08 (m, 1H), 2.20-2.34 (m, 2H), 2.40 (s, 6H), 3.58 (s, 2H), 3.83 (s, 3H), 4.12 (d, 2H, J=11.4 Hz), 6.57 (d, 2H, J=7.8 Hz), 6.96 (dd, 2H, J=7.5, 4.5 Hz), 7.23 (d, 2H, J=7.5 Hz), 7.53 (d, 2H, J=7.8 Hz), 8.26 (d, 2H, J=4.5 Hz); ES-MS m/z 416 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:12][C:13](O)=[O:14])([CH3:11])[CH2:8][CH2:7][C:6]=2[CH:16]=1.S(Cl)([Cl:19])=O>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH2:12][C:13]([Cl:19])=[O:14])([CH3:11])[CH2:8][CH2:7][C:6]=2[CH:16]=1
Reactant: CC1(CC(=O)O)CCc2cc(Cl)ccc2O1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC1(CC(=O)Cl)CCc2cc(Cl)ccc2O1

Procedure:
To a solution composed of 2.89 g of (6-chloro-3,4-dihydro-2-methyl-2H-benzopyran-2-yl)acetic acid, 2 drops of N,N-dimethylformamide and 50 ml of benzene was added 0.9 ml of thionyl chloride and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. The above procedure gave (6-chloro-3,4-dihydro-2-methyl-2H-benzopyran-2-yl)acetyl chloride in a quantitative yield of 3.1 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4N=[CH:24][N:23]=[C:22](N)[C:21]=4[C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:16][CH2:15]3)[N:11](C)[CH:12]=2)=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].Br[C:40]1C=NC=CC=1N1CCC(C2NC=C(C3C=CC=C(C(F)(F)F)C=3)N=2)CC1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:21]2[CH:22]=[N:23][CH:24]=[CH:40][C:20]=2[N:17]2[CH2:16][CH2:15][CH:14]([C:10]3[NH:11][CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][CH:2]=[C:3]([C:35]([F:38])([F:36])[F:37])[CH:4]=4)[N:9]=3)[CH2:19][CH2:18]2)=[CH:28][CH:29]=1
Reactant: FC(F)(F)c1cccc(-c2c[nH]c(C3CCN(c4ccncc4Br)CC3)n2)c1
Reactant: COc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cc1
Product: COc1ccc(-c2cnccc2N2CCC(c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamine using 3-bromo-4-(4-{4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidin-1-yl)pyridine instead of 5-bromo-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidin-4-amine. LC-MS: (M+1=479, obsd.=479).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:56])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.CC(O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:56])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][OH:38])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-(2-{1-benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethylamino)-benzoic acid methyl ester (3.88 mmol) in THF (25 mL) at 0° C. was added a mixture of HOAc:1M TBAF (in THF) (2.3 mL:5.8 mL) and the reaction mixture was allowed to stir at rt for 18 h. Extractive workup followed by trituration with 5%EtOAc/hex gave the desired 4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester with slight impurity as an off-white solid (92%, over 3 steps).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:12][O:13][CH3:14])[C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18].O>CN(C)C(=O)C>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:12][O:13][CH3:14])[C:8]([O:10][CH3:11])=[O:9])[N:6]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CON=C(C(=O)OC)c1csc(N)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CON=C(C(=O)OC)c1csc(NC(=O)CCl)n1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
In 90 ml of N,N-dimethylacetamide is dissolved 21.5 g of methyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (syn-isomer) and, under ice-cooling, 13.6 g of chloroacetyl chloride is added dropwise. The mixture is stirred under ice-cooling for 30 minutes and, then, at room temperature for 30 minutes, after which 500 ml of water is added. The mixture is extracted twice with ethyl acetate and the combined extract is washed with a 5% aqueous solution of sodium hydrogen carbonate and water in that order and dried. On removal of the solvent, there is obtained 25 g of methyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate(syn-isomer) as crystals melting at 130.8° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1I)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN(C(=O)OC(C)(C)C)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCCN(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methoxy-ethyl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless oil (70%). MS (ESI): m/z=363.147 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1Cl
Solvent: O
Product: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1NCc1ccccc1

Procedure:
14 g of 2-amino-3-cyano-4-chloro-6-(4-benzylpiperazin-1-yl)quinoline and 28 mL of benzylamine are stirred at 125° C. for 4 hours. The reaction mixture is poured onto 100 mL of water. The precipitated material is filtered off, washed with 2×50 mL of water. After drying 8 g of the title compound is obtained, m.p.: 202° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br>C(Cl)(Cl)Cl.ClCCl>[Br:15][CH2:9][C:8]([C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(6-Bromopyridin-3-yl)ethanone was dissolved in 50 mL of chloroform and cooled to 0° C., to which was added catalytic amount of AlCl3 and 2.65 mL of bromine in 25 mL of chloroform. The addition of bromine lasted 1 h to keep the reaction solution at 0° C. After stirring at 0° C. overnight, the mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated to afford 2-bromo-1-(6-bromopyridin-3-yl)ethanone which was used in the next step with out further purification. LCMS: [M+1]+=279.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][N:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=2)=[N:10]1
Reactant: ClCC1CO1
Reactant: FC(F)(F)c1ccc(-c2n[nH]cc2-c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2cnccn2)cc1
Reaction time: 24 h
Yield: 59 %

Procedure:
To a solution of 2-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (200 mg, 0.69 mmol) and epichlorohydrin (0.540 mL, 6.9 mmol) in DMF (2 mL) was added cesium carbonate (450 mg, 1.38 mmol). The reaction mixture was allowed to stir for 24 h, diluted with EtOAc, and washed with saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 5% acetone/CH2Cl2) to afford 2-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyrazine (141 mg, 59%). TLC (silica, 20% acetone/CH2Cl2): Rf=0.38. MS (electrospray) m/z 347.1 (347.1, calculated for C17H13F3N4O, M++H). 1H NMR (400 MHz, CDCl3): 8.51 (dd, J=2.8, 1.8 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.38 (d, J=12.8 Hz, 1H), 8.01 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 4.57 (dd, J=14.7, 3.1 Hz, 1H), 4.21 (dd, J=14.7, 6.1 Hz, 1H), 3.44 (m, 1H), 2.91 (t, J=4.5 Hz, 1H), 2.62 (dd, J=4.0, 2.5 Hz, 1H).