Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][C:6]=1Br.[F:13][C:14]1[CH:15]=[C:16]([C:29]#[N:30])[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][C:6]=1[C:18]1[CH:19]=[C:14]([F:13])[CH:15]=[C:16]([C:29]#[N:30])[CH:17]=1
Reactant: CCOC(=O)c1cc(Br)c(Br)s1
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cc(Br)c(-c2cc(F)cc(C#N)c2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Under argon, 1.50 g (4.78 mmol) of the compound from Example 8A are provided in 75 ml of 1,2-dimethoxyethane, and 1.30 g (5.26 mmol) of the compound from Example 5A, 4.67 g (14.3 mmol) of cesium carbonate, 159 mg (0.33 mmol) of dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane and 32.0 mg (0.14 mmol) of palladium(II) acetate are added. The mixture is stirred at 50° C. overnight. Water is subsequently added, the mixture is extracted with ethyl acetate and the extract is dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient with addition of 0.1% formic acid). 1.05 g of ethyl 4-bromo-5-(3-cyano-5-fluorophenyl)thiophene-2-carboxylate are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(Br)cc2)cc1
Yield: 22.3 %

Procedure:
In a manner similar to that described in Example 3, 4-bromo-benzoyl chloride (0.070 g, 0.00032 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.021 g of 4-[4-(4-bromo-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+376.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([N:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:19][CH:18]=1)C(=O)OC(C)(C)C)=[O:8]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Si:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]2[NH:9][C:7](=[O:8])[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:22]=2[CH:21]=1)([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(C(=O)c1sccc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)c3sccc3c2c1
Yield: 111.6 %

Procedure:
Following Step 3 from General Procedure A, tert-butyl 3-bromothiophene-2-carbonyl[4-(tert-butyldimethylsilyloxy)phenyl]carbamate (1.0 g, 2.0 mmol) was reacted with bis(tri-tert-butylphosphine)palladium (50 mg, 0.098 mmol) to afford the desired product (740 mg, quant.) as a solid: ESI MS m/z 332 [C17H21NO2SSi+H]+.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[S:14])[S-:13])=[CH:10][C:4]=2[O:3]1.[CH2:16]([NH+](CC)CC)C.BrCBr.C(N(CC)CC)C>CN(C)C=O>[F:15][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]=[C:12]3[S:13][CH2:16][S:14]3)=[CH:10][C:4]=2[O:3]1
Reactant: FC1(F)Oc2ccc(NC(=S)[S-])cc2O1
Reactant: CC[NH+](CC)CC
Solvent: BrCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC1(F)Oc2ccc(N=C3SCS3)cc2O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.36 g (0.021 mol) Triethylammonium N-(2,2-difluoro-1,3-benzodioxol-5-yl)dithiocarbamate was dissolved in 50 ml dimethylformamide. With vigorous stirring, a mixture of 18.25 g (0.105 mol) dibromomethane and 2.12 g (0.021 mol) triethylamine in 20 ml dimethylformamide was added dropwise. It was then stirred for two hours. The reaction mixture was poured into 250 ml ice/water and extracted 3 times with 100 ml diethyl ether. The combined ether phases were dried over magnesium sulphate and concentrated. Purification was then carried out by column chromatography (eluent: hexane/ethyl acetate 4:1).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.C([O-])([O-])=O.[Na+].[Na+].[OH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[OH:40])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OB(O)c1ccccc1O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Temperature: 100 °C
Yield: 60 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO2004/087714, from commercially available methyl indole-6-carboxylate) in a mixture of 1,2-dimethoxyethane and ethanol (5:2, v/v, 0.2 M) were added 2 eq of Na2CO3 (2 M aqueous solution), 1.3 eq of (2-hydroxyphenyl)boronic acid and 0.1 eq of tetrakis(triphenylphosphine)palladium(0). The mixture was degassed thoroughly with a stream of dry nitrogen and then heated to 100° C. overnight. The reaction mixture was allowed to cool, diluted with some EtOAc and filtered over a plug of CELITE. The filtrate was diluted with EtOAc and the organic phase washed with water, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (1:7 EtOAc/petroleum ether, then 1:3) to afford the title compound as a light yellow solid (60%). 1H NMR (400 MHz, DMSO-d6, 300 K) 1.14-1.38 (m, 3H), 1.63-1.81 (m, 5H), 1.82-1.96 (m, 2H), 2.62-2.70 (m, 1H), 3.84 (s, 3H), 6.92 (t, J 7.4, 1H), 7.00 (d, J 8.0, 1H), 7.22 (dd, J 1.3, 7.5, 1H), 7.26 (dt, J 1.4, 8.0, 1H), 7.57 (dd, J 1.2, 8.5, 1H), 7.78 (d, J 8.5, 1H), 7.98 (d, J 1.2, 1H), 9.69 (s, 1H), 11.22 (s, 1H); MS (ES+) m/z 350 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:4]1=[O:33].[H][H].CCOCC>C(O)C.CC#N.C(O)(C)C.O=[Pt]=O>[ClH:1].[OH:2][C@@H:3]1[C@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:8][C:7]2[C:18]([C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)[C:4]1=[O:33]
Reactant: [H][H]
Reactant: COc1ccc([C@@H]2Cc3c(cccc3C(F)(F)F)N(Cc3ccccn3)C(=O)[C@@H]2O)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc([C@@H]2Cc3c(cccc3C(F)(F)F)N(CC3CCCCN3)C(=O)[C@@H]2O)cc1

Procedure:
A solution of 3.00 g (6.09 mmol) of the title compound from Example 23 in 200 ml of ethanol was treated with 0.30 g of PtO2 and placed on the Parr apparatus under 50 psi of hydrogen for 2 hours. TLC at this point indicated the reduction of the pyridyl group was complete. The catalyst was filtered under nitrogen and solvent evaporated to give a solid residue. The latter was dissolved in 30 ml of CH3CN and luted with 330 ml of ether to give a solid. This mixture was cooled overnight and filtered to give 1.29 g (43%) of Isomer A, m.p. 177°-180° C. (s. 160° C.). Isomer A was dissolved in 20 ml of hot isopropyl alcohol, filtered through filter cel (to remove trace of catalyst), cooled overnight and filtered to give 0.72 g of nearly colorless solid, [α]D +112°, (c=1.0 MeOH). After recrystallization from 18 ml of hot isopropyl alcohol, the product weighed 0.63 g (21%); m.p. 177°-180° C. (s. 160° C.); [α]D +113° C. (c=1.0, MeOH); Rf 0.59 (80:20 CH2Cl2 -MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][C:19]2[CH:25]=[C:24](C(=S)N)[CH:23]=[CH:22][C:20]=2[N:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])O.[Na+].BrC[C:36](=O)[CH3:37]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]1[S:18][C:19]2[CH:25]=[C:24]([SH:18]3[CH:37]=[CH:36][N:21]([CH3:20])[CH2:17]3)[CH:23]=[CH:22][C:20]=2[N:21]=1)([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: NC(=S)c1ccc2nc(C(O)(Cn3cncn3)c3ccc(F)cc3F)sc2c1
Reactant: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1C=C[SH](c2ccc3nc(C(O)(Cn4cncn4)c4ccc(F)cc4F)sc3c2)C1

Procedure:
1-(2,4-Difluorophenyl)-1-(6-thiocarbamoylbenzothiazol-2-yl)-2-(1H-1,2,4-triazol-yl)ethanol is reacted with sodium hydrogencarbonate and bromoacetone to obtain 1-(2,4-difluorophenyl)-1-(6-(3-methylthiazol-1-yl)-benzothiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol.
Reaction SMILES: [O:1]=[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([O:20][CH2:21][CH3:22])([CH2:10][CH2:11][P:12]([O:17]CC)([O:14][CH2:15][CH3:16])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OC(C1C=CC=CC=1)C(=O)C1C=CC=CC=1)C.CCOP(OC=C)(OCC)=O.[OH-].[Na+]>C(O)C>[O:1]=[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([O:20][CH2:21][CH3:22])([CH2:10][CH2:11][P:12]([OH:17])([O:14][CH2:15][CH3:16])=[O:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(CCP(=O)(OCC)OCC)(C(=O)c1ccccc1)c1ccccc1
Agent: C=COP(=O)(OCC)OCC
Agent: CCOC(C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(CCP(=O)(O)OCC)(C(=O)c1ccccc1)c1ccccc1

Procedure:
1-Oxo-2-ethoxy-2-(2-diethylphosphonoethyl)-1,2-diphenylethane (25 g, prepared from benzoin ethyl ether and diethyl vinyl phosphonate as described in Example 3 of U.S. Pat. No. 4,082,821) is dissolved in ethanol (200 ml). Sodium hydroxide (20 g) is added to the solution and the mixture is heated under reflux for 3 hours. The ethanol is removed by rotary evaporation, water is added, and the mixture is washed with diethyl ether (4×100 ml) to remove unreacted starting material. Concentrated hydrochloric acid is added to the aqueous mixture until the pH is zero. The resulting mixture is washed with ether, water is evaporated and the residue is recrystallised from a mixture of acetone and ether to give 12.5 g of product, a compound of formula XVIII where R1 is ethoxy, R3 and Ar1 are each phenyl, R7 is --CH2CH2 --and R8 is --CH2CH3.
Reaction SMILES: C1(C(=CC=CC=1)O)O.[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[C:10](=C)C.C(Cl)C(=C)C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[O:13][CH2:9][CH2:10]2
Reactant: C=C(C)COc1ccccc1O
Agent: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1O
Solvent: CC(C)=O
Product: Oc1cccc2c1OCC2
Yield: 45 %

Procedure:
It is furthermore known (see U.S. Pat. No. 3,474,171), that pyrocatechol can be converted into methallyloxyphenol with methallyl chloride in the presence of equivalent amounts of K2CO3 and KI in acetone as the diluent if the mixture is heated under reflux for 30 hours. The yield is 45% of theory. Rearrangement and cyclization to give 7-hydroxycoumaran are carried out at 200° to 275° C. without a solvent; no yields are given for these stages. Particular disadvantages for an industrial procedure are, in the alkylation stage, the long reaction times giving a low yield and the use of an equimolar amount of potassium iodide, which is expensive and can be recovered from the salt mixture for renewed use only with high losses. Because of the highly exothermic effect, solvent-free rearrangement of methallyloxyphenol can be carried out only with a great deal of technical effort.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[S:11][C:12]([CH:15]=O)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[S:11][C:12]([CH:15]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)NO
Reactant: COc1ccc(Sc2ccc(C=O)s2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Sc2ccc(C=[N+]([O-])C(C)(C)C)s2)cc1
Yield: 16.8 %

Procedure:
2-(4-Methoxyphenylthio)-5-thiophenecarboxaldehyde from Step A was mixed with N-tert-butylhydroxylamine (10 g, 112.11 mmol), molecular sieves (4A, 50 g), silica gel (10 g) and chloroform (200 mL). The mixture was refluxed for 15 h, filtered and rotary evaporated. The residue obtained was purified by chromatography over silica gel eluting with hexanes/EtOAc (2:1, v:v) to provide a slightly pinkish powder (4.60 g, yield 16.8%), m.p.100.9° C. (Rf =0.19 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][CH2:9]2>C(OC(=O)C)(=O)C>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([N+:1]([O-:4])=[O:2])[CH:15]=1)[O:12][CH2:11][CH2:10][CH2:9]2
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc2c(c1)CCCO2
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(F)cc2c1OCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of nitric acid (100%, 7.8 ml, 0.16 mol) in acetic anhydride was maintained at room temperatue for 0.5 hour. This mixture was added to a solution of 6-fluorochroman (11.9 g, 0.078 mol) in 40 ml acetic anhydride at 0° C. The reaction mixture was stirred at room temperature for 2 hours then poured into ice-water. The mixture was extracted with methylene chloride (3×60 ml) and washed with saturated sodium carbonate (8×150 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to afford a yellow solid: mp 48-50° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[N:11](CC2C=CC=CC=2)[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[NH:11][CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](Cn2cccn2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN[C@@H](Cn2cccn2)CN1C(=O)OC(C)(C)C
Yield: 115.2 %

Procedure:
(2R,5R)-4-Benzyl-2-methyl-5-pyrazol-1-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (0.24 g, 0.65 mmol) was hydrogenated over 10% palladium on carbon at 4 bar using a similar procedure to that described in Preparation 209. The crude product was dissolved in methanol and solvent re-evaporated and residue dried in vacuo at 40° C. for 6 h to give the title compound (0.21 g). MS: [M+H]+=281.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH2:12](I)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:12][CH2:13][CH3:14])[C:6]=2[CH:11]=1
Reactant: CCCI
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCn1c(=O)oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 100 mL round-bottomed flask was charged with 5-bromo-2-benzoxazolinone (0.750 g, 3.50 mmol), n-propyl iodide (0.684 mL, 7.01 mmol), potassium carbonate (1.211 g, 8.76 mmol) and Dioxane (5 mL). The reaction mixture was stirred at room temperature for overnight. The reaction was quenched with water. Colorless precipitate was collected through filtration and 5-Bromo-3-propyl-3H-benzooxazol-2-one was obtained, ESI-MS: m/z 258.2 (M+H)+
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7](=[O:9])[CH3:8])(=[O:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>[Zn]>[OH:9][C:7]([CH3:8])([CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)CC(CCc1ccccc1)OC(C)=O
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)CC(CCc1ccccc1)OC(C)=O

Procedure:
Using 1.48 g of 4-acetoxy-6-phenylhexan-2one, 1 ml of ethyl bromoacetate and 0.62 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.03 g of ethyl 3-hydroxy-3-methyl-5-acetoxy-7-phenylheptanoate. The ester (0.90 g) thus obtained was dissolved in 5 ml of methanol and 2 ml of 4 N sodium hydroxide was added thereto. The mixture was stirred for 4 hours at room temperature, acidified by the addition of 4 N hydrocholoric acid, 5 ml of ethyl acetate was added and the mixture was stirred for 3 days. The usual treatment of the organic solvent layer afforded 400 mg of the desired compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:8]=[N:9][C:10]=1[C:11]([F:14])([F:13])[F:12])=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[N:7]1[C:6]([CH2:4][OH:3])=[C:10]([C:11]([F:13])([F:14])[F:12])[N:9]=[N:8]1
Reactant: CCOC(=O)c1c(C(F)(F)F)nnn1-c1c(Cl)cccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1c(C(F)(F)F)nnn1-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a 0° C. solution of 3-(2,6-dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (28 g, 79 mmol) in THF (200 mL) is added dropwise 1M DIBAL (166 mL, 166 mmol) keeping the temperature below 5° C. After the addition, the bath is removed and the reaction is stirred for 18 h. The reaction is cooled to 0° C. and ether (300 mL) is added. The reaction is quenched with 1N HCl (250 mL) dropwise keeping the temperature below 15° C. The layers are separated and the water layer is washed with Ether (100 mL). The organics are combined and washed with water, brine, and dried with Na2SO4. The organic layer is concentrated to dryness to yield the title compound (24 g, 97%) and is used with no further purification. ES/MS m/e 312.0 (M+1).
Reaction SMILES: FC(F)(F)CO.Cl.O1CCOCC1.[CH3:14][O:15][C:16]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:17]=1[NH2:18].[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH3:52])[CH:44]=2)[C:40]([Cl:53])=[CH:39][N:38]=1>>[ClH:36].[Cl:53][C:40]1[C:41]([C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH3:52])[CH:44]=2)=[N:42][C:37]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[CH:22][C:16]=2[O:15][CH3:14])=[N:38][CH:39]=1
Reactant: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.8 %

Procedure:
2,2,2-Trifluoroethanol (1.5 ml) was added to a 10 mL vial charged with 4 N HCl in dioxane (0.135 ml, 0.54 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.082 g, 0.27 mmol), and 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole (INTERMEDIATE 49, 0.075 g, 0.27 mmol). The reaction was stirred at RT for 5 min and then microwaved at 150° C. for 50 min. Concentration in vacuo gave a crude residue, and it was purified by silica gel chromatography (10% methanol andl% ammonium hydroxide in DCM) to give the product (0.105 g, 66.8%). The product was stirred in 20 mL of 0.5 N HCl in methanol for 1 min and then concentrated under reduced pressure to give the title product. (yellow solid).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:20][C:21](N2C=CN=C2)=[O:22])[S:5][C:6]=1[C:7]1[N:8]=[C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[S:10][CH:11]=1.C(O)(=O)C.[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH2:35][NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:32][N:33]([CH3:38])[C:34](=[O:37])[CH2:35][NH:36][C:21]([NH:20][C:4]1[S:5][C:6]([C:7]2[N:8]=[C:9]([C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])[S:10][CH:11]=2)=[C:2]([CH3:1])[N:3]=1)=[O:22]
Reactant: CN(C)C(=O)CN
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)NCC(=O)N(C)C)sc1-c1csc(C(=O)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To N-[4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide, prepared as in Step 3 of Example 36, described above (75 mg; 0.19 mmol; 1 eq.) is added DMF (3 ml), glycine dimethylamide acetate (Chem-Impex) (30.1 mg; 0.19 mmol; 1 eq.) and triethylamine (57 μl; 0.41 mmol; 2.20 eq.). The mixture is stirred 3 hours at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (46) as a light yellow solid (49 mg; 60%). 1H NMR (DMSO-d6, 300 MHz) δ 2.44 (s, 3H), 2.86 (s, 3H), 2.94 (s, 3H), 3.68 (m, 6H), 4.01 (m, 2H), 4.33 (m, 2H), 6.83 (m, 1H), 7.91 (s, 1H), 10.70 (br s, 1H). M− (ESI): 437.15; M+ (ESI): 439.09. HPLC (method A), Rt: 2.30 min (purity: 99%).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:33])=[C:11]([CH2:13][N:14]([CH2:31][CH3:32])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[N:12]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:31]([N:14]([CH2:13][C:11]1[N:12]=[C:8]([CH2:1][CH2:21][C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)[O:9][C:10]=1[CH3:33])[C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:30])([C:26]([F:29])([F:27])[F:28])[C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=1)[CH3:32]
Reactant: CCN(Cc1nc(Cc2ccccc2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: CCN(Cc1nc(CCc2ccccc2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 128.5 %

Procedure:
A solution of 40 mg (0.08 mmol) of 2-{4-[(2-benzyl-5-methyl-oxazol-4-ylmethyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol in 1 mL of MeOH was treated with 20 mg of Pd/C (10%) and hydrogenated at atmospheric pressure for 20 hours. Filtration and evaporation gave 25 mg (62%) of 2-{4-[ethyl-(5-methyl-2-phenethyl-oxazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow oil, MS: 487 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O.NN.Cl.[C:24]([C:28]1[CH:37]=[CH:36][C:31]([CH2:32][N:33]=[C:34]=[S:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>CO.O1CCCC1.CN(C)C=O.ClCCl.C(N(CC)CC)C>[C:24]([C:28]1[CH:37]=[CH:36][C:31]([CH2:32][NH:33][C:34]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[S:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCSCC1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(CNC(=S)NCCN2CCSCC2)cc1
Reaction time: 21 h

Procedure:
2-(2-thiomorpholin-4-ylethyl)isoindol-1,3-dione 15-1 (2.76 g) was dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) and to the solution was added dropwise hydrazine hydrate (550 mg), followed by stirring for 21 hours. To the obtained solution was added 2 N aqueous hydrochloric acid solution (6 ml), and the mixture was stirred for 3 hours and then concentrated under reduced pressure. To the concentrate was added water (15 ml) and the undissolved material was filtered off. The filtrate was concentrated to obtain reaction mixture (1.62 g) as a solid. The obtained mixture (150 mg) was dissolved in dimethylformamide (5 ml) and to the solution was added 4-t-butylbenzylisothiocyanate (210 mg) and a small amount of triethylamine, followed by stirring at room temperature for 23 hours. The resulting mixture was diluted with dichloromethane, washed with water, and concentrated under reduced pressure. The residue was purified by column-chromatography (hexane/ethyl acetate=1/3) to the compound 15-3 (0.12 g) as a white solid.