Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[O-2].[Ba+2].[OH-].[Ba+2].[OH-].I[CH3:25]>CN(C=O)C>[CH3:25][O:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Ba+2]
Agent: [O-2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CO[C@H]1Cc2ccccc2[C@H]1NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A mixture of tert-butyl [(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-carbamate (680. mg, 2.73 mmol), DMF (21.1), barium monoxide (5.02 g, 32.7 mmol), barium hydroxide (2.80 g, 16.4 mmol) and iodomethane (1.70 mL, 27.3 mmol) was stirred overnight. LC/MS showed no starting material. The reaction was quenched via addition of a saturated solution of NaHCO3 and was extracted with DCM. The organic layer was washed with H2O (3×), dried over sodium sulfate and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the title compound (178 mg, 25%). LC/MS: Rt=1.24 min, ES+ 264 (AA standard).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20]([OH:22])=[O:21])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
To a mixed solution of ethyl 5-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.80 g) in tetrahydrofuran (15 mL)-methanol (15 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.65 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (735 mg, yield 99%) as pale-yellow crystals. melting point>280° C. (decomposition).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[C:61]2[C:56](=[CH:57][C:58]([C:62]3[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=3)=[CH:59][CH:60]=2)[CH:55]=[CH:54]1>CN(C=O)C>[NH:53]1[C:61]2[C:56](=[CH:57][C:58]([C:62]3[CH:63]=[C:64]([NH:68][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=3)=[CH:59][CH:60]=2)[CH:55]=[CH:54]1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3[nH]ccc3c2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 75 %

Procedure:
DIEA (0.014 mL, 0.073 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.066 mmol) and HATU (0.030 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-Indol-5-yl)-phenylamine (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected were collected and the solvent removed under vacuum to give 0.023 g of product in 68% yield: LCMS (ESI) m/z 465 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.CC(C)=O.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(O)c2ncccc12
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c2ncccc12
Reaction time: 4 h
Yield: 55.1 %

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (346 mg, 2 mmol) in acetone (15 ml) anhydrous potassium carbonate (300 mg, 2.2 mmol) and benzylbromide (0.25 ml, 360 mg, 2.1 mmol) were added at 50° C. and the stirring was-continued for other 4 h at this temperature. The solvent was removed under reduced pressure, the residue taken up with dichloromethane, the organic layer washed several times with water, dried (sodium sulfate) and evaporated under vacuum. The residue was chromatographed on silica gel using as eluant ethylacetate/cyclohexane (2:3) to give 290 mg (55% yield) of 8-benzyloxyquinoline-5-carbaldehyde. The above obtained compound (290 mg, 1.1 mmol) was dissolved in ethanol (10 ml), then 2-oxindole (170 mg, 1.28 mmol) and piperidine (0.15 ml) were added and the, mixture maintained for 4 h at about 60° C. After cooling the precipitate was filtered, washed with cold ethanol and dried to give 300 mg (72% yield) of raw 3-(8-benzyloxyquinol-5-ylmethylen)-2-oxindole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]OS(C(F)(F)F)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Br-:23]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][Br:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(=O)(=O)C(F)(F)F)C1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CBr)C1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 3-trifluoromethanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.85 g, 13.8 mmol) and LiBr (3.61 g, 42 mmol) in dry acetone (30 mL) was refluxed overnight. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The residue was dissolved in CH2Cl2 and washed with water, dried and concentrated under reduced pressure to give 6 g of the crude product. Purification by flash chromatography (Heptane/EtOAc: 1/0→68/32) afforded of 3-bromomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.84 g, 78%) as a colourless oil.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([C:19](=[O:20])[CH2:18][CH2:17][N:5]2[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:16]=[C:4]2[CH2:1][CH2:2][CH3:3])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reactant: C1COCCN1
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.0 g, 15 mmol) in morpholine (20 mL, 0.2 mol) was heated at reflux for two days, allowed to cool to ambient temperature, and concentrated under reduced pressure to provide 5.2 g of 1-(3-morpholin-4-yl-3-oxopropyl)-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:3]1(=[O:5])=[O:4].[CH3:14][O:15][C:16](=[O:19])[CH2:17]Cl.[H-].[Na+]>CN(C)C=O>[OH:13][C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:3](=[O:5])(=[O:4])[N:2]([CH3:1])[C:17]=1[C:16]([O:15][CH3:14])=[O:19]
Reactant: CN1C(=O)c2ccccc2S1(=O)=O
Reactant: COC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reaction time: 2 h

Procedure:
To a solution of 2.9 g. (0.015 mole) of N-methylsaccharin and 2.63 g. (0.03 mole) of methylchloroacetate in 10 ml. of dimethylformamide at 40° C. was added over a period of two hours 864 mg. (0.036 mole) of 99% sodium hydride. Stirring was continued for two hours, maintaining a reaction temperature of 40°-50° C. The reaction mixture was quenched in 150 ml. of 5% hydrochloric acid, and the precipitated product filtered and dried, 3.41 g. (84%).
Reaction SMILES: CO[C:3]1[CH:14]=[CH:13][C:6]2N[C:8](=O)[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25](=[O:27])[N:24]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[N:39]=[CH:38][N:37]=[C:36]([C:40](O)=[O:41])[CH:35]=4)[CH2:30][CH2:29]3)[CH2:23][CH2:22][C:21]=2[CH:43]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]1[C@@H:6]2[C@H:5]([CH2:4][CH2:3][CH2:14][CH2:13]2)[CH2:11][CH2:10][N:9]1[C:40]([C:36]1[N:37]=[CH:38][N:39]=[C:34]([N:31]2[CH2:32][CH2:33][CH:28]([N:24]3[CH2:23][CH2:22][C:21]4[CH:43]=[C:17]([O:16][CH3:15])[CH:18]=[CH:19][C:20]=4[NH:26][C:25]3=[O:27])[CH2:29][CH2:30]2)[CH:35]=1)=[O:41]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: COc1ccc2c(c1)CCNC(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC[C@H]5CCCC[C@@H]5C4)ncn3)CC1)C(=O)N2

Procedure:
Analogously to decahydroisoquinoline-2-carbonyl)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one the following compounds were prepared from 4.0 mg (10 μmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 3.6 mg (11 μmol) TBTU, 12 μmol of the corresponding amine and 3.9 μL DIPEA in 350 μL DMF:
Reaction SMILES: [N:1]([C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:11]2[C:10](=[O:21])[N:9]([CH2:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:8](=[O:32])[N:7]([CH3:33])[C:6]=2[N:5]=1)=[N+]=[N-].[H][H]>C1COCC1.[Pd]>[NH2:1][C:4]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C:11]2[C:10](=[O:21])[N:9]([CH2:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:8](=[O:32])[N:7]([CH3:33])[C:6]=2[N:5]=1
Reactant: [H][H]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(N=[N+]=[N-])n2Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(N)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.6 %

Procedure:
8-azido-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.19 g, 0.4 mmol) was dissolved in THF (5 mL) and 10% Pd/C (20 mg) was added. The reaction was blanketed in a hydrogen atmosphere (balloon) and stirred overnight at room temperature. The mixture was filtered through celite, the filter cake was washed with methanol. The filtrate was concentrated in vacuo to give a 8-amino-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.2 g, 100% yield) as a white solid. LCMS retention time 1.324 min; LCMS MH+-THP 364
Reaction SMILES: [I:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8](=[O:19])[C:9]3[N:10]([N:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[CH3:22][Al](C)C>ClCCl>[OH:19][C:8]1([CH3:22])[CH2:7][O:6][C:5]2[CH:20]=[CH:21][C:2]([I:1])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=[C:9]12
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2=O
Reactant: C[Al](C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(C)O
Temperature: -10 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution ethyl 9-iodo-4-oxo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (3 g, 7.53 mmol, 1.00 equiv) in dichloromethane (50 mL) was added trimethylalumane (2.0M in toluene) (4.5 mL, 1.20 equiv) at −10° C. After being stirred for 2 hours at −10° C. the resulting solution was diluted with 20 mL of dichloromethane, washed with saturated ammonia chloride, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:2) to give 2.4 g (77%) of the titled compound as a light yellow solid; LC-MS (ES, m/z): 415 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Ni].[C].[Pd]>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC=C(c2cc(F)cc(F)c2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: [Pd]
Product: CCCCCC1CCC(c2cc(F)cc(F)c2)CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
Mixture of (4-pentyl-1-cyclohexenyl)-3,5-difluorobenzene (89 mmol), Raney nickel (3.5 g), and 500 ml of Solmix was subjected to a hydrogenation reaction at room temperature under normal pressure for 10 hours. At the time when the amount of hydrogen has come not to further reduce and the reaction has come not to progress, catalyst was changed from Raney nickel to palladium carbon (2.4 g), and stirred for 8 hours. Palladium carbon was filtered off and the solvent was distilled off. The residue was purified by column chromatography (eluent: heptane) to give a (4-pentyl-cyclohexyl)-3,5-difluorobenzene (81 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>CO>[C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][N:10]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of azetidin-3-yl-carbamic acid tert-butyl ester (635 mg, 3.4 mmol), 2,4-dichloropyrimidine (500 mg, 3.4 mmol) and triethylamine (0.5 ml, 3.6 mmol) in methanol (10 ml) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography (0-40% ethyl acetate/petroleum ether) furnishing 561 mg title compound. MS: [M+H]+=283/285
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:18][C:19]#[N:20])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:26]>C1COCC1>[CH3:26][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=3)=[CH:17][CH:16]=2)[C:12]([CH2:18][C:19]#[N:20])=[CH:13]1
Reactant: CI
Reactant: N#CCc1c[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CC#N)c2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Yield: 59.8 %

Procedure:
[1-Methyl-5-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-acetonitrile was prepared from [5-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-acetonitrile (0.377 g, 1.26 mmol), sodium hydride (0.117 g, 2.93 mmol of a 60% dispersion on mineral oil), iodomethane ( 0.17 mL, 2.8 mmol) and THF (10 mL) according to the procedure described in Step 2 of Example 1. Purification by flash chromatography using 5-15% ethyl acetate in hexane as an eluant afforded the title compound as a yellow semi-solid (0.237 g, 60%), 1HNMR (300 MHz, DMSO-d6): δ 8.0 (s, 1H), 7.9 (d, 2H, J=7.7 Hz), 7.8 (d, 2H, J=7.7 Hz), 7.6 (s, 2H), 7.45 (s, 1H) 4.15 (s, 2H) and 3.8 ppm (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>C1C=CC=CC=1>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: OCc1cccnc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccccc1
Product: O=C(OCc1cccnc1)c1ccc(F)cc1
Temperature: 20 °C
Yield: 67.7 %

Procedure:
10.5 g. of 3-hydroxymethyl-pyridine are dissolved in 60 ml. of anhydrous benzene. The solution is stirred at 20° C. and 7.6 g. of 4-fluorobenzoic acid chloride dissolved in 60 ml. of benzene are added dropwise thereto. The reaction mixture is refluxed for 30 minutes and then cooled to 20° C. The precipitated 3-hydroxymethyl-pyridine hydrochloride is filtered off. The filtrate is extracted with 250 ml. of 5% aqueous hydrochloric acid. The separated aqueous acidic layer is washed with 50 ml. of diethyl ether and then adjusted to pH=9 with 20% aqueous sodium carbonate solution. The basified solution is extracted three times with 50 ml. each of diethyl ether, the combined ether extracts are dried with anhydrous sodium sulfate, filtered and the filtrate is evaporated. The evaporation residue is dissolved in 80 ml. of a 1:1 mixture of isopropanol and ether and etheric hydrogen chloride solution is added to adjust the pH-value to 2. The precipitated acid addition salt is separated by filtration and recrystallized from a mixture of equal values of acetone and ethanol. 8.5 g. of 3-[ (4-fluorobenzoyl)-oxymethyl]-pyridine (67.7% of theoretical yield) are obtained; m.p.: 142°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])=[CH:3][C:2]=1[Cl:1]
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A mixture of (3,4-dichlorophenyl)boronic acid (500 mg, 2.62 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (501 mg, 2.88 mmol), K2CO3 (723 mg, 5.24 mmol) and Pd(PPh3)2Cl2 (36 mg, 0.052 mmol) in THF (2 mL) and H2O (1 mL) was heated at 80° C. in a sealed tube for 3 hours. The mixture was cooled to rt and partitioned between EA (20 mL) and H2O (20 mL). The aqueous layer was extracted with EA (20 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with PE to give 1,2-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)-benzene (400 mg, 63.3% yield) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1F.[NH3:11]>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[NH2:11]
Reactant: Fc1cc(F)c(Cl)c(F)c1
Reactant: N
Solvent: CO
Product: Nc1cc(F)cc(F)c1Cl
Temperature: 160 °C

Procedure:
33.4 g of 2-chloro-1,3,5-trifluorobenzene and 200 ml of methanol saturated with ammonia gas at room temperature were sealed in a Teflon-coating autoclave and heated on an oil bath at 160° C. for 40 hours. After the reaction, the solvent and unreacted 2-chloro-1,3,5-trifluorobenzene were distilled off from the reaction mixture under reduced pressure, and the remaining mixture of a solid component and an oily component was extracted with ether to obtain an oily product in an amount of 31.7 g (yield of 2-chloro-3,5-difluoroaniline: 95% determined by GLC analysis).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[N:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[N:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2ncc3ccccc3n2)C[C@H](C)N1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2ncc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinazoline.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[S:16][C:17]([CH2:20][O:21]C3CCCCO3)=[CH:18][N:19]=2)=O)=[N:3]1.C([O-])(=O)C.[NH4+:40].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([C:10]2[NH:40][C:13]([C:15]3[S:16][C:17]([CH2:20][OH:21])=[CH:18][N:19]=3)=[CH:12][CH:11]=2)[CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:3]1
Reactant: [NH4+]
Reactant: CSc1cc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)nn1C
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1cc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)nn1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A mixture of 5-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (0.65 g), ammonium acetate (0.46 g) and acetic acid (6 mL) was stirred at 100° C. for 1 hr. The reaction mixture was neutralized with 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.40 g, yield 80%) as a yellow amorphous solid from the fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). MS: 419 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.O.[C:13]([OH:17])(=[O:16])[CH:14]=O>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:14]/[C:13]([OH:17])=[O:16])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)/C=N/Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of (4-bromophenyl)hydrazine HCl (2.01 g, 8.81 mmol) in water (20 mL) was added conc. HCl (1 mL) followed by glyoxylic acid monohydrate (811 mg, 8.81 mmol). The mixture was stirred vigorously at rt for 30 min and the light yellow suspension was filtered, washed with water (3×15 mL), and dried under suction followed by high vacuum to afford compound 84a as a light yellow solid, used without further purification in the following step. Mass spectrum (LCMS, ESI pos.): Calcd. for C8H7BrN2O2, 243.0/245.0 (M+H). found 243.2/245.1.