Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C:12]2[C:7](=[C:8]([CH2:13][CH:14]=[CH2:15])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=1.[Cl:18]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P(O)(O)([O-])=O.[K+]>ClCCCl.ClC(Cl)C>[Cl:18][CH:5]1[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH:14]=[CH2:15])[C:4]1=[O:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=CCc1cccc2c1CC=C2O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: C=CCc1cccc2c1CC(Cl)C2=O
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
8 g of 3-trimethylsilyloxy-7-(2-propenyl)-indene in 25 ml of 1,2-dichloroethane is cooled to 0° C.; 31 g of N-chlorosuccinimide in 80 ml of dichloroethane is introduced over 25 minutes, with agitation for 30 minutes at 0° C.; 0.6 g of N-chlorosuccinimide in 15 ml of dichloroethane and a few mg of paratoluene sulphonic acid are added. After 30 minutes of agitation at 0° C., the reaction mixture is poured over an iced aqueous solution saturated with monopotassium phosphate, with agitation for 16 hours at 20° C. After decanting and extracting with methylene chloride, the extracts are dried, and concentrated to dryness under reduced pressure. The residue is chromatographed on silica, eluting with a hexane-isopropyl ether mixture (7-3). The fractions recovered are concentrated and chromatographed again on silica, eluting with a hexane-isopropyl ether mixture (3-1) and 2.75 g of expected product is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH2:11])[C:8]=1[C:9]#[N:10].CCO[CH2:15][CH3:16]>[N+](C1C=CC=CC=1)([O-])=O.C1(=O)CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:8]=1[C:9]([NH2:10])=[C:15]1[C:16]([CH2:4][CH2:3][CH2:8][CH2:7]1)=[N:11]2
Reactant: COc1cccc(N)c1C#N
Reactant: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O=C1CCCCC1
Product: COc1cccc2nc3c(c(N)c12)CCCC3
Temperature: 125 °C

Procedure:
6-Methoxyanthranilonitrile (14.0 g) was dissolved in nitrobenzene (150 ml) and cyclohexanone (18.45 g), and freshly fused zinc chloride (25.6 g) was added. The reaction mixture was warmed at 125° C. for 1.5 hr, cooled to room temperature, and poured into ether (1 l). The solid was collected, washed with ether, and distributed between 2-butanone and ammonium hydroxide. The organic phase was washed with brine, dried, filtered, and evaporated. The residue was recrystallized two times from ethyl acetate to give 13.7 g (63.8%), mp 187°-188° C.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[CH:35]=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[C:35]([OH:6])=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C=O)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of sodium chlorite (1.19 g; 13.13 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.03 g; 8.59 mmol; 3.6 eq.) in water (7 mL) was added dropwise to a mixture of 2-methyl-2-butene (2.39 mL) and 3-(5-fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (705 mg; 2.39 mmol; 1 eq.) in 1,4-dioxane (7 mL). The reaction mixture was stirred at room temperature for 16 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The precipitate was filtered off and dried to afford the title compound (625 mg, 84%) as a white solid. 1H NMR (CDCl3) δ 8.17 (dd, J=8.8, 6.7 Hz, 1H), 6.85 (ddd, J=8.9, 7.6, 2.3 Hz, 1H), 6.35 (dd, J=9.9, 2.3 Hz, 1H), 5.25-4.87 (m, 1H), 4.41 (ddd, J=10.1, 6.4, 1.2 Hz, 2H), 4.11 (ddd, J=10.0, 4.0, 1.1 Hz, 2H), 1.45 (s, 9H). HPLC (max plot) 96.4%; Rt 3.60 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:7]=12)=[O:5])[CH3:2].[Na].[CH3:18][O:19][C:20](=[O:28])[CH:21](Br)[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:28])[CH:21]([N:9]1[C:10](=[O:11])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[C:8]12)[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)c1c2cccccc-2[nH]c1=O
Reactant: COC(=O)CC(Br)C(=O)OC
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2cccccc-2n(C(CC(=O)OC)C(=O)OC)c1=O
Temperature: 100 °C

Procedure:
A mixture of 1,2-dihydro-2-oxocyclohepta[b]pyrrole-3-carboxylic acid ethyl ester, sodium salt (12.5 g, described in example 1) and 2-bromobutanedioic acid dimethyl ester (14.5 g) in DMF (14.5 g) was heated at 100° C. for 48 hr. The mixture was cooled, diluted with water and extracted with chloroform. The chloroform extract was passed through a column of silica gel. Subsequent elution of the column with chloroform-methanol (97:3) gave 2.0 g of 2-(3-ethoxycarbonyl-1,2-dihydro-2-oxocyclohepta[b]pyrrol-1-yl) butanedioic acid dimethyl ester, nmr (CDCl3) δ1.4 (t, 3H), 3.35 (m, 2H), 3.6 and 3.7 (2s, 6H), 4.4 (q, 2H), 5.6 (t, 1H), 7.45 (m, 4H), 9.05 (d, 1H).
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1.[CH2:20](Br)[CH:21]=[CH2:22].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([N:17]1[CH2:18][CH2:19][N:14]([C:2](=[O:1])[CH2:3][N:4]2[C:8](=[O:9])[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[S:5]2)[CH2:15][CH2:16]1)[CH:21]=[CH2:20]
Reactant: O=C(Cn1sc2ccccc2c1=O)N1CCNCC1
Reactant: C=CCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN1CCN(C(=O)Cn2sc3ccccc3c2=O)CC1

Procedure:
Compound 10 (30 mg, 0.11 mmol) was treated with allyl bromide (16 mg, 0.13 mmol) and DIEA (40 mg, 0.31 mmol) in anhydrous CH2Cl2 (2 mL) at room temperature for 6 h. Allyl bromide then was removed by reduced pressure and the residue was washed by H2O to give the title compound after purification on a thin-layer silica-gel plate (20 cm×20 cm×2 mm) using CH2Cl2/MeOH (9:1) as the developing solution. C16H19N3O2S; white solid; mp 119-120° C.; IR vmax (neat) 3072, 2920, 2857, 2801, 1717, 1653, 1448, 1339, 1262, 1234, 1136, 1038, 1000, 924, 748 cm−1, 1H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J=8.0 Hz), 7.58 (1H, t, J=7.6 Hz), 7.53 (1H, d, J=8.0 Hz), 7.37 (1H, t, J=7.6 Hz), 5.80 (1H, m), 5.16 (2H, m), 4.69 (2H, s), 3.65 (2H, t, J=5.2 Hz), 3.57 (2H, t, J=5.2 Hz), 2.99 (2H, d, J=6.8 Hz), 2.45 (4H, m); 13C NMR (100 MHz, CDCl3) δ 165.5, 164.7, 134.1, 132.0, 126.7, 125.3, 120.2, 118.5, 61.5, 52.9, 52.5, 45.3, 44.8 (2×), 42.2, 29.8; ESI-HRMS calcd for C16H20N3O2S: 318.1274. found: m/z 318.1274 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Br[C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2.CCN(CC)CC>C(Cl)Cl>[C:32]1([C:19]2([NH:1][C@@H:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:4])[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)C[C@H](N)C(=O)OCc1ccccc1
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1

Procedure:
Pb(NO3)2 (6.06 g, 18.3 mmol) was added over 1 min to a CH2Cl2 (80 mL) solution of (S)-1-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol), 9-bromo-9-phenyl-9H-fluorene (6.44 g, 20.0 mmol) and Et3N (3.0 mL, 21.5 mmol), and the heterogeneous mixture was stirred at ambient condition for 48 Hr. The mixture was filtered and the filtrate was treated with MgSO4 and filtered again, and the final filtrate was concentrated. The resulting crude material was submitted to a Biotage purification (350 g silica gel, CH2Cl2 elution) to afford (S)-1-benzyl 4-methyl 2-(9-phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorless oil (7.93 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 7.82 (m, 2H), 7.39-7.13 (m, 16H), 4.71 (d, J=12.4, 1H), 4.51 (d, J=12.6, 1H), 3.78 (d, J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partially overlapped with solvent). LC (Cond. 1): RT=2.16 min; LC/MS: Anal. Calcd. for [M+H]+ C31H28NO4: 478.20. found 478.19.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:19][CH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1.N#N>CN(C=O)C>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:19][CH2:20][CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1
Reactant: ClCCCC1CCCO1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCCC2CCCO2)c(F)c1
Temperature: 140 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
To a mixture of 2-fluoro-4-nitroaniline (7.02 g, 45.0 mmol), Cs2CO3 (29.3 g, 90.0 mmol), KI (16.6 g, 100 mmol) and DMF (100 mL) was added 2-(3-chloropropyl)tetrahydrofuran (7.43 g, 50.0 mmol) dropwise under N2 and the mixture was stirred at 140° C. for 48 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. To the residue was added water (30 mL) and the mixture was extracted with DCM (30 mL×4). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=20:1) to give the title compound as a yellow solid (3.74 g, 31%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:22]I>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([S:18][CH3:22])[N:15]=[C:14]([OH:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Oc1cc(CCCOCc2ccccc2)nc(S)n1
Agent: [K+]
Agent: [OH-]
Product: CSc1nc(O)cc(CCCOCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(3-benzyloxy-propyl)-2-mercapto-pyrimidin-4-ol (7.94 g), potassium hydroxide (32 mL of 1N solution in methanol) and methyl iodide (1.97 mL) was stirred at room temperature overnight. The precipitate was filtered, washed successively with methanol (2×20 mL), isopropanol (2×20 mL) and water (2×20 mL), then dried to afford 6-(3-benzyloxy-propyl)-2-methylsulfanyl-pyrimidin-4-ol as a white powder (7.0 g). MS m/z 291.0 (M+1), 100%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+].[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].Cl>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:20]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=2)=[O:21])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc([N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 80.5 %

Procedure:
A 85 mg portion (0.43 mmol) of 5-chlorothiophenesulfonamide dissolved in 2 mL of acetone was treated with 110 μL of 4N NaOH (0.43 mmol) followed by addition of 80 mg (0.43 mmol) of 4-nitrobenzoyl chloride. After stirring for 12 h, the solution was acidfied 1N HCl and the precipitate was collected by filtration and dried. Recrystallization from EtOAc/hexane afforded 120 mg (81%) of the titled compound. ES-MS (M+H)+=347 (Cl).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:2]([N:12]1[CH2:20][CH2:19][CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 14 h
Yield: 85.8 %

Procedure:
Benzyl chloroformate (16.4 mL, 115 mmol) in toluene (50 mL) was added dropwise to a stirred solution of 12.9 g (100 mmol) of isonipecotic acid (Aldrich) and 21.0 g (250 mmol) of sodium bicarbonate in 200 mL of water. After 14 h, the mixture was extracted with ether (3×50 ml) and the ether layers were discarded. The aqueous layer was acidified with conc. HCl to pH 2, causing the product to precipitate. The product was partitioned into ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield 22.6 g (86%) of N-CBZ-isonipecotic acid as a viscous oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[Cl:24][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:9]
Reactant: COc1ccc(C(=O)O)cc1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1OC(C)=O

Procedure:
700 mg of 3-acetoxy-4-methoxy-benzoic acid were suspended in 6 ml of anhydrous DCM and 24 μl of DMF were added. Then 5.0 ml of a 2 M solution of oxalyl chloride in DCM were added dropwise. The mixture was stirred until the evolution of gas had ceased (about 30 min). The volatiles were removed in vacuo, the residue was dissolved in 10 ml of DCM and evaporated to yield 750 mg of the title compound which was used in the subsequent step without further purification.
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:10]([OH:12])=[O:11].[CH3:19]O>>[CH3:19][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:7]([F:6])[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 18 h

Procedure:
A 1 L round bottom flask equipped with a stir bar and reflux condenser was charged H2SO4 (4 mL), methanol (400 mL) and 3-fluoro-4-nitrobenzoic acid (10 g). The reaction mixture was heated at reflux temperatures with vigorous stirring for 18 h. The methanol was removed and the crude residue was triturated with hexane and concentrated to give a colorless solid (9.79 g) that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)(=[O:5])=[O:4].[CH2:24]=O>C(O)(=O)C>[F:23][C:2]([F:1])([F:22])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][C:13]2[N:18]3[C:19](=[CH:20][N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH2:24]1)(=[O:5])=[O:4]
Reactant: C=O
Reactant: O=S(=O)(NCCCCNCc1cccc2nccn12)C(F)(F)F
Solvent: CC(=O)O
Product: O=S(=O)(NCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 6.91 g (19.72 mmol) of 5-[N-[4-(trifluoromethanesulfonamido)butan-1-yl]aminomethyl]-imidazo[1,2-a]pyridine in 20 ml of acetic acid was added 22.1 ml (295.8 mmol) of a 37% aqueous solution of formaldehyde. The mixture was heated at 100° C. for 30 minutes. The solvent was then distilled off under reduced pressure, and the residue was dissolved in 100 ml of a saturated aqueous solution of potassium hydrogencarbonate. This solution was neutralized, under ice-cooling, with 1N HCl, which was subjected to extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel chromatography (eluent: chloroform/methanol=20:1) to give 4.86 g (68.0%, pale yellow liquid product).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].Cl.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH:32][CH3:33])[CH2:26][CH2:25]1.N1C=CC=CC=1>ClCCl>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][N:32]([CH3:33])[S:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])[CH2:28][CH2:29]1
Reactant: CNCCN1CCN(c2nc3ccccc3[nH]2)CC1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)N(C)CCN2CCN(c3nc4ccccc4[nH]3)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.7 %

Procedure:
A mixture of 2,4-dichloro-5-methylbenzenesulphonyl chloride (81 mg, 0.31 mmol), {2-[4-(1H-Benzimidazol-2-yl)-piperazin-1-yl]-ethyl}-methyl-amine hydrochloride salt (D23) (80 mg, 0.31 mmol) and pyridine (0.5 ml) in dry dichloromethane (5 ml) was stirred at room temperature for 17 h. The mixture was then diluted with dichloromethane (30 ml), washed with aqueous sodium bicarbonate (1×10 ml) and dried.(MgSO4). The solvent was evaporated and the residue was co-evaporated with toluene (5 ml). Column chromatography of the residue (eluting with methanol-dichloromethane gradient) gave the product as a yellowish solid (25 mg, 17%); MS: m/z (MH+)=482.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[CH:17]([CH:19]=[CH2:20])=[O:18].OS(O)(=O)=O>C1COCC1.CCCCCC>[CH:19]([CH:17]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:8]([F:9])([F:10])[F:11])[C:2]=1[F:1])[OH:18])=[CH2:20]
Reactant: Fc1ccccc1C(F)(F)F
Reactant: C=CC=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C(F)(F)F)c1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 360 g (2.194 mol) of 1-fluoro-2-trifluoromethylbenzene in 3.4 l of anhydrous THF is cooled to -70° C. under a nitrogen atmosphere. 1.508 l (2.412 mol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over 70 minutes while maintaining the temperature below -67° C. and then the mixture is stirred for 30 minutes at -70° C. 154 ml (2.305 mol) of acrolein are then added dropwise over 30 min while maintaining the temperature below -60° C. The mixture is then stirred for 30 min at -70° C. The mixture is allowed to return to room temperature and is poured onto a mixture of 3.8 kg of ice and 300 ml of concentrated H2SO4.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14]>CN(C=O)C.C(OCC)(=O)C.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>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH:13]=[CH2:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OC)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-ethyl-3-fluorobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was prepared following general procedure B, substituting 4-ethyl-3-fluorobenzoyl chloride for 6-trifluoromethyl nicotinyl chloride. (4-ethyl-3-fluorobenzoyl chloride was prepared in five steps from commercially available 4-bromo-3-fluorobenzoic acid. 4-Bromo-3-fluorobenzoic acid (0.828 g, 3.8 mmol) was dissolved in 20 mL of benzene/methanol (5:1) mixture. To the above mixture was added trimethylsilyldiazomethane until the reaction showed a light yellow color. Let stir for 30 minutes and concentrate down to yield methyl 4-bromo-3-fluorobenzoate. Methyl 4-bromo-3-fluorobenzoate was dissolved in 2 mL of DMF and vinyl tributyl tin (0.431 mL, 1.5 mmol), and degassed for 5 min with nitrogen gas. To the above mixture was added Pd(PPh3)2Cl2 (0.086 g, 0.12 mmol) and heated at 80° C. with a condenser for 16 h. Cool to room temperature and dilute with ethyl acetate and wash with a 10% solution of KF in water. The mixture was allowed to stir for ˜30 min at room temperature, then filter and extract the aqueous with ethyl acetate (3×). Dry over MgSO4, filter and concentrate down. The residue was concentrated down and purified with 100% hexane to 10% ethyl acetate/90% hexane to yield 0.140 g, 63% of methyl 3-fluoro-4-vinylbenzoate. Methyl 3-fluoro-4-vinylbenzoate (0.750 g, 4.1 mmol) was reduced in the presence of Pd on carbon (10%) in ethanol to provide methyl 4-ethyl-3-fluorobenzoate (0.450 g, 59%). Methyl 4-ethyl-3-fluorobenzoate was hydrolyzed to the acid by dissolving in tetrahydrofuran and methanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH=5 with 1N HCl to form a white precipitate (0.270 g, 65%). The solid was filtered to give 4-ethyl-3-fluorobenzoic acid. The acid was converted to the acid chloride as described in general procedure B).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15](I)[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1.[F:30][C:31]([F:36])([F:35])[CH2:32][CH2:33][NH2:34]>CN1C(=O)CCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15]([NH:34][CH2:33][CH2:32][C:31]([F:36])([F:35])[F:30])[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(I)c21
Reactant: NCCC(F)(F)F
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(NCCC(F)(F)F)c21
Temperature: 150 °C

Procedure:
40 mg (0.07 mmol) of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 33A) was dissolved in 1 ml of absolute NMP and 334 mg (2.96 mmol) of 3,3,3-trifluoropropan-1-amine was added. The mixture was heated in the microwave for 2 h at 150° C. and 1 h at 150° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 27 mg (purity 93%, 70% of theor.) of the target compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(F)cc4)c3)c2c1
Yield: 23.9 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-fluorophenylacetic acid (0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 52 mg (23% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.23 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.73 (m, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.47–7.34 (m, 3H), 7.17 (m, 2H), 3.7 (s, 2H); ES-MS (m/z) 389 [M+H]+.