Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][CH2:19][C:20]#[N:21].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:19]([CH2:20][NH:21][C:10]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])#[N:18]
Reactant: N#CCN
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)NCC#N
Reaction time: 2 h

Procedure:
A solution comprised of 2-tert-butoxycarbonylamino-4-methylvaleric acid (5 g, 30 mmol) in DMF (20 mL) was cooled in an ice bath and then aminoacetonitrile hydrochloride (3 g, 30 mmol), PyBOP® (11.25 g, 21 mmol) and triethylamine (6 mL, 60 mmol) were added sequentially to the solution. The mixture was stirred for 2 hours and then concentrated under vacuum. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (40 mL). The organic layer was separated, washed with water, 1M hydrochloric acid (20 mL), water and brine, dried (MgSO4) and concentrated under reduced pressure. Product was purified from the residue using a plug of silica with ethyl acetate as the eluant to provide tert-butyl 1-cyanomethylcarbamoyl-3-methylbutylcarbamate.
Reaction SMILES: COC[N:4]1[C:13](=[O:14])[C:12]2[C:11]3[CH:15]=[C:16]([CH2:19][O:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:32].Cl>C1COCC1.O>[CH3:32][C:5]1[NH:4][C:13](=[O:14])[C:12]2[C:11]3[CH:15]=[C:16]([CH2:19][O:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc3ccc4nc(C)n(COC)c(=O)c4c3c2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccc3ccc(COc4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 4-((1,2-dihydro-2-methoxymethyl-3-methyl-1-oxo-benzo[f]quinazolin-9-yl)methoxy)benzoate in THF:1N HCl: concentrated HCl (15:10:1, 26 ml) was stirred at 60° C. overnight. The resulting suspension was diluted with water, concentrated in vacuo to remove the THF, and chilled in an ice bath. The solid was filtered, washed with water, and dried in vacuo at 100° C. The resulting ester was dissolved in 1N NaOH (10 ml) and ethanol (~ 3 ml) and stirred at 60° C. for 4 hours. The solution was acidified with concentrated HCl to pH 1.5 and the resulting precipitate filtered and dried in vacuo at 110° C. to give 4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoic acid (0.195 g). 1H NMR (DMSO-d6, 300 MHz) δ: 2.59 (s, 3H, CH3), 5.46 (s, 2H, CH20), 7.17 (d, J=9 Hz, 2H, Ar), 7.80 (overlapping d, J=9 Hz, 2H, Ar), 7.91 (d, J=9 Hz, 2H, Ar), 8.16 (d, J=8 Hz, 1H, Ar), 9.85 (s, 1H, Ar).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1>CS(C)=O>[Cl:12][C:4]1[N:3]=[C:2]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: NCc1cccc(F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Solvent: CS(C)=O
Product: Fc1cccc(CNc2cc(C(F)(F)F)cc(Cl)n2)c1
Temperature: 90 °C
Yield: 44.8 %

Procedure:
To 2,6-dichloro-4-(trifluoromethyl)pyridine (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 mmol), and (3-fluorophenyl)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90° C. until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 ml of DMSO, filtered and purified by prep LC. After lyphilization, 158 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 305.1 (MH+), rt=1.21 min.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C1COCCN1
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCN4CCOCC4)c23)ccc1OCc1ccccn1
Yield: 40 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and morpholine to give the title compound in 40% yield; NMR Spectrum: 2.50 (hidden by DMSO, 4H), 2.80 (t, 2H), 3.55 (br s, 4H), 4.44 (t, 2H), 5.29 (s, 2H), 7.25 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.86-7.92 (m, 2H), 8.29 (s, 1H), 8.45 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39]C(OC(C)(C)C)=O)[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2].CCN(C(C)C)C(C)C>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH2:39])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2]
Reactant: C=Cc1cccc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=Cc1cccc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](N)C(C)C)N2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
*(S)-1-{(S)-2-((S)-2-Amino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 3-vinyl-benzyl ester was prepared by adding TMS (OTf) (0.17 ml, 0.64 mmol) to a solution of 10a (400 mg, 0.49 mmol) in anhydrous dichloromethane (20 ml) at 0° C. The reaction was stirred for 2 hours at 0° C., quenched by adding iPr2NEt (0.45 ml, 2.56 mmol) and concentrated in vacuo to yield a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-])=O)=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16].[OH-].[NH4+]>O>[CH3:1][O:2][C:3]1[C:4]([NH2:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16]
Reactant: COc1cc2[nH]c(=O)nc(C)c2c([N+](=O)[O-])c1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2[nH]c(=O)nc(C)c2c(N)c1OC
Reaction time: 0.5 h

Procedure:
A solution of 13 equivalents of FeSO4.7H2O in water (6 parts) is heated to 95° C. A slurry of 1 equivalent of 6,7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone in water (800 ml) at 80° C. is added and the resulting yellow mixture is heated at 98°-100° C. for 15 minutes. Ammonium hydroxide (13 eq) is added to the mixture dropwise over a 15 minute period, maintaining the temperature at 98°-100° C. The resulting black reaction mixture is stirred at 98°-100° C. for 30 minutes, the hot mixture is filtered and the insoluble black residue is washed with hot water. The brownish filtrate is extracted with chloroform. The solvent is removed in vacuo to give a dark brown semi-solid crude product, which is chromatographed on a silica gel column. Recrystallization of the crude product from ethyl alcohol affords purified product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([CH3:19])[CH:5]=1.[CH3:20][S-:21].[Na+].CO>O>[CH3:19][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:13](=[O:14])[C:4]([CH2:3][S:21][CH3:20])=[CH:5]1
Reactant: Cn1cc(CCl)c(=O)c2ccc(C(F)(F)F)cc21
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSCc1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C

Procedure:
3-Chloromethyl-1-methyl-7-trifluoromethyl-4-quinolone hydrochloride (4.7 g.) was added to a stirred solution of sodium methanethiolate in methanol (16 ml. containing 0.039 mole NaSMe) at 0° during 5 minutes. The resulting mixture was allowed to warm to room temperature then poured into water (100 ml.). The resulting precipitate was collected, dried and crystallised from dichloromethane:petroleum ether (b.p. 60°-80°) to give the novel 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone, m.p. 182°-184°.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](O)[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].C(Cl)[Cl:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCCC.C(Cl)(Cl)(Cl)Cl>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([Cl:20])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5]
Reactant: ClCCl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
Via chloride: A solution of 374 g (1.48 mol) (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.61 CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3-5° C. and treated in 10 min with 1.241 (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction temperature was raised during 2 h to 35° C. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4 l of n-heptane, the reaction was evaporated to 2.9 l, cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2 l of CH2Cl2. The solvents were evaporated and filtered through silica gel with hexane/tert.-butyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: C[CH:2]1[NH:7][CH:6](C)[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]=[C:19]4[N:21]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=[C:23]([CH2:24][CH3:25])[C:18]4=[C:17]([O:32][CH3:33])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:3]1.[C:34](OC(N1CCNCC1)=O)(C)(C)C.Cl>>[CH2:33]([O:32][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:4]3[CH2:3][CH2:2][NH:7][CH2:6][CH2:5]3)=[CH:10][CH:11]=2)[N:20]=[C:19]2[N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:22]=[C:23]([CH2:24][CH3:25])[C:18]=12)[CH3:34]
Reactant: CCc1nn(-c2ccccc2)c2nc(-c3ccc(N4CC(C)NC(C)C4)cc3)cc(OC)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Product: CCOc1cc(-c2ccc(N3CCNCC3)cc2)nc2c1c(CC)nn2-c1ccccc1

Procedure:
The title compound was prepared according to the procedure as described in Example 98 reacting 6-(4-bromo-phenyl)-3-ethyl-4-ethoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine (according to Example 98) and piperazine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13]C(N)=[CH:11][CH:10]=2)[N:6]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CI.[CH3:29][N:30]([CH3:33])[CH:31]=O>>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:31]([N:30]([CH3:33])[CH3:29])=[CH:13][CH:14]=2)[N:6]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(C)cc(-c2ccc(N)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1cc(C)cc(-c2ccc(N(C)C)cc2)n1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4-methyl-6-(4-aminophenyl)-2-pyridinecarboxylate hydrochloride (3.5 g), anhydrous potassium carbonate (8.8 g), dimethylformamide (30 ml) and methyl iodide (10 ml) is agitated at 50° C. for 30 minutes and further at 130° C. for 3 hours. After cooling, the reaction mixture is filtered to remove potassium carbonate. The filtrate is concentrated under reduced pressure in order to distill off the solvent. To the resulting residue is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water and dried, and ethyl acetate is distilled off to give ethyl 4-methyl-6-(4-dimethylaminophenyl)-2-pyridinecarboxylate (2.2 g). M.P. 143°-144° C.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10]C)=[C:8]([O:12]C)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>>[F:1][C:2]1[C:9]([OH:10])=[C:8]([OH:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(F)c1OC
Agent: BrB(Br)Br
Product: O=Cc1ccc(O)c(O)c1F

Procedure:
As outlined in Example 6, 2-fluoroveratraldehyde is treated with boron tribromide to give 2-fluoroprotocatechualdehyde which is dibenzylated to 3,4-dibenzyloxy-2-fluorobenzaldehyde.
Reaction SMILES: [N+:1]([NH:4][C:5]([NH2:7])=[NH:6])([O-:3])=[O:2].N[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>O>[N+:1]([NH:4][C:5]([NH:7][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[NH:6])([O-:3])=[O:2]
Reactant: NCc1cccnc1
Reactant: N=C(N)N[N+](=O)[O-]
Solvent: O
Product: N=C(NCc1cccnc1)N[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 48.3 %

Procedure:
A mixture of 0.53 g of nitroguanidine, 0.61 g of 3-(aminomethyl)pyridine and 10 ml of water was stirred for 1.5 hours at 70°-80° C. and allowed to stand over night at room temperature. The precipitate collected by filtration was washed with ethanol to obtain 0.48 g of N-nitro-N'-(3-pyridylmethyl)guanidine (Compound No. 12).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:17][CH2:18][O:19][CH3:20])[C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:8]2[O:7][C:6]([N:5]([CH2:17][CH2:18][O:19][CH3:20])[CH2:4][CH2:3][O:2][CH3:1])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2=[O:16])=[CH:22]1
Reactant: CCOC(=O)C1=C(N(CCOC)CCOC)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(N(CCOC)CCOC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 11.6 %

Procedure:
To a solution of ethyl 2-[bis(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.048 g, y. 11%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[CH2:17][C@H:16]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])[CH2:15][CH2:14][C@@H:13]2[NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:38])([F:37])[F:36])[C:28]=3[N:27]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br-].[CH2:41]([Zn+])[CH2:42][CH3:43]>C1COCC1.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:20]([N:18]([CH3:19])[C@@H:16]1[CH2:15][CH2:14][C@H:13]([NH:23][C:24](=[O:39])[CH2:25][C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:38])([F:37])[F:36])[C:28]=3[N:27]=2)[C@H:12]([CH2:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:41][CH2:42][CH3:43])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Reactant: CCC[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N(C)C(C)C)CC[C@@H]2NC(=O)Cc2nc3c(C(F)(F)F)cccc3[nH]2)cc1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
(1S,2R,4R)-N-[2-(4-Bromo-benzenesulfonylmethyl)-4-(isopropyl-methyl-amino)-cyclohexyl]-2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetamide, Example 3, was dissolved in THF (1 ml) prior to the addition of propyl zinc bromide (0.32 ml), Pd(PPh3)4 (3 mg). The mixture was stirred under microwave conditions (150° C.) for 5 min. After cooling, the crude reaction was filtered and the filtrate was concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the two fractions, one of which contained the title compound (8 mg). MS found: (M+H)+=594.5
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([C:22]([F:23])([F:25])[F:24])[N:9]=3)[CH:3]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(3,4-Dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.37) (0.40 g, 0.89 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.275 g, 1.07 mmol) according to the general procedure VI. Obtained as white foam (0.45 g), which was subsequently deprotected.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:18]1[CH:19]=[C:20]([C:24]#[N:25])[CH:21]=[CH:22][CH:23]=1>C1COCC1>[Cl:16][C:14]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[CH:15]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1-c1cccc(C#N)c1)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from example 151 step (iv), 3-bromobenzenenitrile and THF as solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1cc(Cl)ccc1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(Cl)ccc1C(=O)OC
Yield: 79.8 %

Procedure:
26.1 g of the methyl 4-chloro-2-(3-methoxy-3-oxo-1-propenyl)-benzoate prepared according to Example 1 are taken up in 300 ml of methanol and transferred into an autoclave and then hydrogenated at 30° C. and a hydrogen pressure of 30 bar for 5 h, until the theoretical amount of hydrogen has been taken up. The substance contains the palladium catalyst required for the Heck coupling, so that separate addition of a hydrogenation catalyst can be dispensed with. The pressure is reduced to 1 bar, and insoluble components are then filtered off. Solvent is then removed under reduced pressure until the hydrogenation product precipitates. Recrystallization gives 21 g of methyl 4-chloro-2-(3-methoxy-3-oxo-1-propanyl)-benzoate.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([O:8][CH2:15][CH2:16][CH2:17][Cl:18])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Yield: 97 %

Procedure:
A mixture of 100 g (0.549 mole) of methyl vanillate, 172.8 g (1.1 mole) of 1-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a white solid as residue. The solid was triturated with petroleum ether, collected by filtration, and dried to yield 137.8 g (97%) of the title compound as a white powder, mp 104°-105° C. (2-propanol).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:23])([F:22])[F:21])=[N:7]2.[NH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C1(C)C=CC=CC=1>[NH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:23])([F:22])[F:21])=[N:7]2
Reactant: NCCCN
Reactant: COc1ccc(-c2cc3nc(C(F)(F)F)ccc3c(Cl)n2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3nc(C(F)(F)F)ccc3c(NCCCN)n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-7-(4-methoxy-phenyl)-2-trifluoromethyl-[1,6]naphthyridine (55 mg, 0.2 mmol) and 1,3-diaminopropane (2.5 mL) in a sealed reaction vessel was heated at 100° C. for 3 hours. The mixture was diluted with toluene and concentrated three times to azeotropically remove excess 1,3-diaminopropane. The residue was diluted with EtOAc, washed sequentially with sat. NaHCO3, H2O, sat. NaCl, dried over Na2SO4, and concentrated giving the title compound (60 mg, quantitative) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>ClCCl.FC1C=CC(C(Cl)=O)=CC=1.N1C=CC=CC=1>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a suspension of 30.0 gm (0.217 mole) 4-nitroaniline in 225 mL dichloromethane were added 17.57 mL (0.217 mole) pyridine. The suspension was cooled to 0° C. and then 25.66 mL (0.217 mole) 4-fluorobenzoyl chloride were added slowly. Within 15 minutes the reaction mixture became homogeneous and was allowed to warm to room temperature. After an hour an additional 2.56 mL (21.7 mMol) 4-fluorobenzoyl chloride and 1.75 mL (21.7 mMol) pyridine were added and the reaction continued at room temperature for an additional hour. The reaction mixture was then washed with 200 mL water at which point a precipitate formed. The solid was filtered, washed with 100 mL hexane, washed with 200 mL water and dried under reduced pressure at 60° C. to give 56.6 gm (100%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=O)=[C:4]([OH:26])[CH:3]=1)=[O:9].O.[NH2:28][NH2:29]>C(O)C>[N:28](=[CH:24][C:5]1[C:6]2[O:17][C:16]3[C:15]([C:18]([OH:20])=[O:19])=[CH:14][C:13]([O:21][CH3:22])=[C:12]([CH3:23])[C:11]=3[O:10][C:8](=[O:9])[C:7]=2[C:2]([CH3:1])=[CH:3][C:4]=1[OH:26])[NH2:29]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=NN)c1O2

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added hydrazine hydrate (1 mmol). The reaction was stirred for half an hour and monitored by TLC. Upon completion, all of the solvent was removed by rotary evaporation. The residue was redissolved in ethanol and dried over anhydrous magnesium sulfate, filtered, and evaporated by a rotary evaporator to yield a white solid product.