Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][C:7]#[C:8][C:9]#[N:10])[CH2:2][CH2:3][CH3:4].Cl.Cl.[CH2:17]([NH:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>C(O)C>[NH2:10][C:9]1[N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]=[C:7]([CH2:6][N:5]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][CH2:2][CH2:3][CH3:4])[CH:8]=1
Reactant: NNCc1ccccc1
Reactant: CCCCN(CC#CC#N)CCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(CCCC)Cc1cc(N)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
A solution of 4-dibutylamino-2-butynenitrile in ethanol (10 mL) was added to a stirring solution of benzylhydrazine dihydrochloride (3.0 g, 15.4 mmol) and 3.0 N NaOH (5.00 mL, 15.4 mmol) in ethanol (50 mL). The resulting solution as stirred (2 hours, 25° C.), then concentrated. The residue was taken up in ethyl acetate (250 mL), washed with brine (3×90 mL), then dried (MgSO4) and concentrated in vacuo. The resulting oil was chromatographed on silica (80:20 hexane:ethyl acetate) to yield 0.70 g (14.5%) of 5-amino-3-[(dibutylamino)methyl]-1-(phenylmethyl)-1H-pyrazole as an orange oil. 1H NMR (250 MHz, CDCl3 δ 7.22 (m, 6H), 4.56 (s, 2H), 4.00 (br s, 2H), 2.30 (m, 4H), 1.34 (m, 8H), 0.90 (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)C>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3nsc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3nsc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
To a suspension of benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (6.2 g) in methylene chloride (60 ml) were added anisole (9.3 g) and trifluoroacetic acid (24.5 g), and the mixture was stirred at ambient temperature for 1.5 hours. After removal of the solvent, the residue was added dropwise to diisopropyl ether (600 ml), and the precipitated substance was collected by filtration. This substance was suspended in water (50 ml) and then adjusted to pH 7.5 with 2N aqueous sodium hydroxide, followed by washing twice with a mixture of ethyl acetate (50 ml) and tetrahydrofuran (50 ml). To the resultant aqueous solution were added ethyl acetate (50 ml) and tetrahydrofuran (50 ml), and the mixture was saturated with sodium chloride and adjusted to pH 1.0 with 10% hydrochloric acid. The organic layer was separated, and the remaining aqueous solution was extracted twice with a mixture of ethyl acetate and tetrahydrofuran. The combined organic solution was washed with an aqueous solution chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diethyl ether to obtain 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (3.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[NH:11][C:10](=[O:20])[C:9]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[C:26](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[C:10]([O:20][CH3:26])[C:9]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(C)cc(C)c2[nH]c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(OC)nc2c(C)cc(C)cc2c1-c1ccccc1Cl
Yield: 90.3 %

Procedure:
To a mixture of ethyl 4-(2-chlorophenyl)-1,2-dihydro-6,8-dimethyl -2-oxo-3-quinolinecarboxylate (0.71 g), potassium carbonate (0.28 g) and DMF (8 ml) was dropwise added methyl iodide (0.15 ml) under stirring, followed by stirring for 15 minutes at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and concentrated to obtain ethyl 4-(2-chlorophenyl)-2-methoxy-6,8-dimethyl-3-quinolinecarboxylate. Yield 90.3% mp 135°-136° C. (from ethanol)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([N:19]2[C:27]3[C:22](=[C:23](O)[CH:24]=[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=3)[CH:21]=[CH:20]2)[CH2:18][CH2:17]1.N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH:16]1([N:19]2[C:27]3[C:22](=[C:23]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:24]=[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=3)[CH:21]=[CH:20]2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1cc(O)c2ccn(C3CC3)c2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccn(C3CC3)c2c1
Reaction time: 0.5 h

Procedure:
In a 500-mL egg plant-type flask, a chloroform (50 mL) solution of trifluoromethanesulfonic acid anhydride (6.30 mL, 37.5 mmol) was dropwise added to a chloroform (100 mL) solution of ethyl 1-cyclopropyl-4-hydroxy-1H-indole-6-carboxylate (6.12 g, 25 mmol) and pyridine (6.06 mL, 75 mmol) with cooling with ice, and stirred at that temperature for 30 minutes, then poured into aqueous hydrochloric acid solution, extracted with chloroform, washed with aqueous saturated sodium hydrogencarbonate solution, and dried with sodium sulfate. The reaction solution was filtered, concentrated, and purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a colorless oil.
Reaction SMILES: [O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([OH:24])[CH:13]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>C(OCC)(=O)C.[Pd]>[O:1]([CH:9]([C:39]([F:47])([F:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:10][CH2:11][C@H:12]1[C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([OH:24])[CH:13]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH3:37])[CH3:38])=[O:34])[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:3])[CH3:4]
Reactant: CCCCCCC(F)(F)C(CC[C@@H]1C(C/C=C\CCCCCC(=O)OC(C)C)[C@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCC(F)(F)C(CC[C@@H]1C(CCCCCCCCC(=O)OC(C)C)[C@H](O)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C

Procedure:
The compound (12-9)(1.39 g) was subjected to catalytic reduction in ethyl acetate (15 ml) using 5% Pd—C (0.14 g) under hydrogen atmosphere. The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=8/2) to give the titled compound (12-10).
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.C1C=CC=CC=1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(Cl)nc(C)nc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-n2c(C)c(C)c3c(-c4ccccc4C(F)(F)F)nc(C)nc32)c(C)c1

Procedure:
A mixture of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine (425 mg, prepared as described by Y. L. Chen in Patent Application WO94/13676), 2-(trifluoromethyl)phenylboronic acid (310 mg) tetrakis(triphenylphoshine)palladium(0) (50 mg), 1M aqueous sodium carbonate (2 mL), ethanol (0.75 mL) and benzene (6 mL) was refluxed for 6 hr. The cooled mixture was diluted with ethyl acetate and the aqueous layer was removed. The organic layer was washed with 1N aqueous sodium hydroxide, and brine, dried, and concentrated in vacuo. The crude reaction product was chromatographed on silica gel using ethyl acetate/hexanes (1:3) as eluent. The title compound was obtained as a glass (300 mg) that crystallized on trituration with ether to give crystals, mp 176.5-177.5°. Elemental Analysis: Calcd. for C22H24N3F3 : C, 70.91: H, 5.71; N, 9.92. Found: C, 70.69; H, 5.72; N, 9.84.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:13])=[N:10][S:11][N:12]=2)=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:13][CH3:14])=[N:10][S:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: Oc1nsnc1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nsnc1-c1ccc(Cl)cc1
Yield: 86.3 %

Procedure:
By the method of L. Weinstock, et al., supra, 0.5 g (0.0023 mole) 4-(4-chlorophenyl)-3-hydroxy-1,2,5-thiadiazole, 0.36 g (0.0026 mole) of potassium carbonate and 0.37 g (0.0026 mole) of iodomethane in 15 ml of N,N-dimethylformamide were reacted to produce 0.45 g of 4-(4-chlorophenyl)-3-methoxy-1,2,5-thiadiazole, Compound 25 of Table I. Compounds 22-24, 26-29, 31, 35, 37, and 39-41 were also prepared by this method, except that, in some cases sodium carbonate was used in place of potassium carbonate and/or an appropriate bromide or chloride was used in place of methyl iodide.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][CH3:20])=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c2ccccc2nc2ccccc12
Yield: 77.6 %

Procedure:
A solution of acridine-9-carboxylic acid 81 (2.0 g, 8.96 mmol), methyl iodide (3.82 g, 26.9 mmol) and potassium carbonate (4.95 g, 35.8 mmol) in DMF (25 mL) was stirred at room temperature for 3 h then diluted with brine and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to afford compound 82 (1.65 g, 78%) as a light yellow solid. LRMS (ESI): (calc) 237.25 (found) 238.2 (MH)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[NH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccnc3)ccc12
Yield: 18.7 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 3-(aminomethyl)pyridine (0.064 mL, 0.636 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (115 mg, 0.185 mmol) and NaOtBu (169 mg, 1.759 mmol) in DMA (5 mL) was heated at 85° C. for 2 h. The mixture was allowed to cool, then filtered. Preparatory HPLC afforded 4-chloro-6-[(pyridin-3-ylmethyl)-amino]-2H-phthalazin-1-one hydroformate (31 mg) as a yellow solid, 1H (400 MHz, d6-DMSO) δ: 4.41 (d, 2H), 6.78 (d, 1H), 7.12 (dd, 1H), 7.31 (dd, 1H), 7.60 (t, 1H), 7.10 (m, 1H), 7.88 (d, 1H), 8.09 (s, 1H), 8.41 (dd, 1H), 8.56 (d, 1H), 12.31 (s, 1H) ppm; m/z (M+1) 286.99.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[CH3:34][C:35]1([OH:41])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.FC1C=CC(C(/N=C2\NC3C=CC(CN4CCN(S(C)(=O)=O)CC4)=CC=3N\2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)=O)=CC=1>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30][N:38]4[CH2:39][CH2:40][C:35]([OH:41])([CH3:34])[CH2:36][CH2:37]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC1(O)CCNCC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Agent: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCN(S(C)(=O)=O)CC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C)(O)CC4)cc32)CC1

Procedure:
The title compound was prepared from (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide and 4-methylpiperidin-4-ol using a method analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide. The title compound was isolated as a white powder (37 mg, 30% yield). MS, m/z (C31H40FN5O3): calcd, 549.3. found, 549.9 [M+H]
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[N:5]2[C:9]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=1)=[CH:8][CH:7]=[CH:6]2.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[CH:19]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[N:5]4[C:9]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=3)=[CH:8][CH:7]=[CH:6]4)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[CH:19]=1
Reactant: COC(=O)c1ccc(/C=N/O)n2cccc12
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Temperature: 68 °C
Yield: 6.6 %

Procedure:
A solution of crude (E)-methyl 5-((hydroxyimino)methyl)indolizine-8-carboxylate (1.0 mmol) in THF (10 mL) was added to a stirred solution of DIB (644 mg, 2.0 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (480 mg, 2.0 mmol) in THF (15 mL) at rt. Then the mixture was heated at 68° C. for 2 h. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and Combiflash to give methyl 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylate (30 mg; yield 7% over 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J=2.0 Hz, 1H), 7.77 (t, J=1.6 Hz, 1H), 7.57-7.62 (m, 3H), 7.23-7.27 (m, 2H), 7.06 (m, 1H), 4.57 (d, J=18.0 Hz, 1H), 4.46 (d, J=18.0 Hz, 1H), 3.87 (s, 3H) ppm; MS: m/z=456.7 (M+1, ESI+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[NH:6][C:5](=O)[CH:4]=1.P(Br)(Br)([Br:24])=O>>[Br:24][C:5]1[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)[nH]1
Reactant: O=P(Br)(Br)Br
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (example A.17 step 2) (15 g, 49 mmol) and phosphoryl bromide (42 g, 146 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as a brown solid (18 g, quant.). MS (EI) 368.9 [(M)+] and 370.8 [(M+2)+]; mp 35-37° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([F:28])([F:27])[F:26].[O:29]1CCC[CH2:30]1>O.CN(C)C=O>[Br:19][C:20]1[CH:24]=[C:23]([CH:30]=[O:29])[S:22][C:21]=1[C:25]([F:28])([F:27])[F:26]
Reactant: FC(F)(F)c1sccc1Br
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: O=Cc1cc(Br)c(C(F)(F)F)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a solution of N,N-diisopropylamine (680 μL, 5.19 mmol) in tetrahydrofuran (5 ml) was added dropwise a solution of 1.67 mol/L n-butyllithium in hexane (3.11 ml, 5.19 mmol) at −78° C. under argon atmosphere, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was slowly warmed to 0° C., and stirred for 20 minutes, and then cooled to −40° C. Then, thereto was added dropwise a solution of 3-bromo-2-(trifluoromethyl)thiophene (1000 mg, 4.33 mmol) in tetrahydrofuran (15 ml). The mixture was stirred at the same temperature for 20 minutes, and the reaction solution was slowly warmed to −10° C., and then stirred for 5 minutes. The reaction solution was cooled to −40° C., and then thereto was added dropwise N,N-dimethylformamide (1 mL). Then, the mixture was slowly warmed to 0° C., and stirred overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→9:1) to give 4-bromo-5-(trifluoromethyl)thiophene-2-carbaldehyde (527 mg, 47%) as a yellow oil.
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH:27]1([C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:2])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Reactant: c1ccc2c(c1)CCNC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)C1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 115.5 %

Procedure:
To a stirring solution of 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (0.800 g, 2.2 mmol) in N,N-dimethylformamide (50 ml) were added sequentially 1,2,3,4-tetrahydroisoquinoline (322 mg, 1.1 eq), 1-hydroxybenzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to Yield 1.24 grams of a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[N+:11]([C:14]1[C:15]([C:19](Cl)=[O:20])=[N:16][NH:17][CH:18]=1)([O-:13])=[O:12].[N+](C1C(C(O)=O)=NNC=1)([O-])=O.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:19]([C:15]1[C:14]([N+:11]([O-:13])=[O:12])=[CH:18][NH:17][N:16]=1)=[O:20]
Reactant: O=C(Cl)c1n[nH]cc1[N+](=O)[O-]
Reactant: COc1ccc(N)c(N)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2n[nH]cc2[N+](=O)[O-])c(N)c1
Reaction time: 8 h

Procedure:
By proceeding in a manner similar to Reference Example 36(a), Method A, above but using 4-methoxy-1,2-phenylenediamine (880 mg) and 4-nitropyrazole-3-carboxylic chloride [prepared by treating a solution of 4-nitropyrazole-3-carboxylic acid (1 g) in dry dichloromethane (70 ml) under nitrogen with oxalyl chloride (1.11 ml) and dimethylformamide and after stirring overnight evaporating the reaction mixture then azeotroping three times with toluene (10 ml)] there was prepared 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl)-amide (800 mg). LC-MS (Method J): RT=2.67 minutes, 278.25 (M+H)+, 276.28 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Brc1cccc(I)c1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cccc(Br)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-bromo-3-iodobenzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.31-7.61 (m, 11H), 7.08 (t, 1H), 6.64-6.73 (m, 2H), 6.44 (d, 1H), 4.95 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1)[CH3:3].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[C:29](Br)=[N:28][C:27]([Br:31])=[CH:26][N:25]=1)(=[O:22])=[O:21]>>[Br:31][C:27]1[N:28]=[C:29]([O:11][CH2:10][C:8]2[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)[C:24]([NH:23][S:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])(=[O:22])=[O:21])=[N:25][CH:26]=1
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl
Reactant: CN(C)Cc1ccc(CO)o1
Product: CN(C)Cc1ccc(COc2nc(Br)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1

Procedure:
Prepared by the method of Example 31 using (5-dimethylaminomethyl-2-furanyl)methanol (0.2 g) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (Example 31a) (0.2 g). Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures and recrystallised from acetonitrile. Yield 0.058 g.
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=1[CH3:32])[CH2:3][CH3:4]>CCCCCC.C(OCC)(=O)C>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[C:9]3[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:6]([CH3:32])=[C:5]([C:2](=[O:1])[CH2:3][CH3:4])[C:13]=3[O:12][CH2:11]2)=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 18 %

Procedure:
Using a diastereo mixture of N-(7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in the synthesis in Examples 30 and 31, the title compound was synthesized in the same manner as in Example 32. Yield: 18%. Melting point: 163-164° C. (hexane-ethyl acetate).