Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:85]1[CH2:89][CH2:88][CH2:87][C:86]1=[O:90]>O1CCOCC1.C(OCC)(=O)C.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]>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([NH:26][CH2:25][C:7]2([C:21]([F:24])([F:23])[F:22])[C:6]3[CH:36]=[C:2]([N:85]4[CH2:89][CH2:88][CH2:87][C:86]4=[O:90])[CH:3]=[CH:4][C:5]=3[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8]2)=[O:35])=[CH:29][CH:30]=1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(N4CCCC4=O)ccc32)cc1

Procedure:
A mixed solution of N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (100 mg, 0.176 mmol), tris(dibenzylideneacetone)dipalladium (8.0 mg, 0.008 mmol), xantphos (15.2 mg, 0.024 mmol), cesium carbonate (57.4 mg, 0.176 mmol) and 2-pyrrolidinone (26.8 μL, 0.352 mmol) in dioxane (0.5 mL) was stirred at 120° C. for 30 minutes under microwave irradiation. After the reaction solution was left to cool, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1), whereby the objective compound (69 mg, 69%) was obtained as a yellow oily substance.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3]1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1)[CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.ClCCl>[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([N:18]2[CH2:17][CH2:16][N:15]([C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]4)=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)=[CH:27][CH:26]=1)[CH3:22]
Reactant: C[C@@H]1CN(c2ccc(N3CCNCC3)cc2)C[C@H](C)O1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3)CC2)cc1
Yield: 81.3 %

Procedure:
A solution of cis-2,6-dimethyl-4-(4-piperazinylphenyl)morpholine (2.00 g), 4-fluorobenzoic acid ethyl ester (1.43 g) and potassium carbonate (1.01 g) in dimethylsulfoxide (40 ml) was stirred for 8 hours at 150° C., during which period additional 4-fluorobenzoic acid ethyl ester (1.35 g) and potassium carbonate (1.0 g) was added to the mixture. The reaction mixture was added to a mixture of water and dichloromethane. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (25:1 dichloromethane-methanol elution) to give 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid ethyl ester (2.5 g).
Reaction SMILES: Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1.[Cl:16][C:17]1[N:21]2[CH:22]=[CH:23][C:24]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:25][C:20]2=[CH:19][N:18]=1.C(C1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2)=CC=1)#N>>[ClH:16].[Cl:16][C:17]1[N:21]2[CH:22]=[CH:23][C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:25][C:20]2=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccn3c(Cl)ncc3c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: Clc1ncc2cc(C3CCNCC3)ccn12

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.2, except tert-butyl 4-(3-chloroimidazo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate (compound 68.2) was used in place of tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.1) to yield the title compound as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:36])[CH2:23][C:24]([C:26]1[N:27]=[C:28]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[S:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[N:27]=[C:28]([N:31]5[CH:35]=[CH:34][N:33]=[CH:32]5)[S:29][CH:30]=4)[CH2:23][C:22](=[O:36])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1csc(-n2ccnc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2csc(-n3ccnc3)n2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K83) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (64 mg).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:35])[NH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=3)[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[CH:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:35])[NH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:41]4[CH:42]=[CH:43][C:38]([CH:36]=[O:37])=[CH:39][CH:40]=4)=[CH:30][CH:29]=3)[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C(NC(c1ccccc1)c1cccc(OCCc2ccc(Br)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(CCOc3cccc(C(NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)cc1
Temperature: 120 °C
Yield: 41.5 %

Procedure:
(R)-quinuclidin-3-yl((3-(4-bromophenethoxy)phenyl)(phenyl)methyl)carbamate (0.40 g, 0.747 mmol), 4-formylphenylboronic acid (0.123 g, 0.822 mmol), and sodium carbonate (0.158 g, 1.494 mmol) were combined in toluene (9.94 mL) and water (2.48 mL). The mixture was degassed with nitrogen for 10 minutes. Tetrakis-(triphenylphosphine)palladium(0) (0.087 g, 0.075 mmol) was added, and the mixture heated at 120° C. for 30 minutes in a microwave. The mixture was filtered, and the filtrate partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a brown oil. The crude material was partially purified using a flash C18 cartridge eluting with 30-60% acetonitrile in water to afford a brown oil (0.174 g). The material was used directly in the next step with no further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[C:5]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=1)=[O:6].[CH2:36](B(O)O)[CH2:37][CH3:38]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=2)[C:5](=[O:6])[C:4]2[CH:3]=[C:2]([CH2:36][CH2:37][CH3:38])[CH:34]=[C:33]([Cl:35])[CH:32]=2)=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCCB(O)O
Reactant: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc(Br)c2)cc1
Product: CCCc1cc(Cl)cc(C(=O)N(CCc2cc(F)cc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared in analogy to example 3, using 3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide (Example B177) and n-propylboronic acid. 534.3 [ISP (M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:17]=[CH:16][N:15]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:36][CH:37]([Cl:41])[C:38](Cl)=[O:39]>ClCCl>[Cl:36][CH:37]([Cl:41])[C:38]([N:20]([CH2:21][CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:19]=1)=[O:39]
Reactant: CC(C)OC(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropyl 3-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)propanoate (520 mg, 1.23 mmol) was dissolved in anhydrous dichloromethane (25 mL) with triethylamine (270 mg, 2.7 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (320 mg, 2.17 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield isopropyl 3-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)propanoate (Cpd. No. 57). 1H NMR (CDCl3): 8.38 (m, 1H), 8.01 (s, 1H), 7.80 (m, 1H), 7.50-7.41 (m, 4H), 7.18 (s, 1H), 6.86 (s, 1H), 6.32 (s, 2H), 5.08 (m, 1H), 1.38 ppm (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:32][CH2:31][CH2:30][CH2:29][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)=[O:8].C(N(CC)CC)C.[Cl:40][S:41]([C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47](Cl)=[O:48])(=[O:43])=[O:42]>ClCCl>[Cl:40][S:41]([C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([NH:1][C:2]1[S:3][C:4]2[CH2:32][CH2:31][CH2:30][CH2:29][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)=[CH:14][CH:15]=1)=[O:8])=[O:48])(=[O:43])=[O:42]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 29.3 %

Procedure:
To a mixture of 3.34 g of methyl 4-[3-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)propyl]benzoate, 2.2 mL of triethylamine, and 40 mL of dichloromethane were added a mixture of 2.2 g of 3-(chlorosulfonyl)benzoyl chloride and 10 mL of dichloromethane under ice-cooling, followed by stirring at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was suspended in ethanol. The precipitate was collected by filtration to obtain 1.42 g of methyl 4-[3-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)propyl]benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([P:5]([CH2:21][CH2:22][CH2:23][CH3:24])[O:6]C1C=CC(C(C)(C)C)=CC=1C(C)(C)C)[CH2:2][CH2:3][CH3:4].O>C(#N)C>[CH2:1]([PH:5](=[O:6])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCP(CCCC)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Solvent: CC#N
Solvent: O
Product: CCCC[PH](=O)CCCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
35 g (0.1 mol) of 2.4-di-tert.-butylphenyl dibutylphosphinite from Example 5 were reacted in 100 ml of acetonitrile with 2.0 g (0.11 mol) of water at 20° C., and the mixture was then stirred at 70° C. for 1 hour. The solvent was distilled off in vacuo, 50 ml of water and 100 ml of ethyl acetate were added, the phases were separated, and the organic phase was extracted two more times with 50 ml each of water. The combined aqueous phases were evaporated, and the residue distilled in vacuo, giving 10.2 g (70%) of a colorless liquid having a boiling point of 102° to 104° C./0.25 mbar.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH2:21])[CH3:16].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(N(CC)CC)C.C1(C)C=CC=CC=1.O1CCCC1.CO>[CH2:15]([N:17]([CH2:18][CH2:19][CH2:20][NH:21][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:22][CH3:23])[CH3:16]
Reactant: CCN(CC)CCCN
Reactant: CC(C)(C)OC(=O)c1ccnc(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)CCCNc1cc(C(=O)OC(C)(C)C)ccn1

Procedure:
1.02 g (4.77 mmol) of tert-butyl 2-chloroisonicotinate, 5 ml of 3-diethylamino-1-propylamine, 0.66 g (4.77 mmol) of potassium carbonate, a spatula tip of Cu powder and a spatula tip of 18-crown-6 were refluxed for 4 hours. Flash chromatography of the reaction mixture (toluene/tetrahydro-furan/methanol, 4/1/1+2.5% triethylamine) resulted in 0.69 g of pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([F:29])([F:28])[F:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:15](O)=[O:16])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([F:28])([F:27])[F:29])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:15]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:16])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: O=C(O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2cccnc2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1
Temperature: 0 °C

Procedure:
26 mg (purity 92%, 0.06 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. The reaction mixture was freed from DMF and the residue was stirred with ice-water. The crystals obtained were filtered off, washed with water and dried under reduced pressure. Yield: 33 mg (purity 94%, 92% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:34]=[CH:33][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:35][CH2:36][CH2:37][CH2:38]Cl)=[CH:4][CH:3]=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:34]=[CH:33][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:35][CH2:36][CH2:37][CH2:38][N:51]2[CH2:50][CH2:49][N:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[O:41][CH3:40])[CH2:53][CH2:52]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(OCCCCl)c2)c2ccccc21
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Ethyl 4-{3-[4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl]indol-1-yl}butanoate (2.59 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (30 ml). 1-(2-Methoxyphenyl)piperazine (1.36 g), potassium carbonate (0.85 g), and potassium iodide (1.02 g) were added to the resultant solution and stirred overnight at 60° C. The reaction mixture was poured into water and extracted with ethyl acetate. The resultant extract was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), obtaining 2.47 g of ethyl 4-{3-{4-(4-methylphenylmethoxy)-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:30]=[O:31])=[CH:3][C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: CN(C)C=O
Reactant: COCCCCc1cc(Br)ccc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCCCc1cc(C=O)ccc1OC
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-1-methoxy-2-(4-methoxy-butyl)-benzene (8.10 g, 29.7 mmol; described in EP0678 503 B1) in absolute THF (170 mL), cooled to −78° C., is added dropwise over 30 min and under an argon atmosphere a 1.6M solution of n-butyllithium in hexane (20.4 mL, 32.6 mmol). After stirring for 5 min, a mixture of DMF (5.03 mL, 65.2 mmol) in THF (20 mL) is added over 30 min at −78° C. Stirring is continued over 15 min at −78° C., and the reaction mixture is gradually warmed and stirred for an additional hour at room temperature before quenching with 1N HCl. The aqueous layer is extracted with diethyl ether (3×200 mL), the combined organics are dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 4:1) gives the title compound as yellowish oil. TLC, Rf (hexane/AcOEt 4:1)=0.27. MS: 223.2 [M+H]+. 1H-NMR (CDCl3): δ 1.6-1.74 (m, 4H) 2.70 (t, 2H), 3.37 (s, 3H), 3.43 (t, 2H), 3.96 (s, 3H), 6.99 (dd, 1H), 7.73 (d, 1H), 7.76 (dd, 1H), 9.70 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:17]([F:18])=[C:16]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:24])=[C:12]([F:23])[C:13]=3[C:14]([F:22])([F:21])[C:15]2([F:20])[F:19])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:32]1([C:41](Br)([F:43])[F:42])[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:33]1>CN(C=O)C>[F:42][C:41]([F:43])([C:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH3:40])[CH2:34][CH:33]=1)[O:24][C:11]1[CH:10]=[CH:9][C:8]2[C:7]3[C:16](=[C:17]([F:18])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)[C:15]([F:19])([F:20])[C:14]([F:21])([F:22])[C:13]=2[C:12]=1[F:23]
Reactant: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c-2ccc(O)c1F
Reactant: CCCC1CCC(Br)(C(F)(F)Br)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1CC=C(C(F)(F)Oc2ccc3c(c2F)C(F)(F)C(F)(F)c2c-3ccc(OCC)c2F)CC1
Yield: 78.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of compound (91) (3.76 g, 10.80 mmol) and potassium carbonate (4.48 g, 32.4 mmol) was heated and agitated at 110° C. for 1 hour in a DMF (40 mL) solvent. Subsequently, 1-bromo-1-(bromodifluoromethyl)-4-propylcyclohexane (92) (7.21 g, 21.59 mmol) was added dropwise to the reaction mixture at 110° C., and the resultant mixture was further agitated for 3 hours. The reaction mixture was quenched with water, and extracted with 50 mL of toluene three times. Combined organic layers were washed with water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 2-(difluoro(4-propylcyclohexa-1-en-1-yl)methoxy)-7-ethoxy-1,8,9,9,10,10-hexafluoro-9,10-dihydrophenanthrene (93) (4.40 g, yield 78.0%) was obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[C:13]1([CH:19]([Mg]Cl)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20])[CH3:12]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CC([Mg]Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)C(C)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (1.80 mL, 10.1 mmol) in THF (20 mL) was added slowly a THF solution of (92) prepared above at −78° C. After stirring at −78° C. for 3 hours, to this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate═19/1) to give 1,1-diethoxy-3-phenylbutan-2-one (93) as a colorless oily substance (330 mg, 1.37 mmol, 13.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][N:24]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Reactant: Clc1cc(I)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(Cl)c3)n2)cc1

Procedure:
The title compound was prepared from 2-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.19) (1.11 g, 3.0 mmol), commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (740 mg, 3.1 mmol) and i-PrMgCl/ZnCl2 according to the general procedure IVc protocol a. Obtained as a white solid (0.601 g, 50%). MS (ISP) 403.3 [(M+H)+] and 405.2 [(M+2+H)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([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:4][N:3]=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:35]=[CH:36][CH:37]=[C:38]([C:2]2[CH:7]=[C:6]([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:24])([F:23])[F:25])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
3-{4-[4-(3,4-Dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.38) (0.4 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as light brown foam (0.41 g), which was subsequently deprotected.