Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:28]=1)(O)[CH2:17][CH2:16][CH2:15]2.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:7][C:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=2)[C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:25][CH:24]=1
Reactant: COc1ccc2c(c1)CCCC2(O)c1ccc(OCCN2CCCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(Br)=C2c1ccc(OCCN2CCCC2)nc1
Reaction time: 18 h
Yield: 69.3 %

Procedure:
Pyridinium bromide perbromide (3.5 g, 12.2 mmol) was added to a solution of 6-methoxy-1-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-1,2,3,4-tetrahydronaphthalen-1-ol (3.3 g, 8.9 mmol) in CH2Cl2 (50 mL). The reaction was stirred for 18 h and aqueous NaHCO3 (satd) was added. The aqueous layer was extracted with CH2Cl2 and the combined organic solution was washed with water and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3: MeOH, 95:5) provided the desired vinyl bromide (2.65 g, 70%). 1H NMR (250 MHz, CDCl3): δ8.0 (d, J=2.4 Hz, 1 H), 7.41 (dd, J=2.4, 8.4 Hz, 1 H), 6.83 (d, J=8.4 Hz, 1 H), 6.69 (m, 1 H), 6.55 (m, 2 H), 4.92 (t, J=5.8 Hz, 2 H), 3.76 (s, 3 H), 2.94 (m, 6 H), 2.64 (m, 4 H), 1.82 (m, 4 H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH:17]=[CH:18][C:19]1[CH:28]=[CH:27][C:22](/[CH:23]=[CH:24]/[CH:25]=O)=[CH:21][CH:20]=1.[O:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35].N1CCCCC1.C(O)C>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([CH2:23][CH2:24][CH2:25][CH:33]2[O:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])=[CH:21][CH:20]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1C=Cc1ccc(/C=C/C=O)cc1
Reactant: O=C1COC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1CCc1ccc(CCCC2OC(=O)NC2=O)cc1
Yield: 11.7 %

Procedure:
A mixture of (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]cinnamaldehyde (2.00 g), 2,4-oxazolidinedione (1.11 g), piperidine (0.23 g), ethanol (100 ml) and tetrahydrofuran (50 ml) was refluxed under heating conditions for 8 hours. After the reaction mixture was concentrated, chloroform was added to the residue; the mixture was then washed with 2N HCl and water. The organic layer was washed with water, dried (MgSO4) and then concentrated. The residue was subjected to silica gel column chromatography. The crystal obtained from the fraction eluted with ethyl acetate-chloroform (1:9, v/v) was dissolved in tetrahydrofuran (100 ml), and subjected to catalytic hydrogenation at 1 atm and room temperature in the presence of palladium-carbon (5%, 0.5 g). After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to yield 5-[3-[4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]ethyl]phenyl]propyl]-2,4-oxazolidinedione (0.29 g, 12%) from the fraction eluted with methanol-chloroform (2:98, v/v), which was then recrystallized from dichloromethane-isopropyl ether to yield a colorless prisms having a melting point of 168°-169° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11]2)=[CH:7][CH:6]=1.[S:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32](=[O:40])[CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:40]=[C:32]1[N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:29]=[CH:28][C:8]([CH2:9][N:10]3[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:11]3)=[CH:7][CH:6]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[S:30][CH2:31]1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCCBr)cc2)nc1-c1ccccc1
Reactant: O=C1CSc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1cn(Cc2ccc(OCCN3C(=O)CSc4ccccc43)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (883 mg), 2H-1,4-benzothiazin-3(4H)-one (320 mg), potassium carbonate (530 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated to obtain 3-[1-[4-[2-(3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (680 mg, yield: 69%) as a colorless amorphous substance.
Reaction SMILES: Cl.N[C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH:9]([CH3:20])[N:10]3[C:15]=2[C:14]=1[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11]3.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[C-:31]#[N:32].[Na+]>C(O)(=O)C.O>[C:31]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH:9]([CH3:20])[N:10]3[C:15]=2[C:14]=1[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11]3)#[N:32]
Reactant: [C-]#N
Reactant: CC1CCc2ccc(N)c3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC1CCc2ccc(C#N)c3c(=O)c(C(=O)O)cn1c23
Temperature: 50 °C

Procedure:
A mixture of 70 ml. of 6N hydrochloric acid and 10-amino-6,7-dihydro-5-methyl-1-oxo-benzo[ij]quinolizine-2-carboxylic acid (10 g., 0.039 mole) is treated at 0° to 5° C. with sodium nitrite (2.7 g., 0.39 mole) in 10 ml. of water. The solution is stirred for about ten minutes, then neutralized by the addition of solid sodium carbonate. A solution of cuprous chloride (4.7 g., 0.048 mole) in 20 ml. of water and sodium cyanide (4.75 g., 0.097 mole) in 10 ml. of water is cooled to 0° C., then the diazonium solution is added dropwise with vigorous stirring. After stirring for 30 minutes at 0° C. the mixture is heated at 50° C. for 15 minutes, then stirred at about 25° C. for about 65 hours. The solution is acidified to pH 6 with glacial acetic acid to provide a brown solid which is collected by filtration, washed with water, then extracted into two 200 ml. portions of boiling dichloroethane. The hot dichloroethane extracts are filtered, then the filtrate is concentrated to provide an orange solid. The solid is washed thoroughly with hexane, recrystallized from N,N-dimethyl formamide, dissolved in dilute base, reprecipitated with glacial acetic acid and recrystallized again from N,N-dimethyl formamide to provide 10-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >300° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[Cl-:22].[NH4+]>CO>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=12)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[ClH:22]
Reactant: [Cl-]
Agent: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: [NH4+]
Solvent: CO
Product: Cl
Temperature: 42.5 °C

Procedure:
To (S)-(+)-N-methyl-3-(1-naphthaleneoxy)-3-(2-thienyl)propanamine free base (65 gm) prepared as above, methanol (520 ml) is added under stirring. To the clear solution at 20-25° C., ammonium chloride (12.3 gm) is added under stirring. The reaction mixture is stirred at 20-25° C. for 1.5 hours. The solution is heated to 40-45° C. and methanol is distilled out under vacuum, residue is degassed. To the residue, dichloromethane (650 ml) is added under stirring, at 25-30° C. and the clear solution is stirred for 30 minutes. Then dichloromethane layer is washed with D.M Water (2×130 ml). Organic layer (dichloromethane layer) is charcoalised at 25-30° C., filtered through Hyflo bed and dried over sodium sulfate. Dichloromethane is distilled out under vacuum at 40-45° C. and residual mass is degassed under vacuum. Acetone (195 ml) is added to the residual mass at 25-30° C. to get a slurry and the resultant slurry is gradually cooled to 5-10° C. and maintained for 1-2 hours. The product is filtered and washed with acetone (100 ml), dried in air oven at 65-70° C. for 2-3 hours to obtain pure duloxetine HCl (35 g, 100% ee).
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][C:44](=[S:70])[NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]3)=[CH:48][CH:47]=1>>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][C:44](=[S:70])[NH:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]3)=[CH:50][CH:51]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4OC)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: COc1ccccc1NC(=S)Nc1ccc(-c2ccc3c(c2)CN([C@H](C(=O)O)C(C)C)C3=O)cc1
Yield: 76 %

Procedure:
The compound of example 281 was prepared analogous to compound of example 257 by hydrolysis of compound of example 280.
Reaction SMILES: C1C[O:4][CH2:3]C1.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:11]([F:23])[C:10]=1[F:24])[CH3:7].C([Li])(CC)C>CN(C=O)C>[CH2:6]([O:8][C:9]1([CH:3]=[O:4])[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:11]([F:23])[CH:10]1[F:24])[CH3:7]
Reactant: CCOc1ccc(-c2cccc(F)c2F)c(F)c1F
Reactant: C1CCOC1
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Product: CCOC1(C=O)C=CC(c2cccc(F)c2F)=C(F)C1F
Temperature: -65 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
THF (400 ml) was added to 4-ethoxy-2,2′,3,3′-tetrafluorobiphenyl (6) (39.25 g) prepared by means of a conventional coupling reaction in a reaction vessel under an atmosphere of nitrogen. The solution was cooled to −65° C. or lower, and sec-butyllithium (1.08 M in cyclohexane and n-hexane; 141.3 ml) was added dropwise. After the reaction mixture had been stirred at −65° C. for another 1 hour, N,N,-dimethylformamide (21.2 g) was added dropwise, and the reaction mixture was warmed slowly to room temperature. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and water (500 ml) was added to give two layers. The water layer was extracted with toluene (200 ml) twice, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was treated with silica gel chromatography (silica gel: 30 g, eluent: toluene) to give 4-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-carboaldehyde (7) (30 g) in 70% yield.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21](=[O:22])[CH2:20][O:19][C:18]3[CH:23]=[CH:24][C:25]([Br:27])=[N:26][C:17]2=3)[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21](=[O:22])[CH2:20][O:19][C:18]3[CH:23]=[CH:24][C:25]([Br:27])=[N:26][C:17]2=3)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(Br)nc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(Br)nc32)CC1

Procedure:
tert-Butyl{1-[2-(6-bromo-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 80) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[N:12][C:11]=1[CH3:18].[CH:19](=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[OH:28][CH:19]([CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][C:11]1[C:10]([CH3:9])=[N:15][C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1
Reactant: Cc1nc(C)c(C)nc1C
Reactant: O=CC=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CC(O)C=Cc2ccccc2)nc1C
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of cinnamaldehyde (14.5 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedures of Example I to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccnc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 90 °C

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-3-yl-1H-benzoimidazol-2-yl)ethylamine (80 mg, 0.31 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (51 mg, 0.33 mmol) and DIPEA (0.16 mL, 0.93 mmol) in IPA (0.7 mL) was heated in a sealed tube for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PPC, gradient 0-10% 2M NH3 in MeOH/DCM) to give a pale yellow oil. The residue was taken up in EtOAc and product triturated with cyclohexane. The solid was filtered to afford 348 as an off white solid (31 mg, 26%). LCMS (Method K): RT 3.04 min [M+H]+ 3.75. 1H NMR (DMSO-d6, 400 MHz): δ 8.73 (1H, d, J=2.5 Hz), 8.64 (1H, dd, J=5.0, 1.5 Hz), 8.01-7.98, (1H, m), 7.81 (1H, s), 7.76-7.73 (2H, m), 7.55 (1H, ddd, J=8.0, 5.0, 1.0 Hz), 7.18 (2H, bs), 7.12 (1H, ddd, J=10.0, 9.0, 2.5 Hz), 6.93 (1H, dd, J=7.0, 2.5 Hz), 7.48 (1H, dq, 7.0, 7.0 Hz), 1.55 (3H, d, J=7.0 Hz)
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]=1[CH:19]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)C>[Cl:6][C:7]1[C:8]([CH:19]=[CH2:1])=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: [Li]CCCC
Reactant: O=Cc1c(Cl)cccc1-c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
Under a dry argon atmosphere n-butyllithium (1.3 g, 0.020 mole) was added slowly to a stirred ice cold mixture of (methyl)triphenylphosphonium bromide (7.3 g, 0.0203 mole) in 30 ml of tetrahydrofuran. The mixture was warmed to room temperature, stirred for two hours, and 3-chloro-[1,1'-biphenyl]-2-carboxaldehyde (4.4 g, 0.0203 mole) in 30 ml of tetrahydrofuran added. The reaction mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then cooled. The reaction mixture was diluted with 300 ml of diethyl ether and washed with 100 ml of water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to give a residue. Distillation of the residue at 88°/0.05 mm gave 3-chloro-2-ethenyl-[1,1'-biphenyl] (2.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.B(OC)(OC)OC.Cl.B(O)(O)O.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]2[CH:41]=[C:40]([F:42])[C:39](I)=[C:38]([F:44])[CH:37]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].C(C1CCC(=O)CC1)CCCC.FC1C=C([Mg]Br)C=C(F)C=1.[Li]CCCC.II.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1COCC1.CN(CCN(C)C)C.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.C1(C)C=CC=CC=1.O>[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]2[CH:37]=[C:38]([F:44])[C:39]([C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=3)=[C:40]([F:42])[CH:41]=2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC[C@H]1CC[C@H](c2cc(F)c(I)c(F)c2)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCC1CCC(=O)CC1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2cc(F)c(-c3ccc(OC(F)(F)F)cc3)c(F)c2)CC1
Reaction time: 1 h

Procedure:
A solution of 0.1 mol of p-bromotrifluoromethoxybenzene in 100 ml of THF is added dropwise to a suspension of 0.1 mol of Mg turnings in 50 ml of THF at such a rate that the reaction mixture boils gently. After the mixture has been stirred for one hour, 0.1 mol of trimethyl borate is added dropwise at room temperature, and the mixture is stirred for a further hour and hydrolyzed using dilute hydrochloric acid. After extractive work-up, the resultant boric acid (0.05 mol) is refluxed for two hours together with 0.05 mol of 4-(trans-4-n-pentyl cyclohexyl)-2,6-difluoroiodobenzene [obtainable by reacting 4-pentylcyclohexanone with 3,5-difluorophenylmagnesium bromide, eliminating water, and hydrogenating the cyclohexenebenzene on Pd/C. The resultant 3,5-difluoropenyl [sic] compound is metallated at −70° in THF/TMEDA using n-BuLi and subsequently reacted with iodine in THF at −70°], 38 ml of 2 molar aqueous Na2CO3 solution, 0.6 g of tetrakis(triphenylphosphine)palladium(0) and 75 ml of toluene. Customary aqueous work-up and chromatographic purification give 4-(trans-4-n-pentylcyclohexyl)-2,6-difluoro-4′-trifluoromethoxybiphenyl.
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[K+].Cl>CO>[F:17][C:2]([F:1])([S:13]([OH:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 95 %

Procedure:
25 g (0.074 mol) of potassium perfluorobutanesulphonate are suspended in 63 ml of methanol. The suspension is heated to a temperature of 50° C. and at the same time hydrochloric acid gas is bubbled through for approx. 1 hour. At the end of the addition the suspension is cooled to a temperature of 0°±5° C. and the potassium chloride filtered. The solution is concentrated under vacuum so as to eliminate the solvent. 26.5 g of a yellowish residue is obtained with a titre of 79.63% equal to 21.1 g of perfluorobutanesulphonic acid (Expected theoretical yield 22.21 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:17])=[O:16].[CH:18]1([CH2:23][C:24](OC)=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+].Cl>C(O)C>[CH:18]1([CH2:23][C:24]2[NH:17][C:15](=[O:16])[C:3]3[CH:4]=[N:5][N:6]([C:7]4[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=4[CH3:14])[C:2]=3[N:1]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)CC1CCCC1
Reactant: Cc1cccc(C)c1-n1ncc(C(N)=O)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C)c1-n1ncc2c(=O)[nH]c(CC3CCCC3)nc21
Temperature: 25 °C

Procedure:
0.1 g (0.43 mmol) of 5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (Example 15A) is dissolved under argon in 6 ml of absolute ethanol and 0.24 g (1.7 mmol) of methyl cyclopentylacetate and 0.17 g (4.34 mmol) of 60% sodium hydride (suspension in mineral oil) are added. The reaction mixture is heated to reflux overnight. Cooling to room temperature is followed by acidification with concentrated hydrochloric acid. The sodium chloride precipitated thereby is filtered off. The filtrate is concentrated in vacuo, and the remaining residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 74 mg (53% of theory) of the product are obtained as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)[C:3]=1[C:21]#[N:22].C([O:30]C1C=C(C=CC=1)C(O)=O)C1C=CC=CC=1>>[NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:30])[CH:15]=2)[C:3]=1[C:21]#[N:22]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(O)c2)c(C#N)c1N

Procedure:
Compound 36A was prepared in a similar manner to the synthesis of compound 31F by substituting 4-(benzyloxy)benzoic acid with 3-(benzyloxy)benzoic acid: 1H NMR (DMSO-d6): δ 9.70 (s, 1H), 7.68 (s, 2H), 7.25-7.32 (m, 3H), 6.86-6.89 (m, 1H), 1.60 (s, 9H). MS (ESI(+)): m/z 322 (M+Na).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][C:29]([CH3:31])=[CH:30][C:26]=2[CH:25]=1)=[O:23]>C(Cl)Cl>[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][C:29]([CH3:31])=[C:30]([C:15](=[O:16])[C:14]3[CH:18]=[CH:19][C:11]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:12][CH:13]=3)[C:26]=2[CH:25]=1)=[O:23]
Reactant: COC(=O)c1ccc2oc(C)cc2c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(C)c(C(=O)c3ccc(-c4ccccc4)cc3)c2c1
Yield: 118.7 %

Procedure:
Aluminum chloride (0.80 g) was stirred in methylene chloride (10 ml) at room temperature. Thereto was added 4-phenylbenzoyl chloride (0.67 g), and then a solution of 5-(methoxycarbonyl)-2-methylbenzo[b]furan (0.67 g) in methylene chloride (5 ml), and the mixture was stirred for 4 hr. Ice was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and saturated brine (once), dried over sodium sulfate and concentrated to give the objective compound (1.36 g).