Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:58][CH2:57][C:56]([F:60])([F:59])[F:55])=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol), N,N-diisopropyl ethyl amine (552 μL, 3.22 mmol) and 2,2,2-trifluoroethylamine 77 μL, 0.77 mmol). The resulting reaction mixture was stirred for 12 h at ambient temperature. After dilution with ethyl acetate (20 mL) it was washed with water (20 mL) and aqueous sodium carbonate (saturated, 40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 20:80) afforded the title compound (213 mg, 84%) as a white solid. MS: m/e=392.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([SH:16])[CH2:14][SH:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:22]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CCCCCC.C(OCC)(=O)C.CO.C1C=CC=CC=1.O.C1C=CC=CC=1>[CH3:30][O:29][C:25]1[CH:24]=[C:21]([C@H:22]2[S:16][C@H:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:14][S:15]2)[CH:20]=[C:19]([O:18][CH3:17])[C:26]=1[O:27][CH3:28]
Reactant: COc1cc(C(S)CS)cc(OC)c1OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(OC)c1OC
Reaction time: 2.5 h

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (38) (0.56 g, 2.15 mmole), 3,4,5-trimethoxybenzaldehyde (24) (0.35 g, 1.78 mmole) and 0.178 g of pyridinium paratoluene sulfonate are added to 40 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope for 24 hours. The benzene is removed in vacuo, and the remaining oil redissolved in ethyl acetate. The organic layer is washed with H2O and was dried over MgSO4, filtered, and evaporated in vacuo to a white foam which is purified by flash column chromatography using 1:1 hexane/ethyl acetate as eluent (0.630 g, 81%). The trans isomer is isolated from the 1:1 mixture of diastereomers after three recrystallizations from methanol (25 mg). If the above reaction is performed under reduced pressure (aspirator) at 45° C. for 2.5 hours using camphor sulfonic acid as the catalyst, the product mixture contains a 3:1 cis/trans ratio of diastereomers. The cis diastereomer is isolated from this product mixture by recrystallization from either methanol or hexane/ethyl acetate.
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH:4]([C:6](O)=O)[OH:5])[OH:3].[NH2:11][C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][C:17]=1[NH2:18].Cl.P(=O)(O)(O)O>O.C(O)C>[CH3:19][C:14]1[CH:15]=[CH:16][C:17]2[N:18]=[C:1]([CH:2]([OH:3])[CH:4]([OH:5])[C:6]3[NH:11][C:12]4[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][C:17]=4[N:18]=3)[NH:11][C:12]=2[CH:13]=1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: Cc1ccc(N)c(N)c1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1ccc2nc(C(O)C(O)c3nc4ccc(C)cc4[nH]3)[nH]c2c1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 15.0 g (0.10 mole) tartaric acid, 29.32 g (0.24 mole) 3,4-diaminotoluene, 25 ml water, 15 ml ethanol, 25 ml hydrochloric acid (conc.) and 10 ml 85% phosphoric acid was heated at 120° C. for 40 hours, poured into water and the mixture acidified with concentrated hydrochloric acid. After extraction with chloroform and making the aqueous phase alkaline with sodium hydroxide, a precipitate formed and was collected by filtration. The solid was washed with a small amount of acetone and held in vacuo for 18 hours. The residual moisture was removed by azeotropic distillation of its mixture with benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[N:9]=1)[C:5]#[N:6].[CH2:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[N:9]=1)[C:5]#[N:6].[CH2:11]([N:14]([CH2:15][CH2:16][CH3:17])[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[N:9]=1)[C:5]#[N:6])[CH2:12][CH3:13]
Reactant: CCCNCCC
Agent: Cc1cc(C#N)cc(Cl)n1
Product: CCCN(CCC)c1cc(C#N)cc(C)n1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
To 2-chloro-6-methylisonicotinonitrile (0.230 g, 1.51 mmol) was added di-n-propylamine (5 mL). The mixture was heated at 80° C. in a sealed, thick-walled glass vessel for 12 h and then at room temperature for 17 h. Excess di-n-propylamine was removed under reduced pressure and the residue was partitioned between dichloromethane and aq. sodium bicarbonate. After drying over sodium sulfate and concentration, the residue was chromatographed on silica gel using ethyl acetate-hexane (10/90) to give 0.14 g of 2-chloro-6-methylisonicotinonitrile and 0.059 g of 2-(dipropylamino)-6-methylisonicotinonitrile. Using the above conditions, 2-chloro-6-methylisonicotinonitrile (0.14 g) was converted to an additional 0.043 g of 2-(dipropylamino)-6-methylisonicotinonitrile.
Reaction SMILES: [C:1]12[CH2:15][CH2:14][C:13](=[O:16])[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18].C([N-]C(C)C)(C)C.[Li+]>>[CH3:19][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30]([CH:14]1[C:13](=[O:16])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]=2[CH2:15]1)=[O:31])[CH3:18]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: O=C1CCC2=C1CCCCCCCCCC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CC2=C(CCCCCCCCCC2)C1=O

Procedure:
The title compound, mp 225°-229° C., was prepared from bicyclo[10.3.0]pentadec-12(1)-en-13 one (5.0 g, 0.022 mol), 2,6-diisopropylphenyl isocyanate (4.60 g, 0.022 mol), and lithium diisopropylamide (0.022 mol) using the procedure described in Example 1. ##STR12##
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CS(O[CH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:20]=[N:19][N:18]([CH:31]4[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]4)[CH:17]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)OC1CCS(=O)(=O)CC1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCS(=O)(=O)CC4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A mixture of (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.160 g, 0.47 mmol), 1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (0.320 g, 1.40 mmol) and cesium carbonate (0.457 g, 1.40 mmol) in N,N-dimethylformamide (5 mL) stirred overnight at 110° C. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 50% ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RP18 5 um, 19×150 mm; Mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (40% to 80% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded of methyl (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ6-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (0.040 g, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.18 (d, J=6.40 Hz, 3H), 1.29-1.31 (m, 1H), 1.47-1.49 (m, 1H), 1.60-1.62 (m, 1H), 2.01-2.08 (m, 4H), 2.11-2.24 (m, 1H), 2.45-2.47 (m, 1H), 2.63-2.68 (m, 4H), 2.90-2.94 (m, 1H), 3.10-3.17 (m, 2H), 3.45-3.47 (m, 2H), 3.78 (s, 3H), 4.06-1.10 (m, 1H), 4.45-4.58 (m, 2H), 7.22 (d, J=8.40 Hz, 1H), 7.31 (d, J=8.40 Hz, 1H), 7.81 (s, 2H). MS (ESI, pos. ion) m/z 474 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH2:26][CH3:27])[CH3:25]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([CH:24]([CH3:25])[CH2:26][CH3:27])=[CH:29][CH:30]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CCC(C)c1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCC(C)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 18.5 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-sec-butylaniline (51.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(1-methylpropyl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl)pyrrolidine-2-carbonitrile (13.0 mg).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([NH2:14])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C(OCC)(=O)C>[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([NH:22][C:23]([NH:14][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[O:13][N:12]=1)=[O:24])=[O:21]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1cc(-c2cccc(C(F)(F)F)c2)on1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1cc(-c2cccc(C(F)(F)F)c2)on1

Procedure:
5-(3-(Trifluoromethyl)phenyl)-3-aminoisoxazole (300 mg.) and excess 2,6-dichlorobenzoyl isocyanate were mixed in 50 ml. of ethyl acetate under nitrogen, and stirred for several hours at room temperature. The product was separated by filtration, m.p., 233° C. (dec)
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)(=[O:15])=[O:14].[CH3:25][O-:26].[Na+]>CN1CCCC1=O.CO>[CH3:1][N:2]([CH3:24])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[N:18]=[N:19][C:20]([O:26][CH3:25])=[CH:21][CH:22]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nn3)cccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1ccc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)nn1

Procedure:
5-Dimethylamino-N-(6-chloro-3-pyridazinyl)-1-naphthalenesulphonamide (0.36 g), was suspended in N-methylpyrrolidone (1 ml) and freshly prepared 1M sodium methoxide in methanol (3 ml) was added. The reaction mixture was heated to reflux for 4 hours, cooled and evaporated to dryness. The residue was purified by flash chromatography on silica gel (5 g) eluting with a methanol/dichloromethane gradient to give 5-dimethylamino-N-(6-methoxy-3-pyridazinyl)-1-naphthalenesulphonamide (0.14 g), m.p. 125-127° C.; mass spectrum (+ve CI): 359 (M+N)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[P:11]([O-:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].Br[CH2:20][C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[CH3:24][Si:23]([CH3:26])([CH3:25])[C:22]#[C:21][CH2:20][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CCOP([O-])OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC#C[Si](C)(C)C)OCC
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
Into a solution of LiHMDS (1M in THF, 63.8 mL, 63.8 mmol) in anhydrous THF (162 mL) was added dropwise under stirring at −10° C. in nitrogen atmosphere diethyl phosphite (7.4 mL, 63.8 mmol). The obtained solution was stirred at the same temperature for 20 min. Afterwards, 3-bromo-1-trimethylsilyl-1-propyne (10 mL, 63.8 mmol) was dropped into and the reaction mixture was stirred at −10° C. for 2 h., then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford 14.86 g of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][OH:13].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OC(C)C)(C)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C@@H:11]([CH3:14])[CH2:12][OH:13].[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:2])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: COc1ccccc1SC[C@@H](C)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)OC(C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 ml of methylene chloride, 2 g (9.4 mmol) of (S)-3-(2-methoxyphenylsulfanyl)-2-methylpropanol, 2 g (10.5 mmol) of para-toluenesulfonyl chloride and 115 mg (0.94 mmol) of 4-dimethylaminopyridine are introduced into a three-necked flask under an inert atmosphere and 1.2 g (12.1 mmol) of triethylamine are then added dropwise. After stirring for 2 hours at ambient temperature, 10 ml of demineralised water are added. The pH is adjusted to 6.5 by adding 2N hydrochloric acid. The phases are separated and then the organic phase is washed with 10 ml of demineralised water. The organic phase is concentrated under reduced pressure. The yellow oil obtained (3.2 g) is taken up in a mixture of methylene chloride (4.8 ml) and 19.2 ml of isopropyl ether. The precipitate obtained is filtered off and then washed twice with 10 ml of isopropyl ether and dried at 40° C. under reduced pressure. The title product (3) is obtained in the form of a white powder 2.6 g (75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>CC(C)=O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)[CH3:23]
Reactant: CCI
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(C2CCC(=O)CC2)cc1
Yield: 100 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodoethane (10.5 mL, 20.5 g, 131 mmol, 5 equiv.). The reaction was heated at 6520 C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-ethoxyphenyl)cyclohexanone (5.74 g, 100%). 1H NMR (CDCl3) 7.15 (dt, 2H), 6.86 (dt, 2H), 4.02 (q, 2H), 2.99 (tt, 1H), 2.46-2.54 (m, 4H), 2.16-2.24 (m, 2H), 1.83-2.00 (m, 2H) and 1.41 (t, 3H); MS (electrospray) m/e, 219 (M+1)+, Calcd for C14H18O2, 218.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([C@@H:14]1[O:16][CH2:15]1)[Cl:13]>>[Cl:13][CH2:12][C@H:14]([OH:16])[CH2:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: ClC[C@H]1CO1
Product: O[C@@H](CCl)Cc1cccc(C(F)(F)F)c1

Procedure:
(R)-1-chloro-3-(3-trifluoromethylphenyl)-2-propanol was prepared using the same procedure as described for example 2, intermediate (d), but using 3-bromobenzotrifluoride and (R)-epichlorohydrin.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3([CH3:32])[CH2:31][O:30][CH2:29]3)=[CH:22][C:21]=1[N+:33]([O-])=O)[CH:15]=[CH:14]2)C1C=CC=CC=1.[CH2:36](N(CC)CC)C.C(O)=O.C(O)(=O)C.C(N)=N>[OH-].[OH-].[Pd+2].C(O)C>[CH3:32][C:28]1([CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]3[N:19]([C:16]4[CH:15]=[CH:14][C:13]5[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=5)[N:17]=4)[CH:36]=[N:33][C:21]=3[CH:22]=2)[CH2:31][O:30][CH2:29]1
Reactant: CCN(CC)CC
Reactant: CC1(COc2ccc(Nc3ccc4cccc(OCc5ccccc5)c4n3)c([N+](=O)[O-])c2)COC1
Agent: [Pd+2]
Agent: N=CN
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O=CO
Product: CC1(COc2ccc3c(c2)ncn3-c2ccc3cccc(O)c3n2)COC1
Temperature: 50 °C
Yield: 82 %

Procedure:
The compound (8-Benzyloxy-quinolin-2-yl)-[4-(3-methyl-oxetan-3-ylmethoxy)-2-nitro-phenyl]-amine (5 g, 10.6 mmol, 1.0 equivalent), ethanol (50 mL, 10 volumes)i triethylamine (7.8 mL, 56.2 mmol, 5.3 equivalents), and palladium hydroxide on carbon (500 mg, 0.1 weight equivalents) were charged to a 100 mL round bottom flask. The solution was deoxygenated and then heated to 50° C. Once the reaction reached 50° C., formic acid (2.2 mL, 56.2 mmol, 5.3 equivalents) was charged slowly to control any exotherm or off-gasing. The reaction was then heated at 55° C. for 15–25 hours. After nitro group reduction and benzyl group removal was noted by APCI MS, the reaction was cooled to 40° C. and filtered through a pad of Celite. The flask and the filter cake were washed once with ethanol (2.5 volumes). The filtrate was then charged to another 100 mL round bottom flask containing formamidine acetate (2.3 g, 22.3 mmol, 2.1 equivalents) and the reaction was heated at reflux for ˜8 hours. At reaction completion, the reaction was cooled to 20–25° C. and allowed to granulate for 10–20 hours. The solids were isolated by filtration and dried under vacuum at 40° C. with a slight nitrogen bleed to afford 3.14 g of 2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-ol as a yellow solid (82% yield). 1H NMR (d6-DMSO): δ 9.88 (s, 1H), 9.25 (s, 1H), 8.61 (d, 1H, J=9.1 Hz), 8.51 (d, 1H, J=9.1 Hz), 8.10 (d, 1H, J=9.1 Hz), 7.44 (m, 2H), 7.35 (d, 1H, J=2.5 Hz), 7.18 (dd, 1H, J=7.5, 1.7 Hz), 7.08 (dd, 1H, J=8.7, 2.5 Hz), 4.51 (d, 2H, J=5.8 Hz), 4.31 (d, 2H, J=5.8 Hz), 4.12 (s, 2H), 1.39 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][C:6]1[CH:7]=[N:8][N:9]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[C:10](=[O:12])[CH:11]=1)#[N:2].[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[C:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][C:6]1[CH:7]=[N:8][N:9]([CH:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:15])[C:10](=[O:12])[CH:11]=1)#[N:2]
Reactant: N#Cc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C#N)cc2=O)n1
Yield: 58 %

Procedure:
Using the method described in Example 17, 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 58) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.83 g, 58%); ES+-HRMS m/e calcd for C26H30N6O4 [M+H+] 491.2402 found 491.2402. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.28-1.76 (m, 8H), 1.94 (m, 1H), 2.29 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.49 (dd, J=4.3, J=10.9 Hz, 1H), 6.08 (d, J=2.8 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.54 (td, Jo=7.7 Hz, Jm=0.9 Hz, 1H), 7.58 (d, Jo=8.1 Hz, 1H), 7.81-7.91 (m, 1H), 8.03 (dd, Jo=7.7 Hz, Jm=1.6 Hz, 1H), 8.24 (d, J=2.8 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[O:14][CH3:16])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(Br)c(OC)c(C(C)=O)c1

Procedure:
1 eq. of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (preparation, see Example 19) was reacted, in acetone, with 2.0 eq. of K2CO3 and 2.1 eq. of methyl iodide to give methyl 3-acetyl-5-bromo-4-methoxybenzoate. Colorless oil, MS (ES): 288 (M+1).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:15]2[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[C:13]#[N:14].C(O)C>CCCCCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.CCOCC>[F:6][C:7]1[CH:8]=[C:9]([C@H:15]2[CH2:20][CH2:19][C@H:18](/[CH:21]=[CH:1]/[CH2:2][CH2:3][CH3:4])[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1ccc(C2CCC(C=O)CC2)cc1F
Reactant: [Li]CCCC
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCCC
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(C#N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.4 ml of 1.7M n-butyllithium in hexane are added, with stirring and under an atmosphere of nitrogen, to a suspension of 5.4 g of n-butyltriphenylphosphonium bromide in 100 ml of ether. After 30 minutes the orange solution is cooled to -40° and 2.1 g of 4-(3-fluoro-4-cyanophenyl)-cyclohexanecarbaldehyde in 20 ml of ether are added. After stirring for 2 hours at -40°, 60 ml of ethanol are added dropwise. The reaction mixture is then allowed to warm up to room temperature, is stirred for one hour and worked up in the customary manner. 2-fluoro-4-[trans-4-(trans-1-pentenyl)-cyclohexyl]-benzonitrile is obtained after isomerisation in the customary manner analogously to European Published Application No. 0,122,389.
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[O:18][C@H:15]2[CH2:16][OH:17])=[CH:10][CH:9]=1.COCCO[AlH2-]OCCOC.[Na+].Cl>C(OCC)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]([OH:18])[CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=1
Reactant: OC[C@@H]1O[C@@H]1c1ccc(Cl)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: OCC[C@H](O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
500 ml of a dimethoxyethane solution of 15.0 g of (2S,3R)-3-(4-chlorophenyl)-2,3-epoxy-1-propanol was cooled to -25° C., and 25.1 ml of a red-Al solution (3.4 mol/l toluene solution) was added dropwise over 0.5 hour. After stirred at 20° C. for 2 hours, the mixture was brought to 0° C. over 1 hour, and 300 ml of diethyl ether was added thereto. While the mixture was kept below 5° C., 100 ml of 2N hydrochloric acid was added dropwise. After stirring for 15 minutes, the mixture was filtered through celite. Then, 100 ml of ethyl acetate was added, and the resulting mixture was allowed to separate. The aqueous layer was extracted again with ethyl acetate. The organic layers were combined, dried over sodium sulfate and filtered through celite. The solvent was distilled off the filtrate, and the resulting residue was purified by silica gel column chromatography (eluent; methanol/chloroform=5/95). It was crystallized to obtain 14.56 g of the title compound as white crystals.