Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:8][C:7]1[C:2]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2nccnc2Cl)cc1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
2,3-Dichloropyrazine (2.67 mL, 25.6 mmol), 4-aminophenol (2.29 g, 21 mmol), and cesium carbonate (8.21 g, 25.2 mmol) in dimethyl sulfoxide (70 mL) under argon was stirred at 100° C. for 18 h. The cooled reaction mixture was poured into water (100 mL), resulting in the precipitation of a brick-colored solid. After stirring for 10 min, the brown slurry was filtered to give a relatively pure crop of 4-(3-chloropyrazin-2-yloxy)aniline (3.67 g, 79% yield) as a brick-colored solid. [M+1]=222.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:24][N:23]=3)[O:19][N:18]=2)[CH:14]=[C:13]([CH3:33])[C:4]=1[O:5][CH2:6][CH2:7]OS(C)(=O)=O)[CH3:2].C[O:35][C:36]([CH:38]1[CH2:41][NH:40][CH2:39]1)=[O:37].C(N(CC)CC)C.Cl>C(O)C.[OH-].[Na+]>[CH2:1]([C:3]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([CH2:29][CH:30]([CH3:31])[CH3:32])=[CH:24][N:23]=3)[O:19][N:18]=2)[CH:14]=[C:13]([CH3:33])[C:4]=1[O:5][CH2:6][CH2:7][N:40]1[CH2:41][CH:38]([C:36]([OH:35])=[O:37])[CH2:39]1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCOS(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19305.2 %

Procedure:
A solution of methanesulfonic acid 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethyl ester (300 mg, 633 μmol), azetidine-3-carboxylic acid methyl ester (218 mg, 1.84 μmol) and triethylamine (129 mg, 1.26 mmol) in ethanol (10 mL) is stirred in a sealed vial at 80° C. for 96 h. The mixture is cooled to rt, diluted with 3 M aq. NaOH and again stirred at rt for 1 h. The mixture is acidified by adding aq. HCl and is then extracted with EA (2×25 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (170 mg) as a colourless oil; LC-MS: tR=0.90 min, [M+H]+=479.10; 1H NMR (CDCl3): δ0.98 (d, J=6.5 Hz, 6H), 1.282 (t, J=7.0 Hz, 3H), 1.93 (hept, J=7.0 Hz, 1H), 2.38 (s, 3H), 2.45 (s, 3H), 2.61 (d, J=7.3 Hz, 2H), 2.73 (q, J=7.3 Hz, 2H), 3.71-3.82 (m, 2H), 3.97-4.08 (m, 1H), 4.19-4.27 (m, 2H), 4.37-4.62 (m, 2H), 4.73-4.97 (m, 2H), 7.87 (s, 1H), 7.89 (s, 1H), 8.07 (s, 1H), 8.53 (s, 1H).
Reaction SMILES: [Br-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH:31]=[C:32]([CH:34]=O)[CH:33]=1>O1CCCC1>[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH:31]=[C:32]([CH:34]=[CH2:2])[CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)cc(C=O)c1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1cc(Br)cc(NC(=O)OC(C)(C)C)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of triphenylmethylphosphonium bromide (28.4 g, 79.5 mmol) in tetrahydrofuran (152 mL) at 0° C. was treated with 2.5 M n-butyllithium in hexanes (31.8 mL, 79.5 mmol) dropwise and stirred at 0° C. for 15 min and at 20° C. for 1 h. The reaction mixture was cooled to 0° C., treated with a solution of tert-butyl (3-bromo-5-formylphenyl)carbamate (10.9 g, 36.2 mmol) in tetrahydrofuran (55 mL), and stirred at 20° C. for 1 h. The reaction mixture was cooled to 0° C., quenched with water (50 mL), concentrated to remove most of the tetrahydrofuran, poured into water (150 mL), and extracted with ethyl acetate (200 mL). The aqueous layer was separated and extracted with additional ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude tan oil. This material was purified by flash column chromatography to give the desired product (9.9 g, 92%) as a white solid. LCMS for C9H9BrNO2 ([M-(t-Bu)+H]+H)+: m/z=241.9, 243.8.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31](O)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])=[C:38]([CH3:50])[CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)=[C:38]([CH3:50])[CH:37]=4)=[O:32])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(N)ccc1C(O)c1ccccn1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(C)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.94 g), (4-amino-2-methylphenyl)(pyridin-2-yl)methanol (0.42 g) and 1-hydroxybenzotriazole (0.45 g) were dissolved in N,N-dimethylformamide (15 ml), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.75 g), triethylamine (0.82 ml) and 4-dimethylaminopyridine (catalytic amout) under ice-cooling at room temperature, and the mixture was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-methylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.95 g) as colorless crystals.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35]N[CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1>O1CCOCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]1[CH:24]=[CH:23][N:22]2[N:25]=[CH:26][C:27]([C:28]([NH:30][CH:31]3[CH2:36][CH2:35][N:4]([S:1](=[O:3])(=[O:2])[NH2:5])[CH2:33][CH2:32]3)=[O:29])=[C:21]2[CH:20]=1
Reactant: O=C(NC1CCNCC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)CC1
Reaction time: 4 h

Procedure:
Sulfamide (9 mg, 0.093 mmol) was added to solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(piperidin-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (25 mg, 0.058 mmol) (Example-32) in 1,4-Dioxane (0.5 mL) and stirring was continued at 110° C. for 4 h. The reaction mixture was concentrated to afford the residue, which was quenched with water, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude. The crude product was purified by Preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 10% MeOH in DCM as eluent) to afford 8 mg, of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[F:22])[N:18]([CH3:23])[C:17](=[O:24])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[Cl:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:24])[N:18]2[CH3:23])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:32]([C:27]2[C:26]([Cl:25])=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:33])[CH:11]=[N:10][CH:9]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)c(F)cc21
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)c4ncccc4Cl)c3)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 238) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as an off-white solid. MS: 455.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[S:31])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2)ccc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NC(=S)c2ccccc2)ccc1OC
Yield: 89.3 %

Procedure:
A 2 liter round bottom flask was charged with 15.7 grams (55 mmol) methyl-2-methoxy-5-benzamidobenzoate and 22.2 grams (55 mmol) of Lawesson's reagent followed by 500 mL of toluene. The reaction mixture was heated under reflux for 1.5 hours. The mixture was diluted with 500 mL of ethyl acetate, and washed with 250 mL of saturated aqueous bicarbonate solution, followed by washes with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica eluting with 96/4 methylene chloride-ether. There was obtained 14.8 grams (89%) of desired material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:23][N:22]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 20.2 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyrimidin-2-yl)piperidin-3-ylcarbamate (150 mg, 0.26 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (106 mg, 0.39 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (28 mg, 23% over 2 steps) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.34 (br s, 1H), 8.45 (s, 2H), 8.25 (dd, J=8.8, 1.9 Hz, 1H), 8.21 (br s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.25 (br s, 1H), 4.81-4.74 (m, 1H), 4.47 (d, J=12.8 Hz, 1H), 3.48-3.31 (m, 3H), 2.80 (br s, 1H), 2.24-2.16 (m, 1H), 1.97-1.87 (m, 1H), 1.81-1.62 (m, 2H), 1.21-1.16 (m, J=7.3 Hz, 4H); ESI MS m/z 533 [C28H26ClFN6O2+H]+; HPLC>99.0% (AUC), tR=10.89 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C([Li])(CC)C.[O:25]1[C:29]2([CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:32]3([OH:35])[CH2:33][CH2:34][C:29]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:30][CH2:31]3)=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: CCOc1ccc(-c2cccc(F)c2F)c(F)c1F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C3(O)CCC4(CC3)OCCO4)c(F)c2F)c(F)c1F
Reaction time: 2 h

Procedure:
4′-Ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl (s75) (50.0 g) and THF (500 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M; in n-hexane-cyclohexane; 222 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. 1,4-Dioxaspiro[4.5]decan-8-one (s7) (28.8 g) in THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The reaction mixture was treated with an aqueous solution of ammonium chloride (3%), and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 8-(4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-yl)-1,4-dioxaspiro[4.5]decan-8-ol. The compound was mixed with p-toluenesulfonic acid (1.5 g) and toluene (300 ml), and the mixture was heated to reflux for 2 hours while distilled water was removed. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in a mixed solvent of toluene (100 ml) and Solmix A-11 (100 ml), to which Pd/C (2.5 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from Solmix A-11 to give 8-(4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-yl)-1,4-dioxaspiro[4.5]decane (s76) (31.9 g). The yield based on the compound (s75) was 42.0%.
Reaction SMILES: [F:1][C:2](Br)([F:14])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>O1CCOCC1>[F:1][C:2]([F:14])([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13]
Reactant: CCOP(OCC)OCC
Reactant: Fc1c(F)c(F)c(C(F)(F)Br)c(F)c1F
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)C(F)(F)c1c(F)c(F)c(F)c(F)c1F
Yield: 89.6 %

Procedure:
Perfluorobenzyl bromide (2.00 g, 7.66 mmol) and P(OEt)3 (1.66 g, 9.96 mmol) were dissolved in 1,4-dioxane (10 ml) and heated at reflux for 14 hours. Fractional distillation (66-78° C., 60 mm Hg) afforded the product as a colorless oil (2.43 g, 96%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>O1CCOCC1>[Cl:9][C:4]1[CH:3]=[C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CC1(C)OBOC1(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Temperature: 80 °C

Procedure:
Dissolve 4-bromo-2-chloro-phenylamine (4.2 g, 20 mmol) in dioxane (80 mL) in a RBF under nitrogen. Add triethylamine (10 mL, 3.6 equiv.) then sparge with nitrogen to de-gas. Add 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.5 mL, 2.9 equiv.) dropwise via syringe over approximately 5 minutes. Sparge an additional 5 minutes with nitrogen then add [1,1′-Bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (0.603 g, 3.7 mol %, 1:1 complex with dichloromethane). Place under nitrogen and heat at 80° C. overnight. After the reaction cools, filter via Celite® washing with hexanes. Concentrate filtrate to dryness and use crude.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1nc(Br)ccc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)c(C)c1
Yield: 50.8 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (986 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (917 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (903 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][CH:39]=[CH:38][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][C:25]2[C:30]3[NH:31][C:32]([C:34](OC)=[O:35])=[N:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:41]=[CH:40][CH:39]=[CH:38][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][C:25]2[C:30]3[NH:31][C:32]([CH2:34][OH:35])=[N:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1nc2cccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)c2[nH]1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCNCC2OCc2cccc3nc(CO)[nH]c23)cc1
Reaction time: 2 h

Procedure:
The solution of 0.100 g of methyl 7-(4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxymethyl)-1H-benzoimidazole-2-carboxylate (Example 247) and 5.0 ml of tetrahydrofuran is cooled to 0° C. and admixed with 0.028 g of lithium aluminium hydride. The mixture is kept at room temperature over 2 hours. The reaction mixture is poured onto 1M sodium hydrogencarbonate solution and extracted with ethyl acetate (2×25 ml). The organic phases are washed with brine (20 ml, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [C:1]([C:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:8][CH2:9][O:10][CH3:11])[CH2:4][CH2:5][O:6][CH3:7])#[N:2].[BH4-].[Na+].C(OCC)(=O)C.[OH-].[Na+]>CO.[Co](Cl)Cl>[NH2:2][CH2:1][C:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])([CH2:4][CH2:5][O:6][CH3:7])[CH2:8][CH2:9][O:10][CH3:11]
Reactant: COCCC(C#N)(CCOC)NC(=O)OC(C)(C)C
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCC(CN)(CCOC)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 141.1 %

Procedure:
To a suspension of tert-butyl (3-cyano-1,5-dimethoxypentan-3-yl)carbamate (G20, 192 mg) and cobalt(II) chloride (183 mg) in methanol (7 mL), sodium borohydride (134 mg) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, ethyl acetate and 1.0 mol/L aqueous sodium hydroxide were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (3-(aminomethyl)-1,5-dimethoxypentan-3-yl)carbamate (G21, 275 mg).
Reaction SMILES: N[C@@H](C[S:6][CH2:7][CH:8]1[CH2:10][CH2:9]1)CO.CN1CCOCC1.FC(F)(F)C(OS(C(F)(F)F)(=O)=O)C1C=CC=CC=1.C1C(C[C@:41]([NH:46][CH:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:48]([F:51])([F:50])[F:49])([CH3:45])[CH:42](S)[OH:43])C1>C1COCC1>[CH2:9]1[CH:8]([CH2:7][S:6][C@:41]([NH:46][CH:47]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:48]([F:49])([F:50])[F:51])([CH3:45])[CH2:42][OH:43])[CH2:10]1
Reactant: N[C@H](CO)CSCC1CC1
Reactant: C[C@](CC1CC1)(NC(c1ccccc1)C(F)(F)F)C(O)S
Agent: O=S(=O)(OC(c1ccccc1)C(F)(F)F)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@](CO)(NC(c1ccccc1)C(F)(F)F)SCC1CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2(R)-amino-3-cyclopropylmethylsulfanylpropan-1-ol (80.5 mg, 0.5 mmol) in anhydrous THF (3 mL) were added activated 4A molecular sieves (250 mg) and N-methylmorpholine (51 mg, 0.5 mmol). After stirring for 10 min, trifluoromethanesulfonic acid 2,2,2-trifluoro-1-phenylethyl ester (190.5 mg, 0.5 mmol) was added and the reaction was stirred at room temperature for 2 days. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography to afford the desired mixture of diastereomers of 2(R)-3-cyclopropylmethyl-sulfanyl-2-(2,2,2-trifluoro-1(RS)-phenylethylamino)-propan-1-ol. LC-MS: 318.3(M−1), 320.8(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][CH:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:8][C:7]=2[C:6]([NH2:20])=[CH:5][CH:4]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:6]2[C:7]3[CH2:8][CH:9]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[CH2:10][CH2:11][CH2:12][C:13]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:23][CH:24]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc(N)c2c1CCCC(N1CCOCC1)C2
Product: COc1ccc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)c2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 4-methoxy-8-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N,N-dimethylbenzenesulfonamide (70 mg, 0.2 mmol) in an analogous manner to Example 944 to afford a white foam (49 mg, 50%). Mp: 196-8° C. LCMS (m/e) 587 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.60 (s, 1H), 8.07 (m, 1H), 7.80 (d, J=8 Hz, 1H), 7.25 (m, 1H), 7.19 (d, J=9 Hz, 1H), 7.11 (m, 1H), 6.81 (d, J=9 Hz, 1H), 6.70 (br s, 1H), 3.86 (s, 3H), 3.60 (m, 4H), 3.42 (m, 1H), 3.22 (m, 1H), 2.75 (s, 6H), 2.59 (m, 3H), 2.33 (m, 4H), 2.00 (m, 3H), 1.72 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([C:24](=[O:25])[NH:12][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[CH:5]=2)[CH3:11])=[CH:22][CH:23]=1)=[O:18]
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1ccc(C(=O)O)s1
Product: COC(=O)c1ccc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 2 from 1-(3-trifluoromethoxy-phenyl)-ethyl amine and thiophene-2,5-dicarboxylic acid monomethyl ester.