Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10](=[O:22])[C:11](N2C3C=CC=CC=3N=N2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[N:28][C:29]2[CH2:30][CH2:31][NH:32][CH2:33][C:34]=2[CH:35]=1.CCN(CC)CC>C1COCC1>[N:1]1([C:10](=[O:22])[C:11]([N:32]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:25]([F:36])([F:24])[F:37])=[CH:35][C:34]=3[CH2:33]2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: O=C(C(=O)n1nnc2ccccc21)n1nnc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C(=O)n1nnc2ccccc21)N1CCc2ncc(C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a suspension of 1,2-bis-benzotriazol-1-yl-ethane-1,2-dione (0.100 g, 0.342 mmol) in THF (3.4 mL) was added 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine monohydrochloride (0.082 g, 0.342 mmol) and the reaction mixture was stirred at ambient temperature for about 4 h. Et3N (0.05 mL, 0.34 mmol) was added and stirring was resumed for about 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated from hot iPrOAc. The solid was removed by filtration and the filtrate concentrated in vacuo then dissolved in EtOAc (10 mL), washed with 1N aq NaOH (2×5 mL), and saturated aqueous NaHCO3 (10 mL). The organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to provide 1-benzotriazol-1-yl-2-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-ethane-1,2-dione as an orange oil (0.056 g, 0.15 mmol). The crude material was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].[CH3:26][N:27]=[C:28]=[S:29]>CN(C)C=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:7]=[C:3]([NH:2][C:28]([NH:27][CH3:26])=[S:29])[S:4][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2nc(N)sc2-c2ccc(OC)cc2)cc1
Reactant: CN=C=S
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=S)Nc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-amino-4,5-bis(4-methoxyphenyl)thiazole hydrochloride (1.00 g) in N,N-dimethylformamide (5 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (0.13 g) in N,N-dimethylformamide (5 ml) at 0° C. for 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes. After methyl isothiocyanate (2.19 ml) was added dropwise to the reaction mixture, the reaction mixture was stirred at 80° C. for 5.5 hours. After allowing to cool to room temperature, the resulting precipitates were collected by filtration, washed with diisopropyl ether and diethyl ether to give 4,5-bis(4-methoxyphenyl)2-(3-methylthioureido)thiazole (0.81 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([NH2:23])[CH:20]=[N:21][CH:22]=4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[S:32]([NH:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[C:7]3[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:18]=1)(=[O:34])=[O:33]
Reactant: Nc1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3nccc(-c4ccncc4)c3c2)c1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 5-[4-(4-pyridinyl)-6-quinolinyl]-3-pyridinamine (82 mg, 0.27 mmol) in anhydrous pyridine (2.0 ml) was treated with neat 2,4-difluorobenzenesulfonyl chloride in one portion. The reaction was stirred at room temperature for 30 minutes then was purified directly by prep-HPLC. The combined, desired fractions were evaporated under reduced pressure to remove organic solvents then diluted with small portions of brine and saturated aqueous sodium bicarbonate. The basic solution was extracted with ethyl acetate then the extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting colorless film was crystallized from methylene chloride and diethyl ether. The solids were collected by filtration, rinsed with diethyl ether then vacuum dried to afford the title compound (219 mg, 48%) as a white solid. MS(ES)+m/e 475 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:13]([SH:17])[CH2:14][CH2:15][SH:16].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[S:17][CH2:13][CH2:14][CH2:15][S:16]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: SCCCS
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(C2SCCCS2)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
74.7 g of 3,4-dimethoxybenzaldehyde are dissolved in 1250 ml of chloroform, treated with 50 ml of 1,3-propanedithiol and cooled at 0° C. with stirring. 20 ml of boron trifluoride etherate are added and the mixture is left to stand in a refrigerator for 18 hours. The mixture is then washed three times successively with 500 ml of a 7% potassium hydroxide solution and 500 ml of a 10% sodium chloride solution. The organic extracts are combined, dried over magnesium sulphate and evaporated. The residue is recrystallized twice from ether. There are obtained 102.6 g of 2-(3,4-dimethoxyphenyl)-m-dithiane of melting point 99°-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](N)=[CH:7][N:6]=1)=[O:4].N([O-])=O.[Na+].[S-:16][C:17]#[N:18].[K+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:16][C:17]#[N:18])=[CH:7][N:6]=1)=[O:4]
Reactant: N#C[S-]
Reactant: COC(=O)c1ccc(N)cn1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(SC#N)cn1

Procedure:
To the solution of 28.3 g of 5-aminopyridine-2-carboxylic acid methyl ester in 80 ml of 20% sulfuric acid, cooled to -4°, the solution of 14.31 g of sodium nitrite in 30 ml of water is added dropwise while stirring and maintaining the temperature below 0°. Thereafter the mixture is stirred for 15 minutes below 0° and the mixture of 28 g of potassium thiocyanate and 8 g of cuprous thiocyanate is added portionwise to said solution. Each addition causes evolution of gas and a black oil to separate. With continued stirring the oil again dissolves and the solution is stirred for 3 hours. It is extracted with methylene chloride, the extract filtered and evaporated, to yield the 5-thiocyanatopyridine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH2:22][O:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>O1CCCC1>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH2:22][O:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COC)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 0 °C

Procedure:
2.85 g (7.6 mmol) of the compound from Example 59 dissolved in 30 ml of absolute tetrahydrofuran are added dropwise under a nitrogen atmosphere to 0.5 g (13.2 mmol) of lithium aluminum hydride in 20 ml of absolute tetrahydrofuran at 60° C. The mixture is heated to reflux for 1 hour, subsequently cooled to 0° C. and 1.5 ml of water and 0.3 ml of 15% strength potassium hydroxide solution are cautiously added dropwise. The solution is filtered from the deposited precipitate with suction and the latter is boiled several times with ether. The combined phases are dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/ petroleum ether 1:9).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.S(Cl)(=O)(=O)N.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:20]=[C:19]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=3)=[CH:33][CH:32]=2)[N:18]=1>CN(C)C(=O)C.CO>[S:2](=[O:3])(=[O:4])([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[C:19]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][N:41]=[C:40]([C:44]([F:46])([F:47])[F:45])[CH:39]=4)=[CH:33][CH:32]=3)[N:18]=[C:17]([NH2:16])[N:22]=2)=[CH:24][CH:25]=1)[NH2:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc(-c2ccc(O)cc2)n1
Agent: NS(=O)(=O)Cl
Solvent: O=CO
Solvent: CO
Solvent: CC(=O)N(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc(-c2ccc(OS(N)(=O)=O)cc2)n1
Temperature: 25 °C

Procedure:
To neat chlorosulfonyl isocyanate (0.166 g, 1.37 mmol) was added dropwise formic acid (97%, 0.63 g, 1.37 mmol) while cooling in ice-water bath. The mixture was stirred at rt until gas evolution ceased. The resulting sulfamoyl chloride was added to a solution of 4-{2-amino-6-[(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)amino]pyrimidin-4-yl}phenol (0.06 g, 0.14 mmol, Example 51) in dry N,N-dimethylacetamide at 0° C. The reaction mixture was then stirred at rt for 12 h. The solution was diluted with methanol and separated by preparative HPLC. The desired fractions were combined, basified with saturated sodium carbonate, and extracted with EtOAc (3×). The extracts were combined, washed with brine, dried over magnesium sulfate, and evaporated to give desired product, 0.025 g (35%). 1H NMR (DMSO-d6) δ 9.42 (s, 1H), 8.59 (d, 1H), 8.09 (d, 2H), 7.98 (m, 2H), 7.85 (m, 2H), 7.35 (m, 3H), 7.10 (m, 3H), 6.42 (s, 1H), 6.36 (s, 2H); MS ES 519 (M+H)+ calcd 519.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1.O>O1CCCC1>[N+:15]([C:14]1[C:9]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:10][CH:11]=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)([O-:17])=[O:16]
Reactant: CS(N)(=O)=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 65.8 %

Procedure:
4.4 g of methanesulfonamide was dissolved in 70 ml of dry tetrahydrofuran, and 1.9 g of 60% sodium hydride was added thereto under cooling with ice. After completion of the addition, the mixture was reacted for one hour under reflux. After cooling, 7.0 g of 2-chloro-3-nitro-5-trifluoromethylpyridine was added thereto, and the mixture was reacted for 6 hours under reflux. After completion of the reaction, the reaction product was poured into 300 ml of water and washed with ethyl ether. Then, the aqueous layer was weakly acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration and dried to obtain 5.8 g of N-(3-nitro-5-trifluoromethyl-2-pyridyl)methanesulfonamide having a melting point of from 138° to 139° C.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5]([CH:15]([CH3:17])[CH3:16])[N:4]=1)=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:16][CH:15]([N:5]1[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:7][C:3]([CH2:1][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4]1)[CH3:17]
Reactant: C1COCCN1
Reactant: CC(C)n1nc(C=O)cc1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)n1nc(CN2CCOCC2)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 3-formyl-1-(1-methylethyl)-1H-pyrazole-5-carboxylate (491 mg) was dissolved in anhydrous DCM (20 ml), morpholine (0.198 ml) was added and the mixture was stirred under nitrogen for 2 h at RT. Sodium triacetoxyborohydride (873 mg) was added and the mixture was stirred at RT for 18 h. Sodium bicarbonate solution (50 ml) and DCM (50 ml) were added and separated and the aqueous layer was re-extracted with DCM (2×50 ml) and separated by hydrophobic frit. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (50 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 30 mins to give the title compound (628 mg) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[N:26][CH:27]=[CH:28][CH:29]=1>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:25]3[C:24]([F:23])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:3]=2)[N:10]=1
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1F
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4ncccc4F)c3)n2)c(F)c1
Yield: 58.1 %

Procedure:
5 5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine (100 mg, 0.27 mmol) was coupled to 3-fluoro-2-tributylstannylpyridine (127 mg, 0.33 mmol) using the method described in Example 22 to give 3-(2,4-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-[1,2,4]triazine as a pale yellow solid (60 mg): δH (400 MHz, CDCl3) 6.99-7.10 (2H, m), 7.39-7.47 (2H, m), 7.56-7.61 (1H, m), 8.29-8.36 (1H, m), 8.41-8.45 (1H, m), 8.53 (1H, dd, J 2.3, 6.7 Hz), 8.60-8.63 (1H, m), 9.68 (1H, s); m/z (ES+) 383.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]Br>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1ccc(Cl)cc1Br
Reactant: BrBr
Product: Clc1ccc(CBr)c(Br)c1
Temperature: 25 °C

Procedure:
In a 500 ml three-necked round-bottom flask equipped with a reflux condenser, thermometer, dropping funnel with pressure-equalizing, magnetic stirring bar and containing 164 g (0.80 mol) of 2-bromo-4-chlorotoluene, 41.3 ml (128 g, 0.80 mmol) of bromine was added dropwise under exposure to a 500 W lamp for 3 hours at 190° C. The resulting mixture was cooled to room temperature. Fractional distillation gave colorless liquid, b.p. 111-115° C./7 mm Hg. Yield 182 g (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[F:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])=[CH:28][C:27]=3[F:39])=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)c(F)c1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1F)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
100 mg (0.29 mmol, 1.0 eq.) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 91 mg (0.43 mmol, 1.5 eq.) of tert-butyl 4-amino-3-fluorobenzoate were reacted according to General Method 5C. The crude product was purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 35%-50% mixtures). Yield: 126 mg (81% of theory)
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1.O.[F:17][C:18]([F:42])([F:41])[CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][C:22]=1[C:23](OCC(F)(F)F)=[O:24]>CO>[CH:33]1[C:32]([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[CH:31][C:22]([C:23]([NH:8][CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:24])=[C:21]([O:20][CH2:19][C:18]([F:17])([F:41])[F:42])[CH:34]=1
Reactant: NCC1CCCCN1
Reactant: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 50 °C

Procedure:
Dissolve in 48 ml of toluene 12.0 g (0.03 mol) of trifluoroethanol 2,5-bis-trifluoroethoxybenzoate. Add 3.94 g (0.0345 mol) of 2-aminomethylpiperidine and heat the solution to a temperature of 80°±5° C. for 8 hours. Cool to 50° C. and add 36 ml of water. Carry out the separation at a temperature of 45°±5° C. Concentrate the organic phase under vacuum at a temperature of 35°±5° C. so as to eliminate as much toluene as possible. A semi-solid residue is obtained which is dissolved in 20 ml of methanol and concentrated again to a residue under vacuum. Methanol (40 ml) is then added and heated with refluxing until a yellow solution is obtained. Then cool until the crude base crystallizes, the precipitation is completed by adding 40 ml of water.
Reaction SMILES: C1COCC1.[C:6]([O:10][C:11]([N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N:24]=[N+]=[N-])=[CH:20][CH:19]=2)=[CH:16][N:15]=[C:14]1[NH2:27])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl.[Pd]>[C:6]([O:10][C:11]([N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:20][CH:19]=2)=[CH:16][N:15]=[C:14]1[NH2:27])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N=[N+]=[N-])cc2)cnc1N
Reactant: CCCCCCC(=O)Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCC(=O)Nc1ccc(-c2cnc(N)n2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a solution of anhydrous THF (5 mL) and 10% Pd/C (0.010 g) was charged 2-amino-5-(4-azidophenyl)imidazole-1-carboxylic acid tert-butyl ester (0.100 g, 0.332 mmol). Air was removed from the system and the reaction was back flushed with hydrogen. This process was repeated three times before setting the reaction under a hydrogen balloon at atmospheric pressure and temperature for 12 h. After that time, the reaction was filtered to remove the catalyst. The filtrate was cooled to −78° C. and triethylamine (0.046 mL, 0.332 mmol) was added prior to the drop-wise addition of heptanoyl chloride (0.049 g, 0.332 mmol) diluted in anhydrous dichloromethane (0.50 mL). The reaction was stirred at −78° C. for 30 mins and then quenched with methanol (1 mL) before being concentrated under reduced pressure and purified by flash column chromatography (10-60% EtOAc/Hexanes) to obtain the title compound 2-amino-5-(4-heptanoylaminophenyl)imidazole-1-carboxylic acid tert-butyl ester (0.124 g, 97%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.14 (br s, 2H), 7.67 (m, 4H), 7.56 (s, 1H), 2.32 (t, 2H, J=7.5 Hz), 1.49 (m, 11H), 1.28 (br s, 6H), 0.87 (t, 2H, J=6.0 Hz); 13C NMR (75 MHz, DMSO-d6) δ 171.4, 147.5, 139.1, 126.4, 124.7, 122.2, 119.2, 119.0, 111.4, 108.4, 36.4, 31.0, 28.3, 27.4, 25.0, 21.9, 13.9; HRMS (ESI) calcd for C21H30N4O3 (M+) 386.2318. found
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:20][CH:19]([CH2:21][OH:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.O.S(=O)(=O)(O)[OH:25]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:3]2[O:20][CH:19]([C:21]([OH:25])=[O:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A portion (6.4 g) of the 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 11 was dissolved in 150 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (7.2 g), water (15 ml) and concentrated sulfuric acid (10.2 g) was added dropwise overtime, and the mixture was agitated for 8 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 6.0 g of 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 199°-200° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 333.
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>O>[F:19][C:18]1[C:13]([O:12][CH2:11][C:10]2[CH:20]=[CH:21][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: C1CCOC1
Reactant: Fc1cccnc1OCc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(COc2ncccc2F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
To a tetrahydrofuran (40 mL) solution of 2-(4-bromo-benzyloxy)-3-fluoro-pyridine (2.03 g, 7.20 mmol) described in Manufacturing Example 149-1-1 was added n-Butyl lithium (5.04 mL, 1.6 M hexane solution, 7.92 mmol) under nitrogen atmosphere at −78° C., which was stirred for 45 minutes at −78° C. Then, N,N-dimethylformamide (725 μL, 9.36 mmol) was added to the reaction mixture at −78° C., which was stirred for 1 hour and 10 minutes while the temperature was raised to room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (887 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]2)[CH3:9])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>C(Cl)Cl.CN(C=O)C>[CH:26]1([NH:29][C:17]([C@H:14]2[CH2:13][CH2:12][C@H:11]([CH2:10][N:8]([C:5]3[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=3)[CH3:9])[CH2:16][CH2:15]2)=[O:19])[CH2:28][CH2:27]1
Reactant: CN(C[C@H]1CC[C@H](C(=O)O)CC1)c1ncc(Br)cn1
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.50 g (1.52 mmol) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid in 4.5 mL of CH2Cl2 was treated at RT with 1 drop of DMF followed by 0.14 mL (1.68 mmol, 1.1 eq) of oxalyl chloride within 5 min, and stirring was continued for 90 min. The solution was evaporated, the residue was redissolved in CH2Cl2 and added dropwise to a solution of 2.14 mL (30.47 mmol, 20 eq) of cyclopropylamine in 3 mL of CH2Cl2 at 0° C. The reaction was warmed to RT and left for 3 h, then partitioned between Et2O (×3)/aqueous 10% NaHCO3, washed once with aqueous 10% NaHCO3, dried over Na2SO4 and evaporated to yield 0.55g (99%) of trans-4-{[(5-bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-cyclohexanecarboxylic acid cyclopropylamide, MS: 367 (MH+, 1Br).