Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([C:9]3C=CC(Cl)=C[CH:10]=3)C(N[C:7](=O)[CH:2]12)=O.[C:16]([OH:23])(=[O:22])/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20]>>[C:16]([OH:23])(=[O:22])/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20].[CH3:7][CH2:2][CH2:1][CH2:3][CH2:9][CH3:10]
Reactant: O=C1NC(=O)C2(c3ccc(Cl)cc3)CC12
Agent: O=C(O)/C=C/C(=O)O
Product: CCCCCC

Procedure:
In the above manner 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide (U.S. Pat. No. 3,344,026) is converted to N-[4,4-bis(p-fluoropphenyl)butyl] -1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide, m.p. 98°-99° C. This compound is reduced as in Example 27 and the base is combined with fumaric acid to give 3-(4,4-bis(p-fluorophenyl)butyl]-1-(p-chlorophenyl)-3-azabicyclo]3.1.0]hexane fumarate as colorless crystals, m.p. 152°-154° C.
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[O:7][C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12>CO>[CH3:1][NH:2][C:3]1[C:4](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CO
Product: CNc1ccccc1C(=O)OC

Procedure:
As disclosed by Staiger, J. Org. Chem. (1959), 24, 1214-19, N-methylisatoic anhydride reacts with methanol under alkaline conditions to produce Methyl N-methylanthranilate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(Cl)Cl>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH2:9]2)[O:7][NH:32]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2C(F)(F)F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1C(F)(F)F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 122.4 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.661 g, 1.59 mmol) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.064 g, 1.59 mmol) dissolved in water (0.500 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.098 mL, 1.59 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8 mL, 48.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.748 g, 122%) as a yellow semi-solid. MS m/z 385 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[NH2:1][C:2]1[N:11]=[C:10]([Cl:19])[C:9]2[C:4](=[CH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(=O)[nH]c(N)nc2c1
Product: COC(=O)c1ccc2c(Cl)nc(N)nc2c1
Yield: 92.3 %

Procedure:
A solution of methyl 2-amino-4-oxo-3,4-dihydroquinazoline-7-carboxylate (500 mg, 2.28 mmol) and phosphoryl chloride (4 mL, 42.9 mmol) was stirred at 110° C. for 6 h. The starting material was consumed and the reaction mixture was concentrated to give the crude product (500 mg, 92.2%) as an oil. 1H NMR (300 MHz, DMSO) δ 3.9 (s, 3H), 7.79 (dd, 1H), 8.05 (d, 1H), 8.13 (d, 1H); Analytic LCMS (M+H)+: m/z=238.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.C(N(C(C)C)CC)(C)C>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Yield: 92.3 %

Procedure:
Piperidine (0.80 g, 9.42 mmol) was added to a solution of 3,4-difluoro-nitro benzene (1.0 g, 6.28 mmol) in acetonitrile (15 mL) and diisopropyl ethylamine (1.62 g, 12.57 mmol) and the mixture was refluxed for 3 h. The acetonitrile was removed in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 1-(2-fluoro-4-nitro-phenyl)piperidine (1.3 g, 92%) as a yellow liquid.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11](/[CH:14]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cc2ccccc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Cc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 20.8 %

Procedure:
A mixture of 6-benzyl-pyridine-3-carbaldehyde (4.7 g, 24 mmol) described in Manufacturing Example 210-1-4, nitromethane (7.3 g, 120 mmol), ammonium acetate (5.6 g, 72 mmol), and acetic acid (40 mL) was stirred for 90 minutes at 100° C. The reaction solution was partitioned into ethyl acetate and water. The organic layer was washed with saturated aqueous sodium bicarbonate and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (1.2 g, 21%).
Reaction SMILES: [F:1][C:2]1[C:7]([Li])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].FC1C(F)=C(F)C(F)=C(F)C=1.C([Li])CCC.[C:29](=[O:31])=[O:30]>>[F:1][C:2]1[C:7]([C:29]([OH:31])=[O:30])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: O=C=O
Reactant: [Li]c1c(F)c(F)c(F)c(F)c1F
Agent: Fc1cc(F)c(F)c(F)c1F
Agent: [Li]CCCC
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Up to now, several synthetic reactions for pentafluorophenyl alkali metal salt are known. For example, a method of producing pentafluorophenyllithium through bromine-metal exchange reaction using relatively expensive bromopentafluorobenzene as a starting raw material for a source of pentafluorophenyl group and butyllithium is already known. For example, in Synthesis of Fluoroorganic Compounds, p. 190, Springer-Verlag (1985), pentafluorophenyllithium is prepared in diethylether-hexane at -70° C. and is reacted with sulfur dioxide to give lithium pentafluorophenylsulfenate with 94% yield. Also, a method of producing pentafluorophenyllithium through hydrogen-metal exchange reaction using pentafluorobenzene as a starting raw material for a source of pentafluorophenyl group and butyllithium is already known. For example, in J. Org. Chem., 29, 2385 (1964), pentafluorophenyllithium prepared from pentafluorobenzene and butyllithium is reacted with carbon dioxide gas to give pentafluorobenzoic acid wherein the reaction yield is unknown, but the purification yield, depending on reaction solvent system, is 68% in diethylether-hexane system, 80.9% in diethylether type and 82% in diethylether-tetrahydrofuran system respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C1C(=O)N([Br:47])C(=O)C1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:47])=[CH:11][C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a solution of 1-(4-benzyloxy-3-methyl-phenyl)-ethanone (12.89 g; 53.1 mmol) in CH2Cl2 was added, dropwise, at 0° C., DIPEA (10.9 mL; 63.7 mmol) and trimethylsilyl trifluoromethanesulfonate (11.1 mL; 61.1 mmol). The resulting mixture was stirred at 0° C. for 1 hour, and subsequently, NBS (10.87 g; 61.1 mmol) was added in one portion. The mixture was allowed to warm to RT stirred overnight. Then the mixture was concentrated in vacuo, the residue dissolved in EtOAc, washed with water twice, and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford 1-(4-benzyloxy-3-methyl-phenyl)-2-bromo-ethanone (11.90 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][O:27][C@H:28]([CH3:37])[C:29](N3CCOCC3)=[O:30])=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C[O:41]CC1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1[N:3]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][O:27][C@H:28]([CH3:37])[C:29]([OH:41])=[O:30])=[CH:24][CH:25]=2)[C:4]2[C:9]([C:10]=1[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)c2c(C)n(-c3ccc(CO[C@H](C)C(=O)N4CCOCC4)cc3)c3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)c2c(C)n(-c3ccc(CO[C@H](C)C(=O)O)cc3)c3ccccc23)cc1

Procedure:
The compound of Example 89-1 (33 mg, 0.06 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N aqueous lithium hydroxide solution (1 ml), followed by stirring under reflux for 10 hours. The mixture was diluted with water and washed with ethyl ether. The aqueous layer was adjusted to around pH 4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (quant.).
Reaction SMILES: [F:1][C:2]1[C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:21][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][N:11]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH2:33]([N:35]([CH2:39][CH3:40])[C:36](Cl)=[O:37])[CH3:34].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:33]([N:35]([CH2:39][CH3:40])[C:36]([NH:14][C:13]1[C:9]([C:7]2[NH:6][C:5]3[CH:21]=[C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:2]([F:1])=[CH:3][C:4]=3[N:8]=2)=[N:10][N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH:12]=1)=[O:37])[CH3:34]
Reactant: CCN(CC)C(=O)Cl
Reactant: Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCCN3CCCCC3)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCCN3CCCCC3)cc2[nH]1
Temperature: 50 °C

Procedure:
130 mg of 3-[5-fluoro-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine are solubilized in 10 mL of tetrahydrofuran and then 372 μl of diethylcarbamoyl chloride and 487 μL of N,N-diisopropylethylamine are added. The reaction medium is heated at 50° C. over night. The solvent is evaporated off under vacuum in a rotary evaporator and the reaction crude is purified by flash chromatography on a 4 g silica cartridge, eluent: 100/0 to 80/20 dichloromethane/methanol. 70 mg of 1,1-diethyl-3-[3-[5-fluoro-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea are isolated in the form of a chestnut-brown oil. Analytical LC/MS: Tr=2.91 min, [M+H]+=542.00 DAD=95%.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]#[N:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Br[CH2:29][Cl:30]>CCCCCC.O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]([CH2:29][Cl:30])([C:26]#[N:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: ClCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCl)CC1
Temperature: 25 °C
Yield: 108.4 %

Procedure:
A solution of 1.42M-BuLi in hexane (7.75 ml) was added dropwise to a stirred solution of diisopropylamine (1.1 g) in tetrahydrofuran (30 ml) at -50° under nitrogen. The solution was warmed to 0°, cooled to -65°, and a solution of 1-tert-butyloxycarbonyl-4-cyanopiperidine (2.1 g) in tetrahydrofuran (20 ml) added dropwise, such that the temperature remained below -65°. The mixture was warmed to ambient temperature, cooled to -65°, and added dropwise to a stirred solution of bromochloromethane (6.47 g), in tetrahydrofuran (10 ml) under nitrogen such that the temperature remained below -65°. The mixture was warmed to ambient temperature, poured into water (20 ml), and extracted with chloroform (3×100 ml). The chloroform extracts were washed with ice-cold 0.011M-potassium hydrogen sulphate solution (1000 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), dried (MgSO4), and evaporated under reduced pressure to give an oil (2.8 g) which slowly crystallised. The solid was purified by trituration with hexane, chromatography (SiO2 ; Et2O) and recrystallisation from diethyl ether-hexane to give the title compound (1.02 g), m.p. 114.5°-115.5°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C([N:27]1[CH2:30][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][N:33]=2)[CH2:28]1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:27]2[CH2:28][CH:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([I:38])=[CH:34][N:33]=3)[CH2:30]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Ic1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)nc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(I)cn2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
4-nitrophenyl chloroformate (692 mg g, 3.44 mmol) was added to a stirred solution of 2-(1-Benzhydryl-azetidin-3-yloxy)-5-iodo-pyridine (1.01 g, 2.29 mol) in dichloromethane (40 mL) at ambient temperature. The resulting solution was stirred at ambient temperature for 18 hr. The solvent was removed in vacuo and the product purified by flash chromatography on silica gel (25 g) eluting with dichloromethane to afford the title compound as a colourless solid (474 mg, 47%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]([C:26]([F:29])([F:28])[F:27])=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O.Cl>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:16]([C:26]([F:29])([F:27])[F:28])=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)c(CN2CCCCC2)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
Methyl 2-[(phenylmethyl)oxy]-4-(1-piperidinylmethyl)-5-(trifluoromethyl)benzoate (may be prepared as described in Description 52; 232 mg, 0.57 mmol) was dissolved in tetrahydrofuran (4 ml) and LiOH (38.8 mg, 1.62 mmol) and water (1 ml) were added. The mixture was heated at 40° C. for 2 hours. The mixture was cooled and 2M hydrochloric acid (0.84 ml, 1.69 mmol) was added and the solvent removed in vacuo to give the title compound as oil. 223 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](/[C:9](/[NH:16][CH2:17][CH2:18][OH:19])=[CH:10]/[C:11]([O:13]CC)=O)=[CH:7][CH:6]=[C:5]([O:20][CH3:21])[N:4]=1.C[Si]([N:26]=[C:27]=[S:28])(C)C>CC1OCCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[N:16]([CH2:17][CH2:18][OH:19])[C:27](=[S:28])[NH:26][C:11](=[O:13])[CH:10]=2)=[CH:7][CH:6]=[C:5]([O:20][CH3:21])[N:4]=1
Reactant: CCOC(=O)/C=C(\NCCO)c1ccc(OC)nc1OC
Reactant: C[Si](C)(C)N=C=S
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCO)c(OC)n1
Temperature: 80 °C
Yield: 15.2 %

Procedure:
To a solution of (Z)-ethyl 3-(2,6-dimethoxypyridin-3-yl)-3-((2-hydroxyethyl)amino)acrylate (100 mg, 0.34 mmol) in 2-MeTHF (1.0 mL) was added (trimethylsilyl)isothiocyanate (0.30 mL, 2.0 mmol) and the reaction mixture was heated at 80° C. for 4 hours. The cooled reaction mixture was diluted with EtOAc and washed with a saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was concentrated in vacuo. The residue was triturated with MeOH and the resulting solids were collected by vacuum filtration to give the title compound (16 mg, 16%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16].C(OCC)C>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:1]([O:8][C:9]([NH:12][CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(CN)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 41.7 ml of chloroformic acid benzyl ester (90%) in toluene is added to 25 g of 3-amino-2(R,S)-methylpropionic acid in 533 ml of 1N sodium hydroxide at 0° C. The reaction mixture is then stirred for 30 minutes at 0° C. After the addition of 400 ml of diethyl ether, the aqueous phase is removed and 140 ml of 4N hydrochloric acid are added. The crude title compound is obtained from the organic phase by extraction with diethyl ether: Rf (dichloromethane/methanol=8:2)=0.41.
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:6]=1[CH2:7]Br.C([O-])(O)=O.[Na+]>O.CN(C)C=O>[F:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:6]=1[CH2:7][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1cc(F)c(CBr)c(F)c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)c(CC#N)c(F)c1
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
A solution of KCN (0.88 g, 13 mmol) dissolved in water (2 mL) was added dropwise to a water-bath-cooled solution of 2,6-difluoro-4-methoxybenzyl bromide (2.50 g, 10.5 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 20 min. Water was added (20 mL) and then the reaction mixture was poured into saturated aqueous NaHCO3 solution (20 mL) and extracted with ether (50 mL). The organic phase was washed with water (5×25 mL), dried over MgSO4, and concentrated to give an oil, which crystallized on standing to provide the title compound as a white solid (1.9 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH2:18])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:39])[N:22]([C:27]2[C:28]([CH3:38])=[CH:29][C:30]([F:37])=[C:31]([CH:36]=2)[C:32]([O:34][CH3:35])=[O:33])[CH:23]=[C:24]([Br:26])[N:25]=1.CCN(C(C)C)C(C)C>O1CCOCC1.Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:20]2[C:21](=[O:39])[N:22]([C:27]3[C:28]([CH3:38])=[CH:29][C:30]([F:37])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])[CH:23]=[C:24]([Br:26])[N:25]=2)[CH2:17][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-n2cc(Br)nc(Br)c2=O)c(C)cc1F
Reactant: NC1(c2ccccc2OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c(C)cc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 111.8 %

Procedure:
A solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (1.026 g) in dioxane (10 mL) was treated with methyl 5-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-2-fluoro-4-methylbenzoate (Example 318d, 1.500 g) and Hunig's Base (0.936 mL) under nitrogen. The resulting solution was stirred at 100° C. for 16 h. The cooled mixture was diluted with 2 M HCl and extracted with diethyl ether. The combined organics were dried (MgSO4) and evaporated to afford the subtitle compound (2.310 g) as a foam.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=2.Cl.[CH3:32][NH:33][CH3:34].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[CH3:32][N:33]([CH3:34])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH2:21][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:23]=1
Reactant: CNC
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.2 %

Procedure:
A solution of 60 mg (0.139 mmol) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzoic acid (example 31) in 1 mL of THF was treated with 31 mg (0.417 mmol) of dimethylamine hydrochloride, 0.09 mL (0.834 mmol) of N-methylmorpholine, 3.7 mg (0.028 mmol) of HOBT, and 37 mg (0.195 mmol) of EDCI. The mixture was stirred for 10 hrs at RT and the solvent evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 to 1:1 yielded 39 mg (60%) of N,N-dimethyl-3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzamide, colorless solid, MS: 459 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:20])[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:14])(C)(C)C>FC(F)(F)C(O)=O>[CH2:18]([O:17][C:15]([CH:13]([CH3:14])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:21])=[O:5])=[O:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)C(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
The ester obtained in Example 2 (5.9 g.) is dissolved in trifluoroacetic acid, the solution is kept at room temperature for one hour, and then concentrated to dryness in vacuo. The residue is dissolved in a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase is acidified and extracted with ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate and concentrated to dryness in vacuo to obtain 1-(2-ethoxycarbonylpropanoyl)-L-proline, yield 4.1 g.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>ClCCl>[O:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:14](=[O:17])[CH2:15][CH3:16])[CH2:3]1
Reactant: CCC(=O)Cl
Reactant: NC1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CCOC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 50 g of 3-aminotetrahydrofuran in 200 ml of dichloromethane was mixed with 63.8 g (0.63 mol) of triethylamine. 58.4 g (0.63 mol) of propionyl chloride were added dropwise with ice-cooling. The mixture was stirred at room temperature for 2 days, resulting in a white precipitate. The solution was filtered and the filtrate was distilled. B.p. 145° C. (12 mm), yield 81 g. 1H NMR (270 MHz, in CDCl3): δ=1.14 (t, 3 H), 1.83 (m, 1H), 2.22 (q, 2H), 2.31 (m, 1H), 3.64 (dd, 1H), 3.72-3.98 (m, 3H), 4.50 (m, 1H), 6.57 (s, 1H).