Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][C@H:20]1[CH2:29][O:30][CH2:31][C:32]([OH:34])=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([N:37](CC)CC)C.O.N>O1CCCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][C@H:20]1[CH2:29][O:30][CH2:31][C:32](=[O:34])[NH2:37])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
A solution of isobutyl chloroformate (9 ml) in tetrahydrofuran (20 ml) was dropwise added to a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-methanesulfonyloxypyrrolidine (24.85 g) and triethylamine (10.75 ml) in tetrahydrofuran (120 ml) at -10°~-5° C. and the mixture was stirred at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (250 ml) at 0°-5° C. and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with water (200 ml×3), 1N hydrochloric acid (300 ml×2), saturated sodium hydrogen carbonate (300 ml) and brine in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (250 g) and eluted with a mixture of methanol and chloroform (2:98 and then 4:96 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-carbamoylmethyloxymethyl-4-methanesulfonyloxypyrrolidine (15.52 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)[S:9][CH:10]=1)C.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.NC1C=CC=CC=1.C[Al](C)C>>[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:4](=[O:3])[CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]4)=[C:14]([O:24][CH3:25])[CH:13]=3)[S:9][CH:10]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)Cc1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: C[Al](C)C
Solvent: Nc1ccccc1
Product: COc1cc(Nc2nc(CC(=O)Nc3ccc(F)cc3)cs2)ccc1-n1cnc(C)c1
Yield: 89 %

Procedure:
The title compound was prepared in analogy to example 27 from 92 mg (0.25 mmol) ({2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetic acid ethyl ester and 98 mg (0.87 mmol) 4-fluoroaniline. After the first addition conversion was not complete. Therefore the same amount of the aniline and trimethylaluminium were added and the reaction was heated again over night. Workup as in example 27 and subsequent purification on silica gel with methylene chloride/methanol 19/1 yielded 95 mg (89%) N-(4-fluoro-phenyl)-2-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-acetamide as a brown oil. MS ISP (m/e): 438.1 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=9.08 (s, 1H), 7.65 (s, 2H), 7.45 (dd, 2H), 7.31 (s, 1H), 7.21 (d, 1H), 7.06-6.88 (m, 3H), 6.51 (s, 1H), 3.80 (s, 3H), 3.73 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pd]>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(=Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Yield: 84.5 %

Procedure:
A solution of 4.00 g of 2-(1-naphthylmethylene)-3-(phenethylcarbamoyl)propionic acid in 120 ml of acetic acid was hydrogenated over 2.0 g of a 10% palladium-charcoal under a hydrogen atmosphere at room temperature. After filtration of the catalyst, the filtrate was evaporated under reduced pressure, and hexane was added to the residue. The precipitated crystals were collected by filtration to obtain 3.40 g of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)-propionic acid as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.S(O)(=O)(=O)C.[C:36]([NH:43][C:44]1([CH2:47]O)[CH2:46][CH2:45]1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>C(#N)C.O1CCCC1>[C:36]([NH:43][C:44]1([CH2:47][O:9][CH:3]2[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]2([CH3:10])[CH3:1])[CH2:46][CH2:45]1)([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]
Reactant: CC1(C)CCC(C)(C)C1O
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CS(=O)(=O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(COC2C(C)(C)CCC2(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2,5,5-Tetramethyl-1-cyclopentanol is added to a dry flask under argon at 0° C. Dry tetrahydrofuran is added with a syringe. Sodium hydride (60% dispersion in oil) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6-ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of N-Boc-1-amino-1-hydroxymethylcyclopropane mesylate is added with vigorous stirring over a 10 minute period. After completion of the reaction, as judged by thin layer chromatography, it is quenched with dimethyl sulfate, poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Boc-O-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-amino-1-hydroxymethylcyclopropane.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)#[N:4].Br[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14]2)#[N:4]
Reactant: CCCCC(Br)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(c1ccc(C(F)(F)F)cc1)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 0 %

Procedure:
Sodium hydride (5 moles, 200 mg of 60% in mineral oil) was added to 5-(2-cyanophenyl)indole (4.6 moles, 1.0 g.) in 50 ml DMF and stirred for 45 minutes. 1-Bromo-1-(4-trifluoromethylphenyl)pentane (5 moles, 1.44 g) was added. The reaction was stirred at room temperature overnight, poured into ice water, and extracted into ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The intermediate was chromatographed over silica gel eluted with 10% ethyl acetate in hexane to yield 820 mg of 5-(2-cyanophenyl)-1-[1-(4-trifluoromethylphenyl)-1-pentyl]indole.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([OH:17])([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:8][CH:7]1[CH3:18])=[O:5])[CH3:2].C1C(=O)N([Br:26])C(=O)C1.O.CCOC(C)=O>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[S:13][C:14]([Br:26])=[CH:15][N:16]=2)([OH:17])[CH2:8][CH:7]1[CH3:18])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1CCC(O)(c2nccs2)CC1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(O)(c2ncc(Br)s2)CC1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of the product of Step 1 (20 g, 74.3 mmol) in DMF (140 mL) was added NBS (15.9 g, 89 mmol). After the initial exotherm had subsided the reaction mixture was heated to 50° C. and stirred for 1 h. It was then cooled to room temperature and water (280 mL containing 7 g of sodium sulfite) was added followed by EtOAc. The layers were cut and the aqueous layer was back extracted with EtOAc (2×), and then the combined organics washed with H2O. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to afford 4-(5-bromo-thiazol-2-yl)-4-hydroxy-2-methyl-cyclohexanecarboxylic acid ethyl ester (20 g, 57.4 mmol), MS ESI: [M+H]+ m/z 347.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5](I)=[CH:4][N:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.CN(C)[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu](I)I.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][N:3]=1
Reactant: c1c[nH]cn1
Reactant: Nc1ncc(I)cc1C=O
Agent: I[Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Nc1ncc(-n2ccnc2)cc1C=O
Temperature: 25 °C

Procedure:
300 mg (1.210 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 24 mg (3.629 mmol) of imidazole are dissolved in ml of DMSO in a nitrogen-filled microwave vessel. 51.6 mg (0.363 mmol) of trans-N,N-dimethyl-1,2-cyclohexanediamine, 69.1 mg (0.363 mmol) of copper iodide, 523.8 mg (2.468 mmol) of K3PO4 and 5 ml of toluene is added. The reaction mixture is irradiated with microwaves for 2 hours at 150° C. The reaction mixture is cooled to room temperature, filtered off, and the solvent is removed. Water/ethyl acetate is added to the residue. The organic phase is separated, and the aqueous phase is extracted a further 2× with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, and the solvent is removed, giving 2-amino-5-imidazol-1-ylpyridine-3-carbaldehyde; HPLC-MS [M+H]+ 189.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)o1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (94 mg, 0.179 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as a white solid (30 mg, 33%). 1H-NMR (DMSO-d6): δ ppm 10.34 (brs, 1H), 8.18-8.19 (d, J=5.2 Hz, 1H), 7.65 (brs, 1H), 7.30-7.34 (t, J=7.4 Hz, 2H), 7.21-7.24 (m, 3H), 6.56 (brs, 2H), 6.45 (d, J=5.2 Hz, 1H), 1.40 (s, 9H); MS: 504 [M+H]+.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]1[C:19]2[N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[N:16]([CH2:29][CH2:30][O:31][CH3:32])[C:15]=2[C:14]([O:33][CH3:34])=[CH:13][C:12]=1[CH2:35][O:36]S(C)(=O)=O>CN(C=O)C>[Br:10][C:11]1[C:19]2[N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[N:16]([CH2:29][CH2:30][O:31][CH3:32])[C:15]=2[C:14]([O:33][CH3:34])=[CH:13][C:12]=1[CH2:35][O:36][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COc3ccccc3)cc(OC)c21
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a cooled solution (ice bath) of phenol (7.2 mg, 0.077 mmol) in 1 ml DMF, NaH (3.1 mg, 0.077 mmol, 60% in mineral oil) is added and the reaction is warmed to RT. Methanesulfonic acid 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-ylmethyl ester (30 mg, 0.059 mmol) is added and the reaction mixture is heated to 60° C. for 1 h. After that the reaction mixture is extracted with sat. NaHCO3-solution and diethyl ether. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 28 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[CH:23]=[O:24])([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:23][OH:24])([CH3:7])[CH3:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)cc1CO
Yield: 84.5 %

Procedure:
2-(4-Benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (185 g, 540 mmol) in ethanol (700 mL) was treated with 10% Pd/C (205 g) and hydrogen (60 psi) at 50° C. for 2 d. The mixture was filtered through Celite, washed with ethanol (1.5 L), and concentrated. The residue was recrystallized from EtOAc/hexanes to give the title compound (116 g). 1H NMR (400 MHz, CDCl3) δ 1.26 (t, 3H, J=7.3 Hz), 1.52 (s, 6H), 2.14 (s, 3H), 4.23 (q, 2H, J=7.3 Hz), 4.59 (brs, 2H), 6.61-6.68 (m, 2H), 6.77 (d, 1H, J=2.8 Hz).
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[OH-].[K+]>C1C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]#[C:5][C:4]#[CH:3])=[CH:8][CH:9]=1
Reactant: COc1ccc(C#CC#CC(C)(C)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C#CC#Cc1ccc(OC)cc1
Yield: 105.2 %

Procedure:
1500 mg of the diacetylene compound obtained were then dissolved in 300 ml of benzene, and 600 mg of potassium hydroxide, which were finely ground, was then added to the reaction mixture, followed by reflux under heating for 30 minutes. After filtration, the solvent was evaporated, and the residue was then purified by silica-gel chromatrgaphy using hexane as an eluent to obtain 1150 mg of 1-(4-methoxyphenyl)-1,3-butadiyne. This compound was a slightly yellowish white crystal.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.[CH3:54][O:55][C:56]1([CH3:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:59]1[CH2:60][CH2:61][C:56]([O:55][CH3:54])([CH3:62])[CH2:57][CH2:58]1)=[O:30]
Reactant: COC1(C)CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1(C)CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.597 g, 1.57 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.188 g, 0.63 mmol) and triethylamine (0.193 mL, 1.39 mmol) in N,N-dimethylformamide (2 mL) at ambient temperature under an air atmosphere. The resulting solution was stirred at 25° C. for 15 minutes. A solution of 4-methoxy-4-methylpiperidine (23) (89.5 mg, 0.69 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution was stirred at 25° C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, s), 1.25-1.34 (1H, m), 1.42 (1H, td), 1.56 (1H, d), 1.75 (1H, dd), 3.10-3.18 (4H, m), 4.09 (3H, q), 4.32 (2H, s), 7.21 (1H, t), 7.31 (1H, dd), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, dd), 8.27 (1H, dd), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=1.79 (M+H 409).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:30]=[C:29]([NH:31][C:32](OC2C=CC=CC=2)=[O:33])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32](=[O:33])[NH:31][C:29]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([F:20])[CH:30]=3)=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1F
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (321 mg, 1.03 mmol, 1.0 eq) in DCM (10 mL) was added TEA (0.28 mL, 0.26 mmol, 2.0 eq) followed by methyl 2-fluoro-4-(phenoxycarbonylamino)benzoate (300 mg, 1.03 mmol, 1.0 eq) at RT and stirred for 16 h. Then the reaction mixture was evaporated, diluted with water (50 mL) and extracted with ethyl acetate (2×70 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified CC using EtOAc/PE (2:3) as eluent to obtain methyl 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoate (300 mg; 63%) as a white solid (TLC: EtOAc/PE (1:1); Rf: 0.3).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>C1COCC1>[CH3:7][N:6]1[C:2]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)C1CCOCC1
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A clear colorless solution of 5-bromo-1-methyl-1H-imidazole (1.12 g, 6.93 mmol) in THF (10 mL) was placed in an ice bath and ethylmagnesium bromide (3.0 M in Et2O, 2.31 mL, 6.93 mmol) was added via syringe. The reaction mixture was stirred for 20 minutes at room temperature. N-Methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (1.0 g, 5.8 mmol, Intermediate 1: step a, Procedure A) was added neat by syringe (using 1 mL THF rinse to quantitate transfer), and the resulting white suspension was stirred at room temperature for 2 days. The mixture was diluted with saturated aqueous NH4Cl followed by water, then was extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography two times (1-4% MeOH-DCM first column; 40-60% CH3CN-DCM second column) to provide the title compound as a white crystalline solid.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([S:17](Cl)(=[O:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][C@H:23]([C@H:26]1[O:30][C:29](=[O:31])[C@H:28]([CH:32]([CH3:34])[CH3:33])[CH2:27]1)[CH2:24][OH:25].O1CCCC1>O>[OH:25][CH2:24][C@H:23]([NH:22][S:17]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=1[N+:14]([O-:16])=[O:15])(=[O:19])=[O:18])[C@@H:26]1[CH2:27][C@@H:28]([CH:32]([CH3:34])[CH3:33])[C:29](=[O:31])[O:30]1
Reactant: CC(C)[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 12 h
Yield: 62 %

Procedure:
14 ml of triethylamine (101 mmol) and 11.12 g of O-nitrobenzenesulfonyl chloride (50.1 mmol) were added to a solution of 8.50 g of (3S,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-isopropyldihydrofuran-2-one hydrochloride obtained in the above reaction (33.5 mmol) in a mixed solvent of tetrahydrofuran (170 ml) and water (17 ml) at room temperature, and the mixture was stirred at the same temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate). Further, 110 ml of diisopropyl ether and 11 ml of ethyl acetate were added, and the precipitated solid was collected by filtration to obtain 8.78 g of the title compound (total yield over two steps: 70%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:4][CH2:3]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:4][CH2:3]1
Reactant: CC1CCN(Cc2cccc(OCCCN)c2)CC1
Reactant: Nc1nnc(Br)s1
Product: CC1CCN(Cc2cccc(OCCCNc3nnc(N)s3)c2)CC1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(4-methyl-1-piperidinyl)methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[C:29](#[N:32])[CH:30]=[CH2:31]>C(O)(C)C>[C:29]([CH2:30][CH2:31][N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)#[N:32]
Reactant: C=CC#N
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Product: N#CCCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 95 °C

Procedure:
A solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (15 g, 0.049 mole) and acrylonitrile (5.2 g, 0.098 mole) in isopropanol (50 ml) was stirred at reflux (95° C.) for twenty hours. The reaction mixture was cooled then concentrated to an oil (17 g, 96%) of which 3.5 g was distilled to an oil of 3-(2-cyanoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine (2.6 g, 235°-237° C./0.1 mm).