Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Br:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Br:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(Br)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: O=CCC1Cc2ccc(Br)cc2C1=O
Reaction time: 1 h
Yield: 80 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 9.86 g of (RS)-2-(2-buten-1-yl)-6-bromo-1-indanone in 150 ml of anhydrous dichloro-methane and 30 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.09 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 1 50 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. The crude product obtained was recrystallized from ethyl acetate/hexane. 7.5 g (80%) of (RS)-2-(2-oxoethyl)-6-bromo-1-indanone were obtained as a light yellow solid with m.p. 84°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]#N)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([Mg]Br)[CH:23]=1.Cl.[OH-:29].[Na+]>C1COCC1.C(Cl)Cl.O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([C:15]([C:3]2[C:2]([F:1])=[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[CH3:14])[CH:6]=[CH:5][N:4]=2)=[O:29])[CH:23]=1
Reactant: Cc1ccncc1-c1ccnc(C#N)c1F
Reactant: [OH-]
Reactant: COc1ccc(F)cc1[Mg]Br
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1nccc(-c2cnccc2C)c1F
Temperature: 25 °C
Yield: 48 %

Procedure:
To a solution of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile (0.031 g, 0.145 mmol) in THF (Volume: 0.727 ml) cooled to 0° C. was added (5-fluoro-2-methoxyphenyl)magnesium bromide (0.727 ml, 0.363 mmol). The reaction mixture was allowed to stir at room temperature. Water and ice were carefully added, followed by acidification with 6 M HCl. After stirring for 1 hr, CH2Cl2 was added and the pH was adjusted to 8.5 with aqueous 4 M NaOH. The layers were separated. The aqueous phase was extracted with CH2Cl2 (5×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a purple residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 60-100% EtOAc in hexanes over 18 min, tr=9 min) gave the title compound (0.024 g, 0.070 mmol, 48.0% yield) as an orange residue. ESI MS (M+H)+=340.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]([CH3:12])=[O:11])[C:5]([CH3:13])=[C:4]2[CH2:14][CH2:15][C@:16]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][C@@H:27]([CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23])([CH3:18])[O:17][C:3]=12.[CH3:35][CH:36]1[C:42]([CH3:43])=[C:41]([OH:44])[CH:40]=[C:39]([CH3:45])[C:37]1([CH2:46][C:47]([O-:49])=[O:48])[OH:38].[CH3:50][CH:51]([CH2:53][CH2:54][CH2:55][C@H:56]([CH2:58][CH2:59][CH2:60][C@H:61]([CH2:63][CH2:64][CH2:65]/[C:66](=[CH:68]/CO)/[CH3:67])[CH3:62])[CH3:57])[CH3:52].[CH3:71]C(CCCC(CCCC(CCCC(O)(C=C)C)C)C)C>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]([CH3:12])=[O:11])[C:5]([CH3:13])=[C:4]2[CH2:14][CH2:15][C@:16]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][C@@H:27]([CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23])([CH3:18])[O:17][C:3]=12.[CH2:43]([C:42]1[CH:36]([CH3:35])[C:37]([CH2:46][C:47]([O-:49])=[O:48])([C:39]([CH3:45])=[C:40]([CH3:71])[C:41]=1[OH:44])[OH:38])/[CH:50]=[C:51](/[CH2:53][CH2:54][CH2:55][C@@H:56]([CH2:58][CH2:59][CH2:60][C@@H:61]([CH2:63][CH2:64][CH2:65][CH:66]([CH3:68])[CH3:67])[CH3:62])[CH3:57])\[CH3:52]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC1=CC(O)=C(C)C(C)C1(O)CC(=O)[O-]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Product: CC1=C(C)C(O)(CC(=O)[O-])C(C)C(C/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C1O

Procedure:
The object is achieved by a new approach to the manufacture of α-tocopheryl acetate (TCPA). According to this approach, 2,3,6-trimethylhydroquinone-1-acetate (TMHQA) is reacted with either phytol (PH), isophytol (IP) or an (iso)phytol derivative to produce TCPA or 3-phytyl-2,5,6-trimethylhydroquinone-1-acetate (PTMHQA), whereupon the latter is submitted to ring closure to obtain TCPA.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C([O-])(=O)C.[NH4+].C(O)(=O)C.[C:15]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=O)[CH:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1.O>[C:3]([C:2]([C:1]#[N:5])=[C:15]([CH:16]([CH3:18])[CH3:17])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:4]
Reactant: N#CCC#N
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=C(C#N)C#N)C(C)C

Procedure:
1.2 30 g of malononitrile, 3.3 g of ammonium acetate and 4 ml of acetic acid are added to a solution of 55 g of ethyl 2-(isobutyryl)acetate (“AA”) in 210 ml of toluene, and the mixture is boiled at 130° for 1 hour on a water separator. Conventional work-up gives 41.0 g of ethyl 4,4-di-cyano-3-isopropylbut-3-enoate (“AB”), boiling point 95-99° at 0.4 mbar.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:22]3[C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[O:25][C:21]=3[CH:20]=2)[CH:15]=[CH:16][CH:17]=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>C1COCC1.CCOC(C)=O>[Br:11][C:12]1[CH:13]=[C:14]([N:18]([C:19]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:22]3[C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[O:25][C:21]=3[CH:20]=2)[S:44]([CH3:43])(=[O:46])=[O:45])[CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(Nc3cccc(Br)c3)c(C3CC3)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 37.5 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1 M in THF) (1.93 mL, 1.93 mmol) was added dropwise to a solution of ethyl 6-((3-bromophenyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (734 mg, 1.48 mmol) in THF (10 mL) at −78° C. The mixture was stirred for 45 minutes and then a solution of methanesulfonyl chloride (0.463 mL, 5.94 mmol) in THF (1.5 mL) was added at −78° C. After complete addition the reaction mixture was allowed to warm to room temperature overnight. Water and EtOAc were added. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane:EtOAc) to give ethyl 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (318 mg, 37%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (s, 1H) 8.03-8.13 (m, 2H) 7.62-7.66 (m, 1H) 7.59 (s, 1H) 7.43 (s, 4H) 7.30-7.39 (m, 1H) 4.26-4.41 (m, 2H) 3.42 (s, 3H) 2.12-2.26 (m, 1H) 1.28-1.37 (m, 3H) 0.71-1.14 (m, 4H) 0.41 (m, 1H). %). LCMS (m/z, ES+)=572, 574 (M+H, M+2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:46])[CH:43]([CH3:45])[CH3:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:42](=[O:46])[CH:43]([CH3:45])[CH3:44])[C:10]([C:20]3[CH:21]=[C:22]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2CCOCC2)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCOCC2)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)C(C)C
Reaction time: 12 h

Procedure:
To a solution of 4-{3-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-4-methoxy-benzyl}-morpholine (100 mg, 0.20 mmol, as in the U.S. Provisional applications incorporated by reference herein, Example 31) in methylene chloride (10 mL) were sequentially added triethylamine (0.10 mL, 0.712 mmol) and isobutyryl chloride (42 μL, 0.392 mmol). The reaction mixture was stirred for 12 h. The solvents were removed under reduced pressure. Saturated sodium bicarbonate (2 mL) and methylene chloride (20 mL) were added and the layers were separated. The aqueous layer was extracted with methylene chloride (1×100 mL). The combined organic extracts were evaporated. Purification of the crude residue by Biotage flash chromatography eluting with 0-5% methanol in ethyl acetate gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2-methoxy-5-morpholin-4-ylmethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C31H34N3O3Cl2[(M+H)+]566.1972, observed 566.1977.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.N1(C2CCCCCCCCCC2)CCCCCC[CH2:15][CH2:14][CH2:13]N1.[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34]>C1C=CC=CC=1>[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:3]2[C:4]([C:8]([O:10][CH:14]([CH3:15])[CH3:13])=[O:9])=[C:5]([CH3:7])[N:6]=[C:2]2[Br:1])=[CH:38][CH:37]=1)([O-:35])=[O:34]
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Reactant: Cc1nc(Br)[nH]c1C(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: c1ccccc1
Product: Cc1nc(Br)n(Cc2ccc([N+](=O)[O-])cc2)c1C(=O)OC(C)C
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 2 g (8.1×10-3 moles) of i-propyl ester of 2-bromo-4-methyl-5-imidazolecarboxylic acid in 20 ml of benzene was added 1.2 ml (8.1×10-3 moles) of diazabicycloundecane, followed by 1.7 g (8.1×10-3 moles) of p-nitrobenzylbromide. The resulting mixture was heated to reflux overnight, cooled to room temperature and filtered. Concentration in vacuo gave a golden oil. This residue was purified by medium pressure liquid chromatography on silica gel to yield 2.1 g (70%) i-propyl 1-(4-nitrobenzyl)-2-bromo-4-methyl-5-imidazolecarboxylate as a yellow oil and 600 mg (20%) of the desired product, i-propyl 2-bromo-3-(4-nitrobenzyl)-4-methyl-5-imidazolecarboxylate also a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([OH:24])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].IC.[OH2:29].[CH3:30]N(C)P(=[O:39])(N(C)C)N(C)C>>[C:22]([OH:24])(=[O:23])[C:9]([OH:39])=[O:29].[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([O:24][CH3:30])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
70 Parts of 4-[(4-fluorophenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylic acid are dissolved in 450 parts of dry hexamethylphosphoric triamide at 120° C. This solution is cooled to room temperature and 6 parts of sodium hydride dispersion 78% are added portionwise at a temperature below 30° C. After stirring for 1.50 hours at room temperature, there are added dropwise 32.5 parts of iodomethane at a temperature below 15° C. Upon completion, stirring is continued for 28 hours at room temperature. The reaction mixture is poured onto 800 parts of water and the product is extracted with methylbenzene. The extract is washed successively with water, a 10% sodium hydroxide solution and again twice with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off and crystallized from 2-propanol, yielding methyl 4-[(4-fluorophenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylate ethanedioate; mp. 168.6° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[N:22][CH:23]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[N:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cn2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cn2)CCN1
Yield: 91.9 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-({5-[({4-[(3-fluorophenyl)amino]-1-piperidinyl}carbonyl)(methyl)amino]-2-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate (D62) (320 mg, 0.593 mmol) in DCM (16 ml) and TFA (4 ml) was stirred at room temp for 2 h. The solvent was removed in vacuo and the residue was taken up in MeOH, and loaded onto an Isolute SCX cartridge which was eluted with MeOH then 2M NH3 in MeOH. The ammoniacal fraction was concentrated to give the crude product as a yellow oil. Column chromatography eluting with 0-10% (2M NH3 in MeOH)/DCM gave the title compound as a pale yellow oil (240 mg). MS (ES) MH+ 441.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:10])[CH3:2].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:10][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:2]
Reactant: CCOC(=O)CCNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)[C@H](Cc1ccccc1)NCC(=O)OCC
Temperature: 60 °C
Yield: 80.4 %

Procedure:
Phenylalanyl-β-alanine ethyl ester (10 g, 0.038 mol) and triethylamine (10.3 g, 0.1 mol) were suspended in toluene (45 g), and the suspension was heated to 60° C. To the resultant suspension, ethyl bromoacetate (9.3 g, 0.057 mol) suspended in toluene (5 g) was added dropwise over 0.5 hours, and then the resultant mixture was stirred for three hours. After completion of reaction, the resultant reaction mixture was subjected to extraction with ethyl acetate (20 g). The organic layer was washed with a 2.5% aqueous solution of citric acid. Subsequently, the solvent was removed, to thereby obtain N-(carboethoxymethyl)phenylalanyl-β-alanine ethyl ester (10.7 g, yield: 80.3%). The compound was dissolved in methanol, and a 48% aqueous solution of sodium hydroxide (6.6 g, 0.08 mol) was added to the methanol solution, and the resultant mixture was stirred for three hours. After completion of reaction, the solvent was removed, and the resultant residue was dissolved in water (20 mL), and then washed with ethyl acetate (10 g). Subsequently, hydrochloric acid was added to the aqueous layer, so as to attain a pH of 3.5. After being cooled, the resultant solution was subjected to filtration, to thereby obtain crude crystals. The crystals were recrystallized from a 20% aqueous solution of isopropyl alcohol, to thereby obtain compound 1 (6.0 g, yield: 67%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(Cc3ccccc3)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Cc3ccccc3)c2)CC1
Yield: 96.2 %

Procedure:
A mixture of 74 mg (0.21 mmol) of 1-tert-butoxycarbonyl-4-((3-benzyl)phenyl)-1,2,3,6-tetrahydropyridine (from Step D) and 6 mg of 10% palladium on carbon in 1 mL of EtOAc and 3 mL of MeOH was hydrogenated at 40 psi of hydrogen on a Parr shaker for 3 hours. The reaction was filtered and concentrated under reduced pressure to yield 71 mg (95%) of the title compound, which was used without further purification. 1H NMR (500 MHz, CDCl3) δ1.43-1.83 (m, 13H), 2.62 (m, 1H), 2.80 (m, 2H), 3.99 (s, 2H), 4.25 (m, 2H), 7.06-7.33 (m, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([C:15]#N)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2].C(O)(=[O:21])C.N1C=CC=CC=1>[Ni].O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH:15]=[O:21])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)Cc1c(C)oc2ccc(C#N)cc12
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1c(C)oc2ccc(C=O)cc12
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of (5-cyano-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (4.31 g, 17.7 mmol), NaPH2O2.H2O (14.99 g, 141 mmol) and Raney nickel (3.06 g, 35.4 mmol) in a mixture of water (50 mL), acetic acid (50 mL) and pyridine (100 mL) is heated for 2 h at 100° C. under an argon atmosphere. After cooling to room temperature the reaction mixture is filtered over hyflo and the filtrate concentrated by rotary evaporation. The residue is partitioned between water and TBME, the layers are separated and the aqueous phase is extracted with TBME. The combined organic layers are washed with a 1 M aqueous HCl solution, a saturated aqueous NaHCO3 solution and brine. After drying over Na2SO4 and evaporation of the solvent in vacuo the crude product is obtained as a brown oil. Further purification by flash column chromatography (silica gel gradient of cyclohexane/EtOAc 100:0 to 6:1) affords the title compound as colorless crystals (2.59 g, 10.5 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=10.08 (s, 1H), 8.07 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.49 (s, 3H), 1.27 (t, J=7.1 Hz, 3H). MS (ES+): 247 (M(C14H14O4)+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[C:47]([CH3:49])[N:46]=[C:45]([CH3:50])[CH:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[CH:44]=[C:45]([CH3:50])[N:46]=[C:47]([CH3:49])[CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2cc(C)c(Cl)c(C)c2)cc(C)n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cc(C)nc(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-chloro-3,5-dimethyl-phenyl)-2,6-dimethyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.10 min; Mass spectrum (ESI+): m/z=552 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])C=1C#N.[CH3:11][Mg]Br.C([O:16][CH2:17][CH3:18])C>>[CH3:11][C:17]([C:18]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10])=[O:16]
Reactant: C[Mg]Br
Reactant: CCOCC
Reactant: N#Cc1c(F)cccc1F
Product: CC(=O)c1c(F)cccc1F
Temperature: 35 °C

Procedure:
2,6-Difluorobenzonitrile (20.0 g, 0.14 mol) is dissolved in anhydrous diethyl ether (30 ml) and methyl magnesium bromide (154 ml of a 2.8 M solution, 0.43 mol) is added. The whole is warmed to reflux (35° C.) overnight (16 hrs.). Then the reaction mixture is quenched in ice-water (150 ml). The resultant mixture is heated to 75° C. for 3 hours and cooled. Pure product is then extracted from the mixture using methylene chloride (17.2 g, 76.7%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4][CH2:3]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[C:21]1([NH:27][C:28]([NH:1][CH:2]2[CH2:20][C:6]3[C:7]4[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=4[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=3[CH2:4][CH2:3]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
The product of Example 15 (0.15 g, 0.5 mmol), phenylisocyanate (0.1 g, 1 mmol) and triethylamine (0.1 g) in 5 mL dimethylformamide were stirred at room temperature for 18 h. The solvent was removed by rotoevaporation and the residue suspended in methanol/dimethylformamide. After heating, the solid was collected by filtration and dried in vacuo. CHN calc'd for C19H17N5O5.0.5H2O.HCON(Me)2 : C, 55.34; H, 5.27: N, 17.60 found-C, 55.38: H, 4.95; N, 17.04. H-NMR (400 MHz, dmso) 1H, s, 12.1; 1H, s, 11.45; 1H, s, 8.4; 1H, s, 7.95; 1H, s, 7.7; 2H, d, 7.4; 2H, t, 7.23; 1H, t, 6.9 1H, d, 6.35; 1H, t, 4.1; +ring protons.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][N:4]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[C:30]1(=O)[CH2:33][CH2:32][CH2:31]1.C[Si](C)(C)[C:37]#[N:38]>ClCCCl>[S:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[S:9]([N:7]1[CH2:6][CH2:5][N:4]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:29])([CH3:28])[C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=2)[C@@H:3]([CH2:2][NH:1][C:30]2([C:37]#[N:38])[CH2:33][CH2:32][CH2:31]2)[CH2:8]1)(=[O:10])=[O:11]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCC1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN)cc1)C(F)(F)F
Solvent: ClCCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNC2(C#N)CCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
A 5-mL vial was charged with 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.202 g, 0.448 mmol, Example 192, Step 2), cyclobutanone (0.0364 g, 0.519 mmol, Alfa Aesar, Ward Hill, Mass.) and 1,2-dichloroethane (2.5 mL). The solution was stirred at room temperature for 20 min then trimethylsilanecarbonitrile (0.120 mL, 0.959 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After stirring at room temperature for 12 h, the material was purified by column chromatography (10 g of silica, 20 to 70% EtOAc in hexanes) to afford 1-((((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)amino)cyclobutanecarbonitrile (0.198 g) as a white solid.