Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH3:15])[C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36][NH2:37])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[C@@H:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:15])[CH:12]([CH3:14])[CH3:13])=[CH:29][CH:28]=1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C1CCCCC1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 358 mg (1.68 mmol) (S)-2-(cyclohexyl-methyl-amino)-3-methylbutyric acid, 0.88 mL (5 mmol) N,N-diisopropylethylamine, and 636 mg (1.68 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was stirred at 3° for 60 minutes, at which time 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride was added, and the reaction stirred an additional 10 minutes at 3°, then warmed to 25° C. for 50 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 40% ethyl acetate in hexanes as eluant, followed by conversion to the hydrochloride salt by treatment with excess diethyl ether which had been saturated with hydrogen chloride gas to give 577 mg (68%) mp 82-86° C. APCI-MS m/z 457.4 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:12].Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.CCN(C(C)C)C(C)C>C(#N)C>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[NH:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:12]
Reactant: Cc1nc(C(=O)N2CC3CCCC3C2CN)c(-c2ccc(F)cc2)s1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C(=O)N2CC3CCCC3C2CNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in ACN was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 477.4 (M+H).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[C:47]([O:51][C:52](=[O:63])[CH2:53][NH:54][C:55](=[O:62])[CH2:56][NH:57][C:58](=[O:61])[CH2:59][NH2:60])([CH3:50])([CH3:49])[CH3:48].P(C#N)(OCC)(OCC)=O.O>CN(C)C=O.C(N(CC)CC)C>[C:47]([O:51][C:52](=[O:63])[CH2:53][NH:54][C:55](=[O:62])[CH2:56][NH:57][C:58](=[O:61])[CH2:59][NH:60][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)CNC(=O)CNC(=O)CN
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)NCC(=O)NCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (400 mg) and glycylglycylglycine t-butyl ester hydrochloride (149 mg) in dimethylformamide (6 ml), triethylamine (0.094 ml) and diethyl cyanophosphate (150 mg) were added at 0° C., followed by stirring at room temperature for 1 hour. After addition of water, the reaction mixture was extracted with chloroform. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was recrystallized (acetone-hexane) to yield the title compound (110 mg, yield 20%) as a wax-like substance.
Reaction SMILES: [OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15].Br[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=1[F:39].C(OCC)(=O)C.O>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[C:32]=2[F:39])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Fc1cc(F)c(F)c(Br)c1
Reactant: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
A mixture of 1.95 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 20 cm3 of triethylamine was stirred for 5 minutes under an inert atmosphere at a temperature in the region of 20° C. 0.284 g of tetrakis(triphenylphosphine)palladium, 0.094 9 of cuprous iodide, and 1.56 g of 1-bromo-2,3,5-trifluorobenzene were added. The mixture was stirred for 2 hours 30 minutes at a temperature in the region of 80° C. After cooling to approximately 20° C., the reaction mixture had 60 cm3 of ethyl acetate and 60 cm3 of water added. After stirring for 30 minutes, the mixture was separated by settling. After separating off the organic phase, the aqueous layer was extracted with 3 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 30 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm, diameter 4 cm; 80 g), elution was carried out with pure ethyl acetate, and first a fraction of 100 cm3 was collected, followed by 20-cm3 fractions. Fractions 23 to 27 were combined and concentrated as above. 1.3 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylate were obtained in the form of a foam.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14]>>[CH3:9][O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH3:14]
Reactant: COC(=O)C=C(C)C
Reactant: O=[N+]([O-])c1c[nH]cn1
Product: COC(=O)CC(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was reacted with methyl-3,3-dimethylacrylate to provide the title compound: 1H NMR (400 MHz, CDCl3) 1.74 (s, 6H), 2.81 (s, 2H), 3.57 (s, 3H), 7.57 (d, 1H, J=1.3 Hz), 7.90 (d, 1H, J=1.6 Hz); MS m/z 228.2 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[CH:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH:9]=[CH2:10])C.[H][H].[ClH:18]>C(O)C.O=[Pt]=O>[ClH:18].[NH2:14][CH2:13][CH:5]([CH2:6][C:7]([CH3:11])([CH3:12])[CH2:8][CH2:9][CH3:10])[C:4]([OH:15])=[O:3]
Reactant: [H][H]
Reactant: C=CCC(C)(C)C=C(C#N)C(=O)OCC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCCC(C)(C)CC(CN)C(=O)O

Procedure:
2-Cyano-4,4-dimethyl-hepta-2,6-dienoic acid ethyl ester (5.88 g, 28 mmol) was dissolved in the mixture of 91 mL of ethanol and 6 mL of HCl and treated with 0.4 g of PtO2. The reaction was carried out under 100 psi of hydrogen pressure at room temperature for 15 hours. The catalyst was filtered and filtrate was concentrated to give 3.8 g of the desired product 2-aminomethyl-4,4-dimethyl-heptanoic acid ethyl ester as an oil. MS (APCI): 216.2 (M+1)+. This oil was refluxed in 75 mL of 6N HCl for 18 hours. While the reaction was cooled, a precipitate formed. The solid was filtered, washed with additional HCl solution and triturated with ether to give the clean title compound. MS (APCI): 188.1 (M+1)+. 186.1 (M−1)+. 1H NMR (400 MHz; CD3OD): 0.91 (9H, m), 1.30 (5H, m), 1.81 (dd, 1H, J=7.2 Hz, 14.4 Hz), 2.72 (1H, m), 3.04 (2H, m); Anal. Calc'd for C10H21NO2.HCl: C, 53.68; H, 9.91; N, 6.26; Cl, 15.85; Found: C: 53.83; H, 10.15; N, 6.22; Cl, 15.40. MP: 229.5–231.0° C.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.N.[NH2:24][C:25]([NH2:27])=[O:26]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:14][CH:13]=3)[CH2:11][O:26][C:25]([NH2:27])=[N:24]2)[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(c1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Reactant: NC(N)=O
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2cccc(Br)c2)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A solution of iodine (2.92 g, 11.5 mmol) in ethyl acetate (50 mL) was added dropwise over 25 min to a mixture of 4-[1-(3-bromo-phenyl)-vinyl]-1-trifluoromethoxy-benzene (3.6 g, 10.5 mmol) and silver cyanate (1.88 g, 12.6 mmol) in acetonitrile (38 mL) and ethyl acetate (18 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 50 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 60° C. for 4 hours. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline. dichloromethane (40 mL) was added to the crude and the two phases were separated; organic layer was collected, dried over magnesium sulfate anhydrous, filtered and evaporated under reduced pressure. Crude was purified by silica gel chromatography eluting with dichloromethane to give 1.9 g of desired product as a colorless oil (45%)
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromoheptane (0.199 g, 1.11 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL), brine (1× 30 mL), dry the organic layer over NaSO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 382.2 (M+H)+, HRMS calcd for C23H32N3O2 382.2495 (M+H)+, found 382.2489, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=12.6 min, 98.6% purity.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[N:5]([C:16]1[CH:21]=[CH:20][C:19](O)=[C:18]([O:23][CH3:24])[CH:17]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[CH:9]=1)[CH3:2].Cl.[C:27](OCC)(=[O:29])C.[CH3:33][CH2:34]CCCC>CC(C)=O.O>[CH2:1]([O:3][C:4]([N:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([O:29][CH3:27])=[C:10]([OH:14])[CH:9]=2)[CH:16]1[CH2:21][C:20]1[CH:34]=[CH:33][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=1)=[O:25])[CH3:2]
Reactant: CCOC(=O)N(CCc1cccc(OC)c1)c1ccc(O)c(OC)c1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37 %

Procedure:
To a stirred solution of (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester (3.7 g, 8.55 mmol) in acetone (150 mL) was added 6N hydrochloric acid (38 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 hrs. The mixture was diluted with water. The solvent was evaporated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded 6-hydroxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (1.17, 37% yield) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:17]=[CH:16][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:18](Cl)(=[O:20])[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:17]=[CH:16][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:18](=[O:20])[CH3:19])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Yield: 88.7 %

Procedure:
To a solution of 5.0 g (0.0202 mole) of 1-(4-(methylsulfonyl)phenoxy)benzene and 2.20 g (0.0280 mole) of acetyl chloride dissolved in 35 ml of methylene chloride (CH2Cl2) was slowly added 6.70 g (0.0503 mole) of anhydrous aluminum chloride. The mixture was heated at reflux for 45 minutes, cooled and poured over ice and concentrated hydrochloric acid (conc. HCl). Additional CH2Cl2 was added and the organic layer separated, washed with water and dried (Na2SO4). Removal of solvent in vacuo yielded 5.2 g (88.9% yield) of purified 1-(4-(4-(methylsulfonyl)phenoxy)phenyl)ethanone, mp 131°-132.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].CC(C)([O-])C.[K+].[F:27][C:28]1[CH:35]=[C:34](F)[C:33]([F:37])=[CH:32][C:29]=1[C:30]#[N:31].O>O1CCCC1.C(O)(C)(C)C>[F:27][C:28]1[CH:35]=[C:34]([O:10][CH:7]([C:6]2[S:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH2:8][CH3:9])[C:33]([F:37])=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CCC(Oc1cc(F)c(C#N)cc1F)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of 900 mg of 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in 2 mL of tetrahydrofuran at 5° C. was slowly added 3.3 mL of a molar solution of potassium tert-butoxide in tert-butanol. After stirring at 5° C. for 30 minutes, the resulting solution was slowly added to a solution of 469 mg of 2,4,5-trifluoro-benzonitrile in 2 mL of tetrahydrofuran at −60° C. The resulting mixture was stirred for 1 h at −60° C. then stirred overnight allowing the temperature to warm up to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 80/ethyl acetate 20) to give 1.25 g of 2,5-difluoro-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzonitrile.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH2:29][CH2:30][O:31][CH3:32]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:29][CH2:30][O:31][CH3:32])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: COCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in tetrahydrofuran (9.1 mL, 9.1 mmmol) under N2 at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (1.0 g, 4.1 mmol) in tetrahydrofuran (2.0 mL). The resulted light brown solution was stirred at −78° C. for 30 min before adding a solution of 1-iodo-2-methoxyethane (0.93 g, 5.0 mmol) in tetrahydrofuran (2.0 mL). The mixture was stirred for an hour at −78° C. then kept in a freezer reading at −20° C. overnight. The reaction was quenched with saturated ammonium chloride. The layers were separated and the aqueous extracted with ether three times. The combined organics were then washed with brine, dried (magnesium sulfate), filtered and purified by flash chromatography (EtOAc/Hexane) to provide the desired product (0.28 g, 23%). LCMS calculated for C15H26NO5: (M+H) 300.2; found 300.2.
Reaction SMILES: CO[C:3](=[O:15])[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[N:6]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20].O>CN1CCCC1=O>[OH:14][C:11]1[CH:12]=[CH:13][C:7]2[N:6]=[C:5]([NH:4][C:3]([NH:20][CH2:19][CH2:18][O:17][CH3:16])=[O:15])[NH:9][C:8]=2[CH:10]=1
Reactant: COCCN
Reactant: COC(=O)Nc1nc2ccc(O)cc2[nH]1
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCNC(=O)Nc1nc2ccc(O)cc2[nH]1

Procedure:
A solution of (6-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester (300 mg, example 61) and 2-methoxy-ethylamine (630 IA) in N-methylpyrrolidinone (8 ml) was heated at 90° C. in a sealed tube for 20 hours. The reaction mixture was poured into water (160 ml) and extracted three times with ethyl acetate (40 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95 C:5 C, v/v) to 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea as a yellow solid (180 mg). Mass spectrum: 251 [M+H]+; retention time=0.55 minutes.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[H][H]>C(OCC)(=O)C.C(O)C.O=[Pt]=O>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2Br)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1ccccc1CC1CCNCC1
Reaction time: 18 h
Yield: 260 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-[(2-bromophenyl)methylene]-piperidine (8 g, 22.7 mmole) in ethyl acetate (75 ml) and ethanol (75 ml) was shaken with PtO2 (0.75 g) and hydrogen (60 psi) for 15 min. Two further batches of 1-(tert-butoxycarbonyl)-4-[(2-bromophenyl)-methylene]-piperidine (8 g each, 24 g total) were similarly reduced and the mixtures were filtered. The filtrates were combined and concentrated in vacuo. The residue was dissolved in dioxane (200 ml) and 3 N HCl (100 ml) and stirred for 18 hr. The solution was concentrated in vacuo and the residue was made basic with 50% sodium hydroxide. The mixture was extracted with CH2Cl2. The extracts were dried over Na2SO4 and concentrated in vacuo to give a yellow oil that was purified by short path vacuum distillation to give 4-(2-bromobenzyl)piperidine as a oil (15 g, 86.6%). The oil converted to the fumarate salt using fumaric acid (6.85 g) in 2-propanol to give 4-(2-bromobenzyl)piperidine fumarate as a white solid (15.8 g, 62.6% overall, mp: 164-165° C.).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(C(C)C)C(C)C)C.[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20]
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 150.4 %

Procedure:
A mixture of ethyl 3-aminopropanoate hydrochloride (88 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford ethyl 3-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)propanoate (387 mg, 151%) which was used without further purification.