Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([OH:31])[C@H:14]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=O)(C)(C)C.Cl>CO>[F:30][C:26]1[CH:25]=[C:24]([C@H:14]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)[C@@H:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[OH:31])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Agent: Cl
Solvent: CO
Product: O[C@H]([C@@H]1CCCN1)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Yield: 48.8 %

Procedure:
(R)-2-[2-(S)-(3-Fluoro-phenyl)-1-hydroxy-2-indol-1-yl-ethyl]-(S)-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) was dissolved in methanol (1 mL) and a 1N ethereal solution hydrochloric acid (1.0 mL, 1.0 mmol) was added. After 16 hours the mixture was concentrated and purified via flash column chromatography (silica, 10% methanol saturated with ammonia in chloroform) to give 19 mg (50%) (1R,2S)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]ethanol. The freebase was dissolved in diethyl ether (2 mL) and treated with 1 N ethereal solution of hydrochloric acid (0.06 mL, 0.06 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 17 mg of (1R,2S)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]ethanol hydrochloride. HRMS: calcd for C20H21FN2O+H+, 325.17107; found (ESI, [M+H]+), 325.1711
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:18])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCc2ccccn2)cc1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Product: O=C(c1ccc(OCc2ccccn2)cc1)N1CCC[C@@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 4-(Pyridin-2-ylmethoxy)-benzoic acid methyl ester and 1-[(2R)-2-pyrrolidinylmethyl]pyrrolidine [CAS 60419-23-0]. MS (ES+) 366.3
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1.COCCOC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: -78 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A solution of 1-bromo-4-fluoro-2-nitrobenzene (3.6 g, 16.4 mmol) in THF (100 mL) was added to a solution of 1 M vinylmagnesium bromide in THF (100 mL, 100 mmol) and DME (100 mL) at −78° C. (bath temp). The reaction was stirred at −78° C. for 4 h, and saturated aqueous NH4Cl was added. The layers were separated, and the organic layer was evaporated. The crude product was purified flash chromatography, giving 2 g (57%) of the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:26][C:21]=1[C:22]([O:24]C)=O)=[O:15])[CH3:12].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[CH3:31][O:30][C:28]1[C:27]([CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])=[CH:26][C:21]2[C:22](=[O:24])[CH:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:17][CH2:18][O:19][C:20]=2[CH:29]=1
Reactant: CCOC(=O)CCCOc1cc(OC)c(CC=C(C)C)cc1C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(OC)c(CC=C(C)C)cc2C1=O
Temperature: -75 °C
Yield: 32.9 %

Procedure:
80 ml of a tetrahydrofuran solution containing 18.6 mmol lithium bis(trimethylsilyl)amide was cooled to −75° C. 3.23 g of methyl 2-(3-ethoxycarbonylpropoxy)-4-methoxy-5-(3-methyl-2-butenyl)benzoate was dissolved in 8 ml of tetrahydrofuran, and the obtained solution was added dropwise to the above solution. After completion of the dropping, the reaction solution was warmed to 0° C. After completion of the reaction, a saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 969 mg of ethyl 8-methoxy-7-(3-methyl-2-butenyl)-5-oxo-2,3,4,5-tetrahydrobenz[b]oxepin-4-carboxylate. Thereafter, 751 mg of the obtained compound was dissolved in 15 ml of tetrahydrofuran. While the reaction solution was stirred under heating at 70° C., 4 ml of a 5 N sodium hydroxide aqueous solution was added thereto in 3 batches. Approximately 2 hours later, tetrahydrofuran as a reaction solution was concentrated under a reduced pressure, and 10 ml of ethanol was then added thereto. Thereafter, 5 ml of 5 N hydrochloric acid was added to this ethanol solution, and the mixture was heated to reflux again. After completion of the reaction, ethyl acetate was added to the reaction solution, and the obtained organic layer was washed with a saturated sodium chloride aqueous solution. The organic layer was then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 422 mg of the subject compound.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[CH:8].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>CCCCCC.O1CCCC1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:6][C:7]#[C:8][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: C#CCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCCCCCCCCCCCCCC#CCOC1CCCCO1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
50 ml of a 15% by weight solution of butyllithium in hexane was added dropwise at -50° C. to a solution of 11.48 g of 2-tetrahydropyranyl propargyl ether in 220 ml of tetrahydrofuran followed by 25 g of palmityl bromide, and the mixture was stirred for 30 minutes, during which time the temperature of the mixture was allowed to rise to room temperature. The reaction mixture was heated under reflux for 16 hours, poured into water and then extracted twice with diethyl ether. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 500 g of silica gel. 14.59 g of the title compound were isolated as an oil from the fractions eluted with a 3:100 by volume mixture of diethyl ether and hexane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[N:16][NH:17][CH:18]=2)[CH2:3][CH2:2]1.[C:20](Cl)(=[O:31])[O:21][CH2:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1.[OH-].[Na+]>C(Cl)Cl>[NH:17]1[CH:18]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:7][CH:4]2[CH2:3][CH2:2][N:1]([C:20]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)=[O:31])[CH2:6][CH2:5]2)=[O:19])[N:15]=[N:16]1
Reactant: O=C(CCCCCc1c[nH]nn1)NC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCCCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(Piperidin-4-yl)-6-(1H-1,2,3-triazol-4-yl)hexanamide (135 mg, 0.509 mmol) in DCM (50 ml) was treated with 3,5-dichlorobenzyl carbonochloridate (134 mg, 0.560 mmol) and 2M sodium hydroxide (25 ml, 50 mmol). The reaction mixture was stirred at room temperature for 5 hrs. The organics were removed, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by mass directed preparative LC to give the title compound, after concentration of the relevant fractions.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])[CH3:12]>[Pd].[Cu](I)I.C1(C(C2C=CC=CC=2)=C(P(C2CCCCC2)C2CCCCC2)C)C=CC=CC=1.C(NC(C)C)(C)C.CN(C)C=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:14]#[C:13][C:11]([CH3:12])([OH:15])[CH3:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: C#CC(C)(C)O
Reactant: N#Cc1ccc(Cl)cc1
Agent: I[Cu]I
Agent: [Pd]
Agent: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 23 h
Yield: 84.2 %

Procedure:
Into a reactor were introduced 1.38 g (10.0 mmol) of 4-chlorobenzonitrile, 1.68 g (20.0 mmol) of 2-methyl-3 butyne-2-ol, 2.7 mg (0.015 mmol) of palladium, 1.4 mg (0.0075 mmol) of copper iodide, 17.6 mg (0.045 mmol) of the 1,1-diphenyl-2-(dicyclohexylphosphine)propene obtained in Example 2, 4.0 mL (0.055 mmol) of diisopropylamine, and 4.0 ml of N,N-dimethylformamide under a nitrogen atmosphere. The resultant reaction mixture was stirred at 100° C. for 23 hours and then cooled. Thereafter, the solvent was removed under pressure. The concentrate was purified by column clromatography to obtain 1.56 g (84%) of 4-(4-cyanophenyl)-2-methyl-3-butyne-2-ol as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][CH2:13]O.OS(O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1Cl
Temperature: 90 °C
Yield: 96.3 %

Procedure:
A solution of 2-chlorophenylacetic acid (10.12 g, 59.3 mmol) in EtOH (150 mL, 2576 mmol) in a 500 mL round bottom flask was treated with concentrated H2SO4 (0.700 mL, 8.28 mmol) and heated at 90° C. for 16 hours. The solution was concentrated in vacuo, diluted with 1N NaOH(aq) (200 mL), and extracted with EtOAc (2×200 mL). The combined organic layers were washed with 1N NaOH(aq) (200 mL), water (100 mL), and brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give ethyl 2-(2-chlorophenyl)acetate (11.344 g). MS m/e=217 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH-].[Na+]>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Reaction time: 2 h
Yield: 98 %

Procedure:
Pyrrolidine (2.5 g, 35.2 mmol) was added to a solution of 4-bromobenzenesulfonyl chloride (4.5 g, 17.6 mmol) in methylene chloride (10 mL) at 0° C. The mixture was stirred for 2 h and an aqueous sodium hydroxide solution (1 M, 5 mL) was added and sting was continued for another 10 min. The organic phase was separated and diluted with methylene chloride (40 mL), washed with aqueous HCl (1 M, 10 mL), and water (2×10 mL). The organic phase was dried (sodium sulfate) and the solvent was evaporated. The title compound was isolated in 5.0 g (98% yield) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.65 (m, 4H), 3.20 (m, 4H), 1.74 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 135.93, 132.17, 128.84, 127.39, 47.84, 25.13; MS (ES) m/z 290 and 292 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[C:18]([OH:24])=[CH:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1([CH3:16])[CH3:15])=[O:9].CC1C=CC(S(O[C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][C@@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1([CH3:16])[CH3:15])=[O:9]
Reactant: CC1(C)CCCN1C(=O)c1ccc(-c2cc(F)ccc2O)cc1Cl
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H](C)Oc1ccc(F)cc1-c1ccc(C(=O)N2CCCC2(C)C)c(Cl)c1
Temperature: 65 °C

Procedure:
The intermediate from step d) (2.83 g) was dissolved in MeCN (30 mL). The product from step e) (2.11 g) and potassium carbonate (2.25 g) were added and the mixture was heated to 65° C. for 16 h. The mixture was cooled to rt and extracted with diethyl ether (×2), dried (MgSO4) and concentrated under reduced pressure to give an oil. The oil was purified by flash column chromatography on silica using isohexane 3:1 ethyl acetate as eluent to give the sub titled product as a colourless oil (2.29 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:18]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CNCCC#Cc1ccccn1
Product: CN(CCC#Cc1ccccn1)C(=O)c1cccc(Cl)c1
Yield: 60.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 3-chlorobenzoyl chloride (109 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 98/2 as eluent) to afford 112 mg of 3-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.C([Li])CCC.[F:23][C:24]([F:37])([F:36])[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:26]>C1COCC1.CCCCCC>[F:37][C:24]([F:23])([F:36])[C:25]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2)([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[OH:26]
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2ccccc12)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a chilled (−78° C.) solution of 2.67 g (9.20 mmol) 5-bromo-1-(4-fluorophenyl)-1H-indazole in 10 mL of anhydrous THF was added 7.36 mL (18.40 mmol) of a 2.5 M solution of n-butyllithium in hexane followed by a solution of 1.00 g (4.69 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-yl)ethanone in 5 mL of THF in one portion. The reaction was then stirred at −78° C. for 30 minutes and quenched with 5 mL of water. The mixture was warmed to room temperature and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (20%-40% ethyl acetate in hexanes). The major fractions were combined and concentrated to afford 978 mg of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(1H-indol-3-yl)ethanol. MS m/z 426.39 (MIT).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[Cl:13][C:14]1[S:15][C:16]([CH2:19]Cl)=[CH:17][CH:18]=1>>[Cl:13][C:14]1[S:15][C:16]([CH2:19][O:1][NH2:2])=[CH:17][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccc(Cl)s1
Product: NOCc1ccc(Cl)s1

Procedure:
Prepared by a similar procedure as described for preparation 15. Starting materials: N-hydroxyphthalimide and 2-chloro-5-(chloromethyl)thiophene (Aldrich). 13C-NMR (DMSO-d6) δ 140.2, 127.9, 126.3, 126.0, 71.1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][O:5][C:6]([CH:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])=[O:7])[CH3:2].[S:29]([O-:32])([OH:31])=[O:30].[Na+:33].N(C(C)(C)C#N)=NC(C)(C)C#N>C(O)(C)C>[CH2:23]([CH:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][O:16][C:14]([CH:9]1[CH:8]([C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:7])[CH2:13][CH2:12][CH:11]([S:29]([O-:32])(=[O:31])=[O:30])[CH2:10]1)=[O:15])[CH3:24].[Na+:33]
Reactant: CCCCC(CC)COC(=O)C1CC=CCC1C(=O)OCC(CC)CCCC
Reactant: O=S([O-])O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCC(CC)COC(=O)C1CCC(S(=O)(=O)[O-])CC1C(=O)OCC(CC)CCCC
Temperature: 81.5 °C
Reaction time: 16 h

Procedure:
In the stream of an argon gas, 80 g of 4-cyclohexene-1,2-dicarboxylic di(2-ethylhexyl)ester (manufactured by Tokyo Chemical Industry Co., Ltd.) and 900 mL of isopropyl alcohol was placed. 660 mL of an aqueous solution of 42.3 g of sodium hydrogen sulfite (manufactured by Wako Pure Chemical Industries, Ltd.) was added. The resulting solution was heated to a reflux temperature, and stirred at 80 to 83° C. for 16 hours. During this stirring, every one hour from the start to 1 to 5 hours after the start of refluxing, as well as after 9 hours and 10 hours, 1.66 g of 2,2′-azobis(isobutyronitrile) (manufactured by Wako Pure Chemical Ltd.) was added. After cooling to room temperature, the reaction liquid was concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:19])[N:5]([CH3:18])[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])[CH3:2].I[CH2:21][CH3:22]>C(O)C>[CH2:21]([S:19][C:4](=[N:3][CH2:1][CH3:2])[N:5]([CH3:18])[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])[CH3:22]
Reactant: CCNC(=S)N(C)c1sc(-c2cccnc2)nc1C
Reactant: CCI
Solvent: CCO
Product: CCN=C(SCC)N(C)c1sc(-c2cccnc2)nc1C
Yield: 39.2 %

Procedure:
A solution of 3-ethyl-1-methyl-1-(4-methyl-2-(pyridin-3-yl)thiazol-5-yl)thiourea (70 mg, 0.239 mmol) and iodoethane (74.7 mg, 0.479 mmol) in ethanol (5 mL) was heated at 80° C. for 6 h in a sealed tube. Upon cooling the solvent was removed under reduced pressure and the residue purified via silica gel chromatography (0 to 100% ethyl acetate/hexanes) to furnish the title compound as a clear oil (30 mg, 39%): 1H NMR (400 MHz, CDCl3) δ 9.10 (d, J=2.0 Hz, 1H), 8.64 (dd, J=4.6 Hz, 1.4 Hz, 1H), 8.20 (d, J=4.2 Hz, 1H), 7.41-7.37 (m, 1H), 3.63 (q, J=7.6 Hz, 2H), 3.22 (s, 3H), 2.72 (q, J=7.8 Hz, 2H), 2.38 (s, 3H), 1.28-1.17 (m, 6H); ESIMS m/z 321 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:28]([O:35][CH2:36][C:37](Cl)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:37](=[O:38])[CH2:36][O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)COCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyloxyacetyl chloride.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[Sn:34](Cl)([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:43]([Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:23]([F:26])([F:25])[F:24])[N:8]=2)[CH:6]=1)[CH2:44][CH2:45][CH3:46]
Reactant: FC(F)(F)c1ccc(-c2cc(-n3cnc(I)c3)nc(C(F)(F)F)c2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.93) (1.2 g, 2.48 mmol) in THF (15 mL) at 0° C. was quickly added added i-PrMgCl.LiCl (1 M in THF, 3.0 mL, 3.0 mmol) and the mixture was stirred at 0° C. for 15 min. Then Bu3SnCl (0.94 mL, 3.48 mmol) was added, the cooling bath was removed and the mixture was stirred at 23° C. for 48 h. Poured into sat. NH4Cl-sol., extracted with EtOAc, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by alox (neutral) column chromatography with heptane/methylene chloride gave a yellow oil (1.7 g, 106%, ca. 90% pure). MS (ISP) 648.3 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[N:9]=2)[CH2:4][CH2:3]1>[OH-].[OH-].[Pd+2].CCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[N:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2cccc(N)n2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(c2cccc(N)n2)CC1
Reaction time: 16 h

Procedure:
A solution of 1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-ylamine (1.1 g, 5.8 mmol) and EtOH (30 mL) was hydrogenated over 20% Pd(OH)2/C (0.3 g) at 40 psi and RT. After 16 h, the mixture was filtered through Celite® and concentrated in vacuo to give the desired compound as a yellow solid. MS m/z: 192.1 (M+H). Calc'd for C11H17N3-191.27.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(CC(=O)O)cc4)CC3)nc2)c1

Procedure:
(4-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-phenyl)-acetic acid was synthesized from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 4-bromo phenyl acetic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H32N4O3 (m/e) 472, obsd 473 (M+H).