Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[CH2:30])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[C:3]([C:25]2[CH:24]=[C:23]([C:26](=[CH2:30])[C:27]([OH:29])=[O:28])[CH:22]=[CH:21][CH:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: C=C(C(=O)O)c1ccc(Br)cc1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Product: C=C(C(=O)O)c1cccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
In a similar manner to Example 9(b), by reaction of 73.4 g (0.30 mol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid with 44.7 g (0.20 mol) of 4-bromophenylacrylic acid, and after recrystallization from ethanol, 48 g (61%) of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacrylic acid are obtained, with a melting point of 207-8° C.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.[OH-].[Na+]>CC(O)=O>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1
Reactant: Nc1ccc(Cl)cc1-c1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
Sodium cyanoborohydride (6.37 g) was added portionwise to a solution of 7.00 g 2-(2-amino-5-chlorophenyl)-1H-indole in 245 ml HOAc at 15° C. The resulting solution was stirred at room temperature for one day. The reaction mixture was diluted and made basic by addition of 50% NaOH in ice. The mixture was extracted with Et2O, and the extracts were washed with water and saturated NaCl solution, and dried (MgSO4). Concentration gave 6.48 g gum which was chromatographed by HPLC using CH2Cl2 /hexane (7:3) as eluent to give 2.56 g solid, m.p. 107°-109° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14](Cl)=[O:15])([CH3:10])([CH3:9])[CH3:8]>[OH-].[Na+].C1COCC1>[C:21]([C:18]1[CH:17]=[C:13]([C:14]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[O:15])[CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:19]=1[OH:20])([CH3:24])([CH3:22])[CH3:23]
Reactant: OC1CNC1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)N2CC(O)C2)cc(C(C)(C)C)c1O
Temperature: -5 °C
Yield: 28.6 %

Procedure:
Azetidin-3-ol hydrochloride (2 g, 18,3 mmoles) was dissolved in a 5% weight/weight (45 ml) of an aqueous solution of sodium hydroxide, the resulting solution cooled to −5° C. and under vigorous stirring 3,5-di-tert-butyl-4-hydroxy-benzoyl chloride (5,4 g, 20 mmoles) obtained according to step (a) dissolved in 8 ml of THF was added. Afterwards the cooling bath was removed, the reaction mixture warmed to room temperature (approximately 25° C.) and stirred for an additional hour under these conditions. The reaction mixture was then extracted several times with diethyl ether, the etherical phases combined, washed with water, dried with sodium sulfate and evaporated to dryness to obtain 1,9 g of the crude product, which is crystallized from ethyl acetate-petroleum ether. 1,6 g (30% of theoretical yield) of (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone were obtained in crystalline form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: Oc1cccnc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (307 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy)propanamide (90.4 mg).
Reaction SMILES: Br[C:2]1[NH:6][C:5]([N+:7]([O-])=O)=[N:4][C:3]=1[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:22])[CH:11]=1>CO.[Pd]>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([C:3]3[N:4]=[C:5]([NH2:7])[NH:6][CH:2]=3)=[CH:11][C:12]([CH3:22])=[N:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(-c3nc([N+](=O)[O-])[nH]c3Br)cc(C)nc2c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(-c3c[nH]c(N)n3)cc(C)nc2c1
Reaction time: 8 h
Yield: 114.2 %

Procedure:
To a solution of the product of Step 2 (114 mg, 0.31 mmol) in 15 mL of MeOH was added 100 mg of 10% Pd/C and the solution was purged with H2. The solution was then stirred under H2 atmosphere overnight. After filtration and concentration, the desired 4-(7-methoxy-2-methyl-quinolin-4-yl)-1H-imidazole-2-ylamine (90 mg, 87%) was obtained as a HBr salt. MS (ESI) (M+1)=255.33. Step 4
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].Cl.[OH-].[Na+]>O>[NH:4]1[CH2:5][CH2:6][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH:1][CH2:2][CH2:3]1
Reactant: NCCNCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C1CNCCNCCNCCN1
Yield: 28.5 %

Procedure:
50 g of (II) (0.257 mol) are dissolved in 350 ml of water. 132.5 g of diethylenetriamine (1.285 mol) are added and pH adjusted to 8 with conc. HCl (265 g). The resulting solution is refluxed for 24 h, then cooled, alkalinized with NaOH in pellets, concentrated under vacuum to a residual weight of 350 g and extracted (I) with toluene. The combined organic extracts are concentrated to an about 90 mL volume and left to crystallize. 31.5 g of high quality 1,4,7,10-tetraazacyclododecane are obtained (GC titre: 99.5%). Yield. 71%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[ClH:7].C([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH2:14]/[C:13]/1=[CH:31]\[C:32]1[N:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:36]=1)(=O)C.C(#N)C>CO.C(OCC)(=O)C>[ClH:7].[CH:21]1([C:19](=[O:20])[CH:18]([N:15]2[CH2:16][CH2:17][CH:12]([SH:11])/[C:13](=[CH:31]/[C:32]3[N:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:36]=3)/[CH2:14]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:23][CH2:22]1
Reactant: COC(=O)Cn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: COC(=O)Cn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
Potassium carbonate (275 mg) was added to a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[2-(methoxycarbonylmethyl)-2H-tetrazol-5-yl]methylidene}piperidine hydrochloride (347 mg) in methanol (10 ml). After being stirred at room temperature for 15 minutes, the mixture was diluted with ethyl acetate, and the reaction was quenched by addition of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 35/65, v/v) to afford the title compound (185 mg, yield: 58%) as a colourless amorphous solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[O:11])=[C:8]([OH:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>S(=O)(=O)(O)O>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:22]=[CH:21][C:9]([C:10]2([C:34]3[CH:29]=[C:30]([NH:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:31]=[CH:32][C:33]=3[O:35][CH3:36])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14](=[O:15])[O:11]2)=[C:8]([OH:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCN(CCCC)c1ccc(C(=O)c2ccccc2C(=O)O)c(O)c1
Reactant: COc1ccc(Nc2ccccc2)c(C)c1
Agent: O=S(=O)(O)O
Product: CCCCN(CCCC)c1ccc(C2(c3cc(Nc4ccccc4)ccc3OC)OC(=O)c3ccccc32)c(O)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
There is described in Japanese Patent Laid-open No. 60-202155 that a known conventional method provides a low melting type 3-dibutylamino-6-methyl-7-anilinofluoran. The conventional method is as follows. 2-(4-Dibutylamino-2-hydroxybenzoyl)benzoic acid and 4-methoxy-2-methyldiphenylamine are dissolved in concentrated sulfuric acid, and the reaction is carried out at 0°-5° C. for 20 hours. After the reaction, the reaction mixture is poured into ice water, whereupon precipitates are formed. The precipitates are collected by filtration and washed with water to provide a cake of 3-(4-dibutylamino-2-hydroxyphenyl)-3-(5-anilino-2-methoxyphenyl)phthalide. The cake is added to a mixture of toluene and water, and then the mixture is neutralized with a 28% by weight aqueous solution of sodium hydroxide. A further amount of sodium hydroxide is added and then the mixture is stirred at a refluxing temperature for three hours. After the reaction, the mixture is left standing, and a toluene layer is separated and concentrated at 70° C. until a syrup is obtained. Methanol is added to the syrup so that 3-dibutylamino-6-methyl-7-anilinofluoran crystalizes out. According to the reference, the obtained compound has a melting point of 148°-152° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[CH3:34][N:35]([CH2:37][CH2:38][CH2:39]Cl)[CH3:36]>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:39][CH2:38][CH2:37][N:35]([CH3:36])[CH3:34])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Reactant: CN(C)CCCCl
Product: COc1cc(-c2nc3ccc(OCCCN(C)C)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 3-(N,N-dimethylamino)propyl chloride essentially as previously described. mp 142° C., NMR, IR, MS 543.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(OC)c(C(=O)Cl)cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a suspension of 2,4,5-trimethoxybenzoic acid (2.12 g, 10 mmol) in dry 10 mL benzene was added thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was stirred at 70° C. for 5 hr. The solvent was evaporated in vacuo. The residue was washed with hexane to give 2.07 g of the title compound which was used for the next step without further purification. 1H NMR (CDCl3) δ: 7.65 (1 H, s), 6.50 (1 H, s), 4.05 (3 H, s), 3.97 (3 H, s), 3.86 (3 H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24](O)=[C:23]([F:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][C:23]=2[F:28])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Oc1ccc(Br)cc1F
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cc2F)cs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
2-{[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 4 and 4-bromo-2-fluorophenol (1.91 g) were dissolved in tetrahydrofuran (20 mL), triphenylphosphine (2.62 g) and diethyl diazodicarboxylate (1.74 g) were added under ice-cooling, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=6:1) to give the title compound (3.2 g) as a colorless oil.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(N(C2CCCC2)C(NC2SC=CN=2)=O)CCCC1.C(OC(=O)CNS(C1SC(N)=NC=1)(=O)=O)C>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([CH3:30])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: O=C(Nc1nccs1)N(C1CCCC1)C1CCCC1
Agent: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid (Example 76) via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine (General procedure 1) and (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-])=O)[CH:3]=1>C(Cl)Cl.CCOC(C)=O>[NH2:12][C:4]1[CH:3]=[C:2]([I:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(I)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
To a solution of methyl 4-iodo-2-nitrobenzoate (2.3 g, 7.4 mmol) in DCM (5 mL) and EtOAc (5 mL) was added SnCl2-2H2O (10.8 g, 89.7 mmol). The mixture was allowed to stir for 12 h at rt. The solvents were evaporated, and the residue was partitioned between 200 mL of saturated aqueous NaHCO3 and 200 mL of DCM. The organic solution was separated and the aqueous solution was extracted with DCM (2×100 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give methyl 2-amino-4-iodobenzoate (1.85 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:37][O:38][CH2:39][CH2:40]O>O1CCCC1>[CH3:37][O:38][CH2:39][CH2:40][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: COCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: COCCOC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 1 h

Procedure:
A suspension of 5.0 gm (16.4 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164°-165° C., in 50 ml of dry tetrahydrofuran was admixed with 2.92 gm (18.1 millimols) of carbonyldiimidazole, whereupon the acid dissolved and carbon dioxide was given off. After one hour, 1.37 gm (18.1 millimols) of glycol monomethyl ether were added, and the mixture was allowed to stand for 2 hours. For isolation of the reaction product, the mixture was evaporated, and the residue was distributed between dilute hydrochloric acid and ethyl acetate, and the organic solution was purified by chromatography on 180 gm of silicagel with cyclohexane/ethyl acetate=1/4. For further purification, the product mixture was recrystallized from cyclohexane/ethyl acetate=4/1. Yield: 3.8 gm (63.8% of theory); m.p. 65°-67° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:10][OH:11])[CH:9]=1.S(OC)(O[CH3:19])(=O)=O>O.ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:10][O:11][CH3:19])[CH:9]=1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
Sodium hydroxide (1.88 g, 44.0 mmol) in water (15 mL) was added to a solution of (5-chloro-2-nitro-phenyl)-methanol (1.1 g, 5.88 mmol) in dichloromethane (15 mL) and stirred for 10 min. Dimethyl sulfate (1.12 mL, 11.8 mmol) and tetrabutylammonium hydrogen sulfate (100 mg) were added and the mixture stirred vigorously for 8 h at room temperature. The reaction mixture was diluted with dichloromethane and the organic phase was separated, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the crude compound. Purification by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in petroleum ether as eluent afforded 4-chloro-2-methoxymethyl-1-nitro-benzene (850 mg, 72%) as a pale yellow liquid.
Reaction SMILES: [OH-].[K+].C1(C)C(S([N:12]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)(=O)=O)=CC=CC=1>CO>[CH3:22][C:21]1([CH3:23])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: Cc1ccccc1S(=O)(=O)N1Cc2ccccc2CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2ccccc2C=N1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a nitrogen-blanketed mixture of potassium hydroxide (KOH, 30 g) and methanol (CH3OH, 60 mL) was added of N-toluenesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (4.0 g, 0.013 mol.). The reaction mixture was heated at reflux for 17 hours and the reaction was followed by gas chromatography. The reaction mixture was cooled to ambient temperature, quenched with water (100 mL) and 10% HCl was slowly added until pH=7 was obtained. The aqueous mixture was extracted with methylene chloride (3×100 mL) and the organic layers were combined and stirred with charcoal and sodium sulfate (Na2 SO4). The solution was filtered through celite and the filtrate was concentrated (25°/150 torr) to give 3,3-dimethyl-3,4-dihydroisoquinoline (1.79 g, yield=90%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:39]1(=O)[CH2:42][CH2:41][CH2:40]1>>[CH2:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][N:28]([C:26]([C:21]2[NH:22][C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([CH:39]4[CH2:42][CH2:41][CH2:40]4)[CH2:9][CH2:10]2)=[O:16])=[CH:25][CH:24]=3)=[O:27])[CH2:33][CH2:32]1)=[O:35])[CH3:38]
Reactant: O=C1CCC1
Reactant: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)ccc3[nH]2)CC1
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C5CCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 47, from 4-[2-(4-ethoxycarbonyl-piperazine-1-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester and cyclobutanone. Light-yellow solid. MS (m/z): 482.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:22]=[CH:21][C:20]([CH:23]([OH:27])[CH2:24][CH2:25][CH3:26])=[CH:19][C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:27][CH:23]([C:20]1[CH:19]=[C:16]([C:17]#[N:18])[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:22][CH:21]=1)[CH2:24][CH2:25][CH3:26]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCC(O)c1ccc(Br)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C#N)c1
Temperature: 140 °C
Yield: 83.2 %

Procedure:
A sealed flask was charged with the (4-(trifluoromethyl)phenyl)boronic acid (1.09 g, 5.76 mmol), 2-bromo-5-(1-hydroxybutyl)benzonitrile (1.33 g, 5.23 mmol) and acetonitrile (17 mL). Once everything get into solution, 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (115 mg, 157 μmol) was added followed by the sodium carbonate 2M aq. (6.54 mL, 13.1 mmol). Flask sealed and heated at 140° C. for 1 hour. Organic solvent removed under reduced pressure and ethyl acetate added. Organics washed with water (1×), with brine (1×), dried over sodium sulfate, filtered and concentrated to provide the crude material. Purification by silica gel flash chromatography (Ethyl Acetate/Heptane) provide the title compound as a colorless oil (1.39 g, 83.2%). 1H NMR (400 MHz, DMSO-d6) δ 0.87-0.93 (m, 3H) 1.25-1.45 (m, 2H) 1.57-1.67 (m, 2H) 4.64-4.70 (m, 1H) 5.41 (d, J=4.68 Hz, 1H) 7.64 (d, J=8.00 Hz, 1H) 7.75-7.79 (m, 1H) 7.82 (d, J=8.00 Hz, 2H) 7.88-7.94 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.C1(C)C=CC=CC=1.[F:25][C:26]1[CH:34]=[C:33]([CH2:35][CH2:36][C@H:37]2[CH2:42][CH2:41][C@H:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:39][CH2:38]2)[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>O>[F:25][C:26]1[CH:34]=[C:33]([CH2:35][CH2:36][C@H:37]2[CH2:38][CH2:39][C@H:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:41][CH2:42]2)[CH:32]=[CH:31][C:27]=1[C:28]([O:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[C:6]([F:11])[CH:7]=1)=[O:29]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C(=O)Cl)c(F)c2)CC1
Reactant: N#Cc1c(F)cc(O)cc1F
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C(=O)Oc3cc(F)c(C#N)c(F)c3)c(F)c2)CC1
Yield: 95.6 %

Procedure:
Then, 1.1 g (6.4 mmol) of 2,6-difluoro-4-hydroxybenzo-nitrile, 0.8 ml of pyridine, and 2 ml of toluene were mixed. To this mixture, was added dropwise 3 ml of toluene solution containing 6.4 mmol of 2-fluoro-4-(2-(trans-4-pentylcyclohexyl)ethyl)benzoyl chloride at room temperature in 5 minutes. After the dropping was finished, they were reacted at 50° C. for 2 hours. After finishing of the reaction, 10 ml of water was added to the reaction product, and then extracted with 30 ml of toluene. The organic layer thus obtained was washed with 6N-hydrochloric acid thrice, 2N-sodium hydroxide thrice, and water thrice, and then dried over anhydrous magnesium sulfate. Solvent was distilled off at a reduced pressure, and the residue was subjected to a silica gel column chromatography (eluent: toluene) to obtain 2.8 g of a crude 3,5-difluoro-4-cyanophenyl 2-fluoro-4-(2-(trans-4-pentylcyclohexyl)ethyl)benzoate. This product was recrystallized from a mixed solvent of heptane/ether to obtain 2.4 g of (yield: 81.6%) the subject compound.