Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:24]([CH3:23])(=[O:26])=[O:25])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2cccc(CNCc3cccnc3)c2)n1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N(Cc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 12 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:26][CH2:25][N:24](C(OCC)=O)[CH2:23][CH2:22]4)[CH:19]=[N:18][C:17]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:38])(=[O:6])=[O:5])([CH3:3])[CH3:2].[OH-].[Na+]>Cl>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:20]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:19]=[N:18][C:17]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:38])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)N1CCC(n2cnc(-c3ccccc3)c2-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCNCC3)cc21
Temperature: 25 °C
Yield: 42 %

Procedure:
Heat a mixture of 1-isopropylsulfonyl-2-amino-6-(1-(1-(ethoxycarbonyl)piperidin-4-yl)-4(phenyl)-imidazol-5-yl)benzimidazole (55 mg) in concentrated hydrochloric acid at reflux for 24 hours. Cool the mixture to room temperature, add 5 N sodium hydroxide until the mixture is basic, and extract with dichloromethane. Concentrate the organic phase under reduced pressure and subject the residue to silica gel chromatography, eluting with dichloromethane followed by 1:1 dichloromethane:methanol to provide 20 mg (43%) of the title compound. MS(ES+): m/z=465.0 (M+H)+
Reaction SMILES: [ClH:1].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:12][O:13][CH3:14])[CH:11]=1)[C:7]#[N:8].[CH2:15]([OH:17])[CH3:16]>>[ClH:1].[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:12][O:13][CH3:14])[CH:11]=1)[C:7](=[NH:8])[O:17][CH2:15][CH3:16]
Reactant: CCO
Reactant: COCc1cc(C#N)cc(CO)c1
Agent: Cl
Product: CCOC(=N)c1cc(CO)cc(COC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Hydrogen chloride gas was passed through a solution of 3-hydroxymethyl-5-methoxymethyl-benzonitrile (720 mg, 4.063 mmol) in anhydrous ethanol (25 mL) at 0° C. After 1 h, hydrogen chloride gas was stopped and the reaction vessel was sealed with a septum. After stirring at room temperature for 1 d, the reaction vessel was cooled to 0° C. and the septum was removed. The solvent was evaporated in vacuo to afford ethyl 3-hydroxymethyl-5-methoxymethyl-benzimidate hydrochloride as a white solid (1.05 g, 100%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:38](=[N:42][OH:43])[C:39]([OH:41])=[O:40])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.C(O)C.C1COCC1.[OH-].[Na+:53]>O>[Na+:53].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:38](=[N:42][OH:43])[C:39]([O-:41])=[O:40])[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:24][CH:25]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)C(=NO)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C([O-])C(=NO)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of bis(4-(2-quinolylmethoxy)phenyl)methyloximinoacetic acid (570 mg, 1.00 mmol), prepared as in step 1, ethanol (7 mL), dry THF (3 mL), and 1N NaOH (1.10 mL, 1.10 mmol) was stirred for 1 hour. The reaction mixture was diluted with water and the aqueous phase was washed with hexane and concentrated in vacuo. The resulting solid was collected by filtration to provide bis(4-(2-quinolylmethoxy)phenyl)methyloximinoacetic acid sodium salt (0.48 g, 81%): 1H NMR (300 MHz, DMSO-d6)δ4.18 (s, 2H), 5.38 (s, 2H), 5.42 (s, 2H), 7.05 (d, 2H, J=8.8 Hz), 7.10 (d, 2H, J=8.8 Hz), 7.29 (d, 2H, J=8.8 Hz), 7.29 (d, 2H, J=8.8 Hz), 7.57 (d, 2H, J=8.8 Hz), 7.62 (m, 2H), 7.69 (m, 2H), 7.79 (m, 2H), 8.02 (m, 2H), 8.43 (m, 2H); MS (FAB+) m/z: 592 (M+H)+. Anal. Calcd. for C33 H26N3O5Na: C, 69.83; H, 4.61; N, 7.40. Found: C, 68.77; H, 4.29; N, 6.74.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid (3.7 g, 0.011 mol), 10% palladium on carbon (0.5 g) and ethanol (100 ml) is shaken on a Parr hydrogenator for 1.5 hours at a hydrogen pressure of 40 psi. The catalyst is filtered off and the filtrate is concentrated to yield 3-amino-4-phenoxy-5-sulfamoylbenzoic acid (IX-A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:36])[S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH:23]=3)[CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>C(O)(C)C>[ClH:1].[NH2:14][CH2:13][CH:12]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][N:29]([CH3:36])[S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CCCS(=O)(=O)N(C)Cc1cccc(C(CNC(=O)OC(C)(C)C)C2(c3ccc(Cl)cc3)CCC2)c1
Agent: Cl
Solvent: CC(C)O
Product: CCCS(=O)(=O)N(C)Cc1cccc(C(CN)C2(c3ccc(Cl)cc3)CCC2)c1

Procedure:
tert-Butyl {2-[1-(4-chlorophenyl)cyclobutyl]-2-(3-{[methyl(propylsulfonyl)amino]methyl}phenyl)ethyl}carbamate (20.9 mg, 0.039 mmol) was treated with hydrochloric acid in isopropanol (5 M, 1 ml) at room temperature. The solvent was evaporated in vacuo. Water (1 ml) was added and the product was freeze-dried. Yield: 16 mg (0.034 mmol, 87%)
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Br[CH2:18][C:19](=[O:22])[CH2:20][CH3:21].C(N(CC)CC)C>C(OCC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thiol of Example 2 (7.1 g, 0.03M) was reacted with 1-bromo-2-butanone (5 g) and triethylamine (4.2 ml) in ethyl ether (25 ml) by the method of Example 8 to give the title compound, m.p. ca. 55°-57° C.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](Br)[CH2:12]Br)=[CH:7][CH:6]=1)[CH2:3]Br.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)#[CH:3]
Reactant: BrCC(Br)c1ccc(C(Br)CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C#Cc1ccc(C#C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.9 %

Procedure:
In a 2 liter-volume four-necked flask having the same equipments as used in 1) above were charged 100 g of 1,4-bis(1,2-dibromoethyl)benzene, 103 g of potassium t-butoxide and 1 liter of t-butyl alcohol, and the mixture was stirred taking care not to rapidly raise the temperature by cooling on an ice bath. The stirring was continued while gradually elevating the temperature finally to a refluxing temperature, at which stirring was conducted for 1.5 hours. The reaction mixture was poured into 6 liters of ice-water, and the thus formed precipitate was filtered by suction. Purification by sublimation (60°±3° C., 1 to 2 mmHg) gave 22.4 g of crystals of p-diethynylbenzene ##STR8## having a melting point of 96.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: [O-][n+]1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1F
Temperature: 25 °C

Procedure:
Concentrated H2SO4 (75 ml) was carefully added to 3-fluoropyridine N-oxide (Preparation 5) (50 g, 0.44 mol), cooled at room temperature by using a water bath. Fuming nitric acid (55 ml) was dissolved in concentrated sulfuric acid (75 ml) and the colourless solution was added drop-wise to the substrate over 15 minutes at room temperature. The yellow mixture was heated for 1.5 hours at 90° C. The mixture was allowed to reach room temperature and slowly poured onto ice (900 g). The aqueous layer was extracted with dichloromethane (3×500 ml) and the solvent evaporated under reduced pressure to yield a yellow solid. This was washed with pentane (200 ml). The residue was dissolved in dichloromethane (50 ml). A yellow precipitate formed which was filtered off to yield the title compound (10 g).
Reaction SMILES: [OH-:1].[K+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[NH:16][N:15]=[CH:14][C:13]=3[C:12]=2[C:20]#[N:21])[CH2:5][CH2:4]1>C(O)(C)(C)C.C(O)C>[NH:3]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[NH:16][N:15]=[CH:14][C:13]=3[C:12]=2[C:20]([NH2:21])=[O:1])[CH2:5][CH2:4]1
Reactant: [OH-]
Reactant: N#Cc1c(OC2CCCNCC2)ccc2[nH]ncc12
Agent: [K+]
Solvent: CCO
Solvent: CC(C)(C)O
Product: NC(=O)c1c(OC2CCCNCC2)ccc2[nH]ncc12
Reaction time: 30 h
Yield: 25.3 %

Procedure:
Potassium hydroxide (powder, 100 mg) was added to a solution of the 5-(azepan-4-yloxy)-1H-indazole-4-carbonitrile (9.2 mg, 0.036 mmol) obtained in Example 691 in t-butanol (2 ml) at room temperature, and the resulting mixture was stirred for 30 hours with heating under reflux while maintaining the temperature. The reaction mixture was diluted with ethanol and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol/28% aqueous ammonia) to obtain 5-(azepan-4-yloxy)-1H-indazole-4-carboxamide (2.5 mg, 25%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:13][CH:14]([C:19]1([CH3:24])OCC[O:20]1)[C:15]([O:17][CH3:18])=[O:16])[C:6]2=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]2[C:7]=1[C:6](=[O:12])[N:5]([CH2:13][CH:14]([C:19](=[O:20])[CH3:24])[C:15]([O:17][CH3:18])=[O:16])[C:4]2=[O:25]
Reactant: COC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C(C)=O

Procedure:
Methyl 2-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (46 mg, 19%) in the same manner as described in the above example 6 (1) from methyl 3-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.24 g, 0.67 mmol) and p-toluenesulfonic acid monohydrate (51 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:11][O:12]C(Cl)Cl.FC1C=C(F)C=C(OC)C=1C=O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[C:7]=1[CH:11]=[O:12]
Reactant: COc1cc(F)cc(F)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COc1cc(F)cc(F)c1C=O
Solvent: ClCCl
Product: COc1cc(F)c(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(Intermediates 26A and 26B were prepared in a similar manner to the preparation described in WO 2004046133). To a stirred solution of 3,5-difluoroanisole (1.0 g, 7.0 mmol) in dichloromethane (6 mL) at 0° C. was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) and dichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion of addition, the reaction mixture was stirred for 1 h and then poured into ice-water (50 mL). The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to give 2,6-difluoro-4-methoxybenzaldehyde, Intermediate 26A [less polar material, 230 mg, 19%, 1H NMR (400 MHz, CDCl3) δ ppm 3.85 (s, 3H), 6.47 (d, J=10.55 Hz, 2H), 10.17 (s, 1H)] and 2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polar material, 740 mg, 62%, 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H) 6.43-6.51 (m, 2H) 10.30 (s, 1H)], both as white solids.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[N:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH:28]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:19][CH2:20][CH3:21])=[O:38])[N:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH:28]=1
Reactant: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCS(=O)c1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccccc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
80 mg of 6-[[1-phenyl-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was dissolved in 2 ml of dichloromethane, mixed with 56 mg of m-chloroperbenzoic acid (about 60%), and the mixture was stirred for 10 minutes at 20° C. It was mixed with sodium disulfite solution, extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 30 mg was obtained.
Reaction SMILES: C1(C[NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[CH3:26][CH2:27][CH2:28][CH:29]([S:33](Cl)(=[O:35])=[O:34])[CH2:30][CH2:31][CH3:32]>>[CH2:28]([CH:29]([S:33]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=1)(=[O:35])=[O:34])[CH2:30][CH2:31][CH3:32])[CH2:27][CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Reactant: CCCC(CCC)S(=O)(=O)Cl
Product: CCCC(CCC)S(=O)(=O)Nc1cccc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
Sulfonation of aniline 17 by heptane-4-sulfonyl chloride following the method used in Example 6 gives tert-butyl 3-(3-(1-propylbutylsulfonamido)phenyl)propylcarbamate.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:5][CH2:6][O:7][C:8]1[CH:29]=[CH:28][C:11]([CH2:12][O:13]/[N:14]=[C:15](/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)\[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:10][CH:9]=1.CO.Cl>O1CCCC1>[CH3:3][N:4]([C:30]1[N:31]=[CH:32][CH:33]=[CH:34][N:35]=1)[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:13]/[N:14]=[C:15](/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)\[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:28][CH:29]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCCN(C)c2ncccn2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCOc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[4-[2-(methyl-2-pyrimidylamino)ethoxy]benzyloxyimino]-4-phenylbutyrate (1.22 g) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[2-(methyl-2-pyrimidylamino)ethoxy]benzyloxyimino]-4-phenylbutyric acid (1.09 g, yield 92%) as colorless crystals. m.p. 72-73° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[O:10]N.O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>>[F:2][C:3]1[C:4]2[O:10][C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]=3[C:5]=2[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NOc1ccc(Br)cc1F
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2oc3c(F)cc(Br)cc3c2C1
Yield: 14 %

Procedure:
The product of step A was reacted with tert-butyl 4-oxopiperidine-1-carboxylate then Boc protected following the procedure of Example 29, step B. Purification by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) provided tert-butyl 6-fluoro-8-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (320 mg, 14%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.33 (s, 1H), 7.16 (dd, J=10.0, 1.6 Hz, 1H), 4.51 (br s, 2H), 3.83 (br s, 2H), 2.88 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.S(O[CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CS(=O)(=O)OCCOCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCCc3ccccc3)cc2)C(O)C1

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46(b)] with 2-phenethyloxy-ethanol mesylate [J.Med.Chem. (1983),26 (11),1570-1576], prepared according to a procedure known from the literature, in the presence of potassium carbonate there was obtained tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate, alkylation of which analogously to Example 1(g) yielded tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 582 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:37][CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][N:41]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:37][CH2:38][O:39][C:40]2[N:41]=[CH:42][C:43]([CH2:44][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:47][CH:48]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 81.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride (60 mg) according to an analogous synthetic method to Example 337 described below and purified by LC-MS, the title compound (34 mg) was obtained.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13]O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]3)[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CCN(c2ccccc2)CC1
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2ccn(CC3CCN(c4ccccc4)CC3)c12
Temperature: 100 °C
Reaction time: 24 h
Yield: 13.9 %

Procedure:
To a mixture of (1-phenylpiperidin-4-yl)methanol (958 mg), methyl 1H-indole-7-carboxylate (590 mg), and toluene (20 mL) was added (tributylphosphoranylidene)acetonitrile (1.0 g) at room temperature. The mixture was stirred at 100° C. for 1 day. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 1-[(1-phenylpiperidin-4-yl)methyl]-1H-indole-7-carboxylate (163 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)[C:2]1C=CC=CC=1.ICC.N1CCOCC1>CN(C)C=O>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH3:2])[CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CCI
Solvent: C1COCCN1
Product: CCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 34: (+)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.40 g, 1.38 mmol), dimethyl formamide (3 mL), iodoethane (1.1 mL, 13.8 mmol) and morpholine (2 mL). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 45:55). Yield: 0.11 g. [α]D=+19.8° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 118-120° C.; MS m/z (relative intensity, 70 eV) 228 (M+, 14), 141, (16), 127 (14), 72 (26), 71 (bp).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[N:5](C(=O)C(F)(F)F)[CH2:4]1.OS(O)(=O)=O>O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: COC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3C(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Temperature: 90 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A suspension of 184 (314 mg, 0.75 mmol) in a mixture of conc. H2SO4 (4.5 mL) and water (0.5 mL) was stirred at 90° C. for 3 h, then cooled and diluted with water (80 mL). The solution was clarified by filtration and adjusted to pH 4 with aqueous NH3. The resulting precipitate was collected, dissolved in EtOAc and the solution was then filtered, concentrated under reduced pressure to a small volume and diluted with hexane to give 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-8-carboxylic acid (187) (226 mg, 95%) as a red solid: mp 205-208° C.; 1H NMR [(CD3)2SO] δ 13.3 (v br, 1H), 8.38 (d, J=1.3 Hz, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.82 (dd, J=9.1, 1.6 Hz, 1H), 7.76 (s, 1H), 6.45 (s, 1H), 4.35-4.25 (m, 1H), 3.91-3.80 (m, 2H), 3.76 (dd, J=11.2, 8.5 Hz, 1H), 3.72 (dd, J=10.3, 2.8 Hz, 1H). Anal. C14H11ClN2O4) C, H, N.