Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:23][CH:22]=1)([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:6][CH2:7][CH3:8])C>CO.[OH-].[Na+]>[N:30]1([CH2:29][CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:5]([S:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)(=[O:10])=[O:11])([CH2:6][CH2:7][CH3:8])[C:4]([OH:37])=[O:3])=[CH:26][CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCCC(Cc1ccc(OCCN2CCCCCC2)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(Cc1ccc(OCCN2CCCCCC2)cc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid was prepared starting from 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester (2 g, 3.76 mmol) dissolved in methanol (300 ml) and 10 N NaOH (15 ml). The resulting mixture was worked up as outlined in example 1. Yield 830 mg (44%); brown solid; mp 55° C.; MS: 504.4 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]2[CH:21]=[CH:22][S:23][C:19]=2[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCCl>[Br:1][C:21]1[C:20]2[CH:24]=[CH:25][C:17]([O:16][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][C:19]=2[S:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(COc2ccc3ccsc3c2)cc1
Solvent: ClCCCl
Product: Brc1csc2cc(OCc3ccccc3)ccc12
Temperature: 80 °C
Yield: 92 %

Procedure:
N-bromosuccinimide (15.70 g, 83.92 mmol) and p-toluenesulfonic add (2.70 g, 15.68 mmol) were added to a solution of 6-benzyloxy-benzothiophene (Zhengying C., CN 1370533 A, 21.2 g, 88.33 mmol) in 1,2-dichloroethane (120 ml). The mixture was maintained at 80° C. for 35 min, cooled in an ice bath, and the succinimide was removed by filtration. The solution was extracted with saturated sodium bicarbonate solution, dried over Na2SO4, filtered, and concentrated under vacuum to give an oil. Crystallisation from pentane afforded a white solid (21.60 g, 92%, mp: 68° C.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:8][CH:9]=2)[C:4](=[O:19])[N:3]1[CH2:20][C:21]([O:23][CH3:24])=[O:22].[CH2:25](O)[CH2:26][CH2:27]C>CCOC(C)=O>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:8][CH:9]=2)[C:4]([OH:19])=[C:20]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1
Reactant: COC(=O)CN1C(=O)c2ccc(Oc3ccccc3C)cc2C1=O
Reactant: CCCCO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccccc3C)cc2c1O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-(1,3-dioxo-5-(o-tolyloxy)isoindolin-2-yl)acetate (10.0 g, 30.8 mmol) in n-butanol (206 mL) at 95° C. was added 1 N sodium n-butoxide solution (62.0 mL, 62.0 mmol). The resulting mixture was stirred at 95° C. for 2 hours before cooling to room temperature. The solvent was partially removed and the residue was diluted with EtOAc (200 mL) and 2 N HCl (40 mL). The resulting mixture was stirred vigorously for 15 minutes at room temperature and the precipitation was collected by filtration. The filter cake was washed with H2O and then dried at 70° C. in vacuo to give a yellow solid. The solid obtained was further suspended in EtOAc (300 mL) and the slurry was heated to reflux with stirring for 2 hours. After cooling to room temperature, the precipitate was collected by filtration and then dried in vacuo to give the title compound in 1.6 g. 1H NMR (CDCl3, 200 MHz): δ=10.38 (s, 1H), 8.42-8.32 (m, 2H), 7.43 (s, 1H), 7.34-7.10 (m, 3H), 7.02 (d, 1H, J=7.6 Hz), 4.39 (t, 2H, J=6.6 Hz)), 2.20 (s, 3H), 1.84-1.38 (m, 4H), 0.99 (t, 3H, J=7.2 Hz).
Reaction SMILES: CO.C([O:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14])C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[OH:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:14])=[O:15]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCOCc5ccccc5)ccc43)ncn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCO)ccc43)ncn2)CC1
Yield: 80 %

Procedure:
Palladium hydroxide (100 mg) was added to a methanol (10 mL)/ethyl acetate (10 mL) mixed solution of the tert-butyl 4-{[6-(5-{[2-(benzyloxy)ethyl]sulfonyl}indolin-1-yl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (486 mg, 0.817 mmol) produced in Reference Example 44, and the mixture was stirred for 19.5 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite (trade name), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2-4:1, V/V) to obtain the title compound as white foam (330 mg, yield: 80%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4].[OH-].[Na+].[Cl:12][C:13]1[S:14][C:15]([CH2:18]Cl)=[CH:16][N:17]=1>CN(C=O)C>[Cl:12][C:13]1[S:14][C:15]([CH2:18][NH:4][C:3]([N:2]([CH3:9])[CH3:1])=[N:5][N+:6]([O-:8])=[O:7])=[CH:16][N:17]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: CN(C)C(=N)N[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reaction time: 13 h

Procedure:
To a mixture of 13.0 g of N,N-dimethyl-N'-nitroguanidine, 5.90 g of powdery sodium hydroxide and 200 ml of dry DMF was dropwise added a solution of 2-chloro-5-(chloromethyl)thiazole in 15 ml of DMF over 2 hours while cooling with ice. The bath was removed, and stirring continued at room temperature for 13 hours followed by removal of the DMF by distillation under reduced pressure. To the residue was added 200 ml of acetonitrile followed by separation of insoluble materials by filtration on celite. The filtrate was purified by column chromatography (eluted with dichloromethane-acetonitrile 2:1-1:2). There was obtained 6.45 g of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitroguanidine (reference compound No. 1), mp 155°-160° C. Crystallization from ethanol raised mp to 165.5°-166.5° C. NMR (DMSO-d6): 2.96(6H, s), 4.50(2H, d, J=5.8 Hz), 7.56(1H, s), 8.53(1H, br t, J=5.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>>[Cl:1][C:2]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(Cl)cccc1Cl
Product: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2,6-dichlorotoluene (200 g) is added dropwise fuming nitric acid (d=1.52, 206 ml) at 25° to 30° C. After stirring for 30 minutes at room temperature, the mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with an aqueous sodium hydrogen carbonate solution and then dried. The solvent is distilled off under reduced pressure to give 2,6-dichloro-3-nitrotoluene as yellow crystals (253.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2O)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]=[CH:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c1CCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2c1CC=C2
Yield: 44.5 %

Procedure:
In the manner of Example 1, step I, 14.0 g (0.078 mole) of 4-nitro-1-indanol (compound D, schema 1, prepared as in Example 1, step D) was heated in the presence of 0.1 g of p-toluenesulfonic acid and 200 mL of toluene to give 5.6 g of 7-nitro-1H-indene.
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]([CH3:19])=[C:9]([C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)[C:10]=1[CH3:11])=O)C.[OH-].[K+]>O.CO>[CH3:19][C:8]1[NH:7][CH:6]=[C:10]([CH3:11])[C:9]=1[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: CCOC(=O)c1[nH]c(C)c(C2=CCN(C)CC2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c[nH]c(C)c1C1=CCN(C)CC1
Yield: 51.2 %

Procedure:
A mixture of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (1.02 g, 3.9 mmol), KOH (0.287 g, 5.1 mmol) in water (5 mL) and methanol (10 mL) was heated to reflux under nitrogen for 3 days. The cooled reaction was extracted with ethyl acetate (3×), dried and concentrated to give 380 mg of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine. The aqueous layer was adjusted to pH 7, the resulted precipitate was collected by filtration, washed with water to give 380 mg of 4-(2,4-dimethyl-1H-pyrrol-3-yl)-1-methyl-1,2,3,6-tetrahydro-pyridine and 480 mg of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([O:17][S:40]([CH3:39])(=[O:42])=[O:41])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1
Yield: 75.3 %

Procedure:
p-Nitrobenzyl (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e1) (147 mg) was suspended in dichloromethane (5 ml) containing triethylamine (100 mg), and the mixture was cooled to 0°. Whilst stirring the mixture at 0°, methanesulphonyl chloride (75 mg in 2.6 ml dichloromethane) was added dropwise over 5 minutes and the solution then stirred at a temperature of between 0° and -10° C. for a further 25 minutes. The solution was diluted with dichloromethane (10 ml) and washed with cold water (20 ml) phosphate buffer (pH 3.1) (20 ml) and 5% NaHCO3 solution (20 ml). The organic layer was dried (MgSO4) and evaporated down to afford a solid which was triturated with ether and collected by filtration to yield p-nitrobenzyl (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6 -[(S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e2) (130 mg); νmax (KBr) 1775, 1690, 1620, 1520, 1340, 1270 and 1175 cm-1.
Reaction SMILES: [ClH:1].C(O)C.C([N:12]1[CH2:19][C:16]2([CH2:18][CH2:17]2)[N:15]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[ClH:1].[F:24][C:21]([F:22])([F:23])[C:20]([N:15]1[CH2:14][CH2:13][NH:12][CH2:19][C:16]21[CH2:18][CH2:17]2)=[O:25]
Reactant: O=C(N1CCN(Cc2ccccc2)CC12CC2)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(N1CCNCC12CC2)C(F)(F)F
Yield: 82.6 %

Procedure:
1 N hydrochloric acid/ethanol (105 ml, 105 mmol) and 5% palladium carbon (3 g) were added to an ethanol (250 ml) solution of the compound (15.5 g, 51 mmol) obtained in Step 4 above and the resulting mixture was subjected to catalytic reduction for 15 hours in a hydrogen atmosphere. The catalyst was removed by filtration through celite and then the filtrate was concentrated under reduced pressure. An ethanol/diethyl ether mixed solvent was added to the residue obtained and the deposited solid was collected by filtration to give the title compound (10.3 g, 83%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[CH:33][C:20]1[NH:21][CH:22]=[C:23]([C:24]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:25])[C:19]=1[CH3:18])[C:11](=[O:17])[NH:12]2
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3F)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(2-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (40 mg, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCCO
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(C2OCCO2)c1
Yield: 96.8 %

Procedure:
3-Bromobenzaldehyde (4.00 g, 21.6 mmol), ethane-1,2-diol (6.03 mL, 108 mmol) and toluene-4-sulfonic acid monohydrate (186 mg, 1.08 mmol) were dissolved in toluene (80 mL), and the solution was stirred under reflux for 4 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (4.79 g, 20.9 mmol, 97%) was obtained as a colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])(=[O:7])[CH3:6].[Br:23]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:23][CH:19]([C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=1)[C:20]([OH:22])=[O:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(CC(=O)O)cc1OC(C)=O
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C(Br)C(=O)O)cc1OC(C)=O
Temperature: 70 °C
Yield: 91.5 %

Procedure:
Thionyl chloride (60 ml) was added to a suspension of 3,4-diacetoxyphenylacetic acid (51.1 g) in carbon tetrachloride (105 ml) and the mixture was heated at 70° C. for one hour. After cooling to room temperature, N-bromosuccinimide (42.3 g), carbon tetrachloride (105 ml) and a little amount of hydrobromic acid were added, and the mixture was heated for an additional one hour. The resulting mixture was concentrated under reduced pressure, and the residue was redissolved in carbon tetrachloride. After filtering off the insoluble matters, the filtrate was dissolved in acetone (400 ml) and the pH of the solution was adjusted to 4.0 with saturated sodium bicarbonate aqueous solution under ice cooling. The resulting mixture was extracted with chloroform. The chloroform layer was washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, giving 61.4 g of the objective compound.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2].C(N(CC)CC)C.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OCC)C>[C:16]([O:8][CH2:7][CH2:6][CH2:5][O:4][N+:1]([O-:3])=[O:2])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)Cl
Reactant: O=[N+]([O-])OCCCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OCCCO[N+](=O)[O-]
Reaction time: 19 h

Procedure:
20 mmol 3-Nitrooxypropanol dissolved in 10 ml Diethylether and 20 mmol Triethylamine were cooled to 0° C. 18.2 mmol hexoylchlorid were dropped over a period of 5 minutes at 0 to 5° C. After 19 hours stirring without cooling, the reaction mixture was extracted with 1N HCl, twice with water, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo leaving 3.1 g.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][CH2:44][CH2:45][OH:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:46][CH2:45][CH2:44][O:43][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][O:37]3)[CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.8 %

Procedure:
A solution of intermediate 95a (1.42 g, 6.15 mmol) and triphenyl phosphine (3.22 g, 12.29 mmol) in THF (50 mL), under an atmosphere of argon was treated with 2-(tetrahydro-pyran-2-yloxy)-ethanol (1.25 mL, 9.22 mmol), followed by the dropwise addition of diethyl azodicarboxylate (1.94 mL, 12.29 mmol). The reaction mixture was then stirred at RT for 1 h. Water (0.5 mL) was added and the mixture was concentrated in vacuo. The residue was taken up in EtOAc (8 mL) and cyclohexane was added until triphenylphosphine oxide had precipitated out of solution. This was filtered and the filtrate was concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to afford the title compound as an orange/brown oil (2.98 g, >100%). LCMS (Method 3): Rt 3.20 min, m/z 360 [MH+].
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][S:8][CH:7]2[CH2:10][C:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:13])[N:6]12)=O.[NH3:28].CO>CO>[C:24]([O:23][C:21](=[O:22])[NH:20][C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12](=[O:13])[N:6]2[CH:7]([S:8][CH2:9][CH:5]2[C:3](=[O:2])[NH2:28])[CH2:10]1)([CH3:25])([CH3:26])[CH3:27]
Reactant: N
Reactant: COC(=O)C1CSC2CC(NC(=O)OC(C)(C)C)(c3ccccc3)C(=O)N21
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CC2SCC(C(N)=O)N2C1=O
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of compound 16 (500 mg, 1.28 mmol) in methanol (10 mL) was added NH3-MeOH (10 mL) at room temperature and stirred for 2 h. The solvent was removed in vacuo and afford compound 17 (470 mg, 97.4%). 1H NMR (400 MHz, CDCl3) δ1.42 (s, 9 H), 3.05-3.08 (m, 1 H), 3.35-3.37 (m, 1 H), 3.37-3.49 (m, 1 H), 3.75-3.80 (m, 1 H), 4.89 (bs, 1 H), 4.98 (bs, 1 H), 5.43 (bs, 2 H), 6.57 (bs, 1 H), 7.37-7.50 (m, 5 H). MS (M+1): 378.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:34])[C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(=O)NCCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)CCn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-acetamide (preparation described herein) was treated with NaH (1.05 eq), MeI (1.05 eq) in dry DMF under argon at RT for 2 h to give after purification by prep. HPLC the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22](O)=[O:23]>>[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:22]([NH:17][CH:15]([C:5]1[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=1)[CH3:16])=[O:23]
Reactant: Cc1cc(C(=O)O)cc(Br)n1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(Br)n1
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (387 mg, a yellow solid) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.0 mmol, Amine-5, single enantiomer) and 2-bromo-6-methylisonicotinic acid (223 mg, 1.0 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:28])[C:10]1[N:14]([CH2:15][CH2:16][CH2:17]O)[C:13]2[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17][O:28]1
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a stirred solution of 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propan-1-ol (Reference example 207, 1.37 g, 3.24 mmol) in pyridine (16 mL) was added methanesulfonyl chloride (502 μL, 6.49 mol) at 0° C. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (32 mL) and potassium carbonate (897 mg, 6.49 mmol) was added. After being stirred for 12 h at 80° C., the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (341 mg, 0.844 mmol, 26%).