Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C(N(CC)CC)C.[C:38](O)([CH3:41])([CH3:40])[CH3:39]>C(Cl)(Cl)Cl>[CH3:39][C:38]([O:23][C:22](=[O:24])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[CH:20][CH:19]=1)([CH3:41])[CH3:40]
Reactant: CC(C)(C)O
Reactant: O=C(O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A solution of 3 g (9.1 mmol) of 4-[2-[[(phenylmethoxy)carbonyl]amino]-ethoxy]benzeneacetic acid in 60 ml of chloroform is cooled to −30° C. and 1.18 g (10.9 mmol) of ethyl chloroformate and 1.52 ml (10.9 mmol) of triethylamine are added. The mixture is stirred for 1 hour at −30° C. and 1.63 g (22 mmol) of t-butanol and 1.52 ml (10.9 mmol) of triethylamine are then added. The mixture is stirred for 16 hours at room temperature and then concentrated under reduced pressure. The evaporation residue is taken up in 100 ml of ethyl acetate and the organic phase obtained is washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel using a dichloromethane/methylcyclohexane mixture (1/1; v/v) as the eluent to give 930 mg of the expected compound (yield=26%).
Reaction SMILES: [K+].[Br:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12](=[O:16])[C:13]([O-:15])=O.[C:17]([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[C:12]([C:8]2[C:7]3[C:11](=[C:3]([Br:2])[N:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[O:16])[C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)nccc12
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(Br)nccc12

Procedure:
Precursor 5f, 1-benzoyl-3-(R)-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from (7-bromo-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4g, and 1-benzoyl-3-(R)-methylpiperazine. MS m/z: (M+H)+ calcd for C21H20BrN4O3: 455.07; found 455.14. HPLC retention time: 1.45 minutes (column B).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:42]=[CH:41][C:29]([O:30][C:31]2[CH:38]=[CH:37][C:36]([CH2:39]Cl)=[CH:35][C:32]=2[C:33]#[N:34])=[CH:28][C:27]=1[C:43]([F:46])([F:45])[F:44]>C(Cl)Cl>[Cl:25][C:26]1[CH:42]=[CH:41][C:29]([O:30][C:31]2[CH:38]=[CH:37][C:36]([CH2:39][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:35][C:32]=2[C:33]#[N:34])=[CH:28][C:27]=1[C:43]([F:44])([F:45])[F:46]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(CSc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 43.2 %

Procedure:
To a suspension of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (35.0 mg, 0.159 mmol) and DIPEA (0.08 mL, 0.458 mmol) in DCM (1 mL) was added 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(chloromethyl)benzonitrile (50 mg, 0.144 mmol). The solution was heated at 60° C. overnight. Purification via MDAP then afforded the title compound (33 mg, 43.1% yield). LCMS: rt=3.28 min, [M+H+]=531
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:22]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])=[O:24]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH2:12][C:13](=[O:15])[NH:20][C:21]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:22]=1[C:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
45 g of carbobenzoxy-glycine dissolved in 1 liter of absolute tetrahydrofuran are treated dropwise while cooling with ice with 20 ml of thionyl chloride and stirred for 1 hour while cooling with ice. There is then rapidly added dropwise thereto a suspension of 50 g of 2-amino-5-nitro-2'-fluorobenzophenone in 200 ml of absolute tetrahydrofuran and the mixture is stirred at room temperature for 18 hours. The solution obtained is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is dissolved in a small amount of hot ethyl acetate, concentrated partially and treated with ether. Benzyl{[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]methyl}-carbamate is obtained. The mother liquors are purified on a 100 g silica gel column using methylene chloride as the eluting agent, an additional amount of the aforementioned product being obtained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:3](=[O:24])[CH:2]([NH:1][C:33]([O:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:34])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCCC2)c2ccccc21
Reaction time: 2 h

Procedure:
The amine was dissolved in anhydrous tetrahydrofuran (9 ml) under an atmosphere of nitrogen, at room temperature, and triethylamine (249 μl) was added dropwise. A solution of 4-nitrophenyl chloroformate (363 mg) in anhydrous tetrahydrofuran (9 ml) was then added, and the reaction mixture stirred for a further 2 h. After this time the undissolved solid was filtered off, washed with tetrahydrofuran, and the filtrate evaporated in vacuo. The residue was azeotroped with toluene (2×20 ml) and ether (20 ml). The resultant solid was then triturated in anhydrous ether to afford the title compound (420 mg) as a white solid. TLC (silica, petrol (60/80):ethyl acetate 2:1) Rf=0.7. 1H NMR (360 MHz, CDCl3) δ 0.77 (3H, d, J=6.6 Hz), 0.83 (3H, d, J=6.6 Hz), 1.40-1.87 (12H, m), 2.06-2.17 (1H, m), 2.98-3.02 (1H, m), 3.48 (1H, dd, J=13.8 and 5.0 Hz), 4.32 (1H, dd, J=13.8 and 9.3 Hz), 5.10 (1H, d, J=8.4 Hz), 6.92 (1H, d, J=8.2 Hz), 7.26-7.39 (4H, m), 7.53 (1H, dd, J=8.5 and 8.5 Hz), 7.61 (1H, m), 8.21 (2H, d, J=9 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: CN1CCN(N)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(Nc2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)CC1
Yield: 34 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (17 mg, 34% yield.) MS/ES+: m/z=429.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][CH:15]=[O:16])[CH2:9][C:10](OC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][CH2:22][CH:21]([NH2:25])[CH2:20]1.CCN(C(C)C)C(C)C.CC(O)=O>CO>[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][CH2:22][CH:21]([N:25]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][C:15]2=[O:16])[CH2:20]1
Reactant: COC(=O)CN(CC=O)C(=O)OC(C)(C)C
Reactant: CC1(C)CCCC(N)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1(C)CCCC(N2CCN(C(=O)OC(C)(C)C)CC2=O)C1

Procedure:
To a solution (0.19 M) of methyl N-(tert-butoxycarbonyl)-N-(2-oxoethyl)glycinate (prepared as described in Bioorg. Med. Chem. 2007, 15, 2092-2105) in MeOH were added 3,3-dimethylcyclohexanamine hydrochloride (1.5 eq), DIPEA (1.5 eq), NaBH3(CN) (1.5 eq) and AcOH (1.4 eq). After stirring for 2 hours at RT more NaBH3(CN) (1.5 eq) was added and reaction mixture was irradiated at MW for 1 hour at 125° C. MeOH was removed under reduced pressure and the residue purified by filtration on silica with elution of the desired intermediate with EtOAc. Evaporation of the organic solvent yielded tert-butyl 4-(3,3-dimethylcyclohexyl)-3-oxopiperazine-1-carboxylate. MS (ES) C17H30N2O3 requires: 310, found: 311 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.[CH3:20][Mg]Br>C1COCC1>[F:17][C:12]([F:16])([O:11][C:7]1[CH:6]=[C:5]([C:4](=[O:18])[CH3:20])[CH:10]=[CH:9][CH:8]=1)[CH:13]([F:14])[F:15]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cccc(OC(F)(F)C(F)F)c1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-methoxy-N-methyl-3-(1,1,2,2-tetrafluoroethoxy)benzamide (7.5 g, 25.2 mmol) was dissolved in THF (84 mL) and cooled to −78° C. Methyl magnesium bromide (3N in diethyl ether, 21.03 mL, 63.1 mmol) was added dropwise and the resulting reaction mixture was stirred for 30 min. The reaction was warmed to 25° C. over 30 minutes and then was quenched by addition to an Erlenmeyer flask containing ice and saturated ammonium chloride solution. This mixture was extracted with EtOAc, the organic layers were collected and dried with anhydrous magnesium sulfate, then filtered and concentrated. Crude material obtained corresponds to 1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]ethanone. 1H NMR (400 MHz, CDCl3) δ 2.62 (s, 3H), 5.96 (t, t, J=53, 2.7 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.88 (d, J=7.8 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[F:42][C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[C:47]([F:49])[CH:48]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:45]3[CH:44]=[C:43]([F:42])[CH:48]=[C:47]([F:49])[CH:46]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Reactant: OB(O)c1cc(F)cc(F)c1
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cc(F)cc(F)c2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 3,5-difluorophenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-])=O.[OH-].[Na+].[C:17](=[S:19])=[S:18].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]2[S:19][C:17](=[S:18])[NH:12][C:3]=2[CH:4]=1)([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: S=C=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2sc(=S)[nH]c2c1
Temperature: 115 °C
Yield: 54.3 %

Procedure:
A solution of 4-chloro-3-nitro-phenylacetic acid (25.0 g, 0.116 mol) in 1N aqueous NaOH (143 mL, 0.143 mol) was added to preformed polysulfide solution (from 72.42 g, 0.301 mol of Na2S.9H2O, 26.87 g, 0.837 mol of S, and 74 mL of H2O) at 50° C. The resulting mixture was mechanically stirred as the temperature of the oil bath was gradually increased to 115° C. over 10 min. The mixture was stirred at that temperature for two hours then allowed to cool to room temperature over two hours. Carbon disulfide (13.9 mL, 0.231 mol) was added and the reaction flask was placed in a 50° C. oil bath. The reaction mixture was stirred at that temperature for 18 hours then cooled in an ice bath, stirred, and acidified by cautious addition of glacial acetic acid (50 mL). The mixture was filtered and the filter cake was washed with water. The solid was stirred with sodium carbonate (30.7 g, 0.29 mol) in water then filtered to remove sulfur. The filtrate was cooled in an ice-bath and gradually acidified to pH 3.3 by addition of 6N HCl (100 mL). The precipitate was collected, washed with ice-cold water (100 mL) and dried in vacuo to a pale brown solid (21.5 g, 82%). This crude product was recrystallized from ethanol to afford 5-carboxymethyl-2-thioxo-2,3-dihydrobenzothiazole as a pale brown solid (14.2 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]2)[C:16](=[O:30])[CH2:15]1.C(N(CC)CC)C>ClCCl>[C:26]([O:25][C:23]([N:19]1[CH2:18][CH:17]2[CH:21]([CH2:22][CH:14]([CH2:13][O:12][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:15][C:16]2=[O:30])[CH2:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)CC(=O)C2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CC(=O)C3CN(C(=O)OC(C)(C)C)CC3C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.6 %

Procedure:
17.5 g of p-toluenesulphonyl chloride are added to a solution of 12.4 g of (3aRS,6SR,7aSR)-6-hydroxymethyl-2-tert-butyloxycarbonylperhydroisoindol-4-one and 12.9 cm3 of triethylamine in 250 cm3 of dichloromethane. The mixture is stirred at room temperature for 20 hours, washed with 200 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (diameter 7 cm, particle size 0.06-0.20 mm, height 70 cm), eluting under a pressure of 0.7 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60:40 by volume) and collecting fractions of 250 cm3. Evaporation to dryness of fractions 16 to 24 under reduced pressure (2.7 kPa) gives 12.6 g of (3aRS,6SR, 7aSR)-2- tert-butyloxycarbonyl-6-tosyloxymethylperhydroisoindol-4-one in the form of an oil.
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])[CH2:4][CH2:3]1.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C1CCN2C(=NCCC2)CC1.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])[CH2:4][CH2:3]1
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Brc1ccccn1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1N(CC2CCN(c3ccccn3)CC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 120 °C
Yield: 24.9 %

Procedure:
A mixture of 1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one hydrobromide(0.20 g, 0.44 mmol), 2-bromopyridine (0.16 mL, 0.65 mmol), tetrabutyl ammonium iodide (0.05 g) and DBU (0.16 mL, 1.09 mmol) in DMF (5.00 mL) was heated at 120° C. for 15 hrs. After cooling down to ambient temperature, water (30.0 mL) was added. The above mixture was extracted twice with ethyl acetate (50.0 mL), the combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 30% ethyl acetate in hexane to give a white solid (0.05 g, 27%): mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 8.17 (d, 1H), 7.47 (td, 1H), 7.31 (t, 1H), 7.18 (d, 1H), 7.06 (t, 1H), 6.92 (d, 1H), 6.66 (d, 1H), 6.59 (dd, 1H), 6.52 (s, 1H), 6.12 (s, 1H), 5.91-5.84 (m, 2H), 4.91 (d, 1H), 4.66 (d, 1H), 4.42-4.27 (m, 2H), 3.82-3.53 (m, 2H), 2.85 (t, 2H), 2.22-2.05 (m, 1H), 1.85-1.70 (m, 2H), 1.53-1.35 (m, 2H); 13C NMR(75 MHz, CDCl3) δ 177.9, 158.8, 156.1, 149.0, 147.4, 142.8, 142.5, 138.0, 132.4, 129.1, 124.2, 123.5, 119.5, 112.9, 108.8, 107.7, 103.1, 101.7, 93.8, 80.7, 58.3, 46.0, 45.5, 45.4, 35.2, 29.8, 29.7; MS (ES+) m/z 456 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:16]1[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[NH:19][CH:20]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[CH3:25][CH2:26]CCCC>CN(C)C=O>[CH2:3]([C:16]1[CH:17]=[C:18]([C:21]([O:23][CH2:25][CH3:26])=[O:22])[NH:19][CH:20]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC
Reactant: CCCCCCCCCCCCCc1c[nH]c(C(=O)O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCc1c[nH]c(C(=O)OCC)c1
Temperature: 25 °C
Yield: 55 %

Procedure:
After washing 140 mg (3.50 mmol) of 60% sodium hydride with hexane, 20 ml of dimethylformamide was added thereto, and then 90 mg (3.38 mmol) of 4-tridecylpyrrole-2-carboxylic acid prepared in Example 2 was further added portionwise under stirring at room temperature. After stirring for 10 minutes, 5.0 g (31.8 mmol) of ethyl idodide was added to the reaction solution followed by heating it at 55° C. for 22 hours. After cooling, an aqueous solution of hydrochloric acid was added to acidify the mixture, and the resulting mixture was then extracted with ethyl acetate, washed with an aquous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/10) to obtain 600 mg (55% yield) of ethyl 4-tridecylpyrrole-2-carboxylate as white crystals, m.p. 59°-60° C.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.ClCl>C(O)(=O)C>[Cl:1][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=2)[C:8]1=[O:12]
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: Cl
Agent: ClCl
Solvent: CC(=O)O
Product: O=C1c2ccc(Cl)cc2CC1Cl
Reaction time: 3 h

Procedure:
Hydrogen chloride gas is passed into a solution of 10.11 g (60 mmoles) of 5-chloro-1-indanone in 50 ml of glacial acetic acid at 10°-15° C. for 30 minutes. 4.25 g (60 mmoles) of condensed chlorine are then allowed to flow slowly into the solution at 10° C. and the mixture is allowed to come gradually to room temperature and is subsequently stirred for 3 hours. After standing overnight, the solution is poured onto ice, the oil which separates out is extracted with acetic acid ethyl ester and the solvent is distilled off under reduced pressure. The oil which remains crystallizes on standing. The product can be recrystallized from petroleum ether and then melts at 63°-66° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:13]([CH2:27][CH:28]([OH:30])[CH3:29])[S:14]([C:17]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:16])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>O.C(N(CC)CC)C.ClCCl.CS(C)=O>[CH2:27]([N:13]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:14]([C:17]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:15])=[O:16])[C:28]([CH3:29])=[O:30]
Reactant: CCCCCCN(CC(C)O)S(=O)(=O)c1cccc2cnccc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCN(CC(C)=O)S(=O)(=O)c1cccc2cnccc12
Temperature: -55 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To 60 ml of a dried dichloromethane solution containing 2.4 ml of oxalyl chloride was added dropwise at -50° C. 12 ml of a dichloromethane solution containing 4.08 ml of dimethylsulfoxide. To the mixture was added dropwise over a period of 20 minutes, while maintaining the temperature at -55° C., 4 ml of a dried dichloromethane solution containing 8.34 g of N-hexyl-N-(2-hydroxypropyl)-5-isoquinolinesulfonamide, followed by stirring at -50° C. to -60° C. for 15 minutes. To the resulting mixture was added 16.8 ml of triethylamine, and the temperature of the mixture was elevated to 15° to 20° C. over a period of 1.5 hours. To the resulting reaction mixture was added 100 ml of water, and the pH was adjusted to 5 with 1N hydrochloric acid solution. The dichloromethane layer was washed with 50 ml of a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. Then, the dichloromethane was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 200 g; solvent: a 2% methanol solution in chloroform) to obtain 7.17 g of N-acetonyl-N-hexyl-5-isoquinolinesulfonamide.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH3:15][CH:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1>>[CH3:15][CH:16]1[NH:17][CH2:18][CH2:19][N:20]([CH2:2][C:3]2[C:11]3[O:10][CH:9]=[CH:8][C:7]=3[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=2)[CH2:21]1
Reactant: CC1CNCCN1
Reactant: O=[N+]([O-])c1cc(CBr)c2occc2c1
Product: CC1CN(Cc2cc([N+](=O)[O-])cc3ccoc23)CCN1
Yield: 95 %

Procedure:
The title compound was prepared according to the procedure of Example 112, Step 1, starting from 7-(bromomethyl)-5-nitro-1-benzofuran (120 mg, 70 mol %, 0.39 mmol; Intermediate 64) and 2-methylpiperazine (196 mg, 1.95 mmol). The crude product was purified by flash chromatography (eluent: 4% MeOH, 1% NEt3 in DCM). The title compound (102 mg, 87%) was obtained as a light yellow sticky oil. HPLC 99%, RT=1.60 min (System A; 5-60% MeCN over 3 min), 100%, RT=1.40 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C14H17N3O3 m/z 276 (M+H)+.