Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13](=[C:21]2[C:22](=[O:23])[O:24][C:17]([CH3:25])([CH3:16])[O:18][C:19]2=[O:20])[OH:15])[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(O)=C2C(=O)OC(C)(C)OC2=O)CCC1
Reaction time: 8 h

Procedure:
1-tert-Butoxycarbonylamino-cyclobutanecarboxylic acid (1.0 g, 4.6 mmol) and Meldrum's acid (2,2-dimethyl-[1,3]dioxane-4,6-dione, 0.74 g, 5.1 mmol) are dissolved in 20 ml dichloromethane. 4-Dimethylaminopyridin (0.88 g, 7.2 mmol) and EDCl (1.07 g, 5.6 mmol) are added and the mixture is left in a refrigerator (4° C.) overnight. The reaction mixture is diluted with additional 200 ml dichloromethane and washed twice with 0.1 N HCl and with brine. Drying of the organic phase and evaporation of the solvent delivered the crude title compound which is used in the subsequent step without further purification.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6].[Br:28][CH2:29][C:30](Br)=[O:31].O>ClCCl>[Br:28][CH2:29][C:30]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[C:9]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=3[N:19]=2)[CH:10]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nc12
Reaction time: 18 h
Yield: 78.4 %

Procedure:
Aluminium trichloride (12.8 g, 0.096 mol) was added portionwise over 1 hour to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (10.0 g, 0.032 mol) and bromoacetyl bromide (5.6 ml, 0.064 mol) in dichloromethane (150 ml) at 0° C. After 18 hours at room temperature, the reaction mixture was poured into ice an water (400 g) and the resulting mixture stirred vigorously. The organic phase was separated and the aqueous phase further extracted with dichloromethane (2×100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum to give an off-white solid, trituration of which from ether gave the title compound as a white solid (10.87 g, 78%), m.p. 159°-160° C. Found C,52,54; H,4.88; N,12.78. C19H21BrN4O3 requires C,52.67; H,4,88; N,12.93%
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:24](=[O:25])[CH2:23][NH:22][C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.8 %

Procedure:
A solution of 4-amino-1-benzylpiperidine (3.80 g, 20 mmol) in CH2Cl2 (40 mL) was treatedwith N-(tert-butoxycarbonyl)glycine (3.48 g, 20 mmol), EDCI (4.02 g, 21 mmol) and HOBt (2.83 g, 21 mmol). After the reaction mixture was stirred at room temperature for 12 h, 2 N NaOH solution (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL×2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, ethyl acetate/MeOH/Et3N=85/12/3) afforded 1-benzyl-4-{N-(tert-butoxycarbonyl)glycyl}aminopiperidine (6.59 g, 95%).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:11]1([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH3:2][O:3][N:4]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CON
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC)c1ccccc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
1.4 g (16.8 mmol) of O-methylhydroxylamine hydrochloride and 1.16 g (8.4 mmol) of potassium carbonate were added to a solution of 0.50 g (2.8 mmol) of ethyl phenylglyoxylate in N,N-dimethylformamide, and the resulting mixture was stirred at 90° C. for 4 hours. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel, eluted with a stepwise gradient of ethyl acetate (10-30%) in hexane, to give 0.47 g (67% yield) of the less polar isomer of the title compound and 0.13 g (19% yield) of the more polar isomer of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:4]1[N:3]=[C:2]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1cccnc1
Reactant: Fc1cccc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: Fc1cccc(-c2cccnc2)n1
Temperature: 110 °C
Yield: 100.9 %

Procedure:
A mixture of 2-chloro-6-fluoro-pyridine (0.436 mL, 3.31 mmol) (Oakwood,), 3-pyridylboronic acid (448 mg, 3.65 mmol) (Combi-Blocks Inc.), and tetrakis(triphenylphosphine)palladium (0) (77 mg, 0.066 mmol) (Strem Chemicals) was purged with argon and dioxane (10 mL) and a 1 M solution of sodium carbonate (4.97 mL, 4.97 mmol) were added. The mixture was heated in a microwave at 110° C. for 30 min. The cooled reaction mixture was treated with 1 N NaOH and extracted with EtOAc (30 mL), washed with brine and dried over MgSO4, filtered and concentrated. Purification on the ISCO (12 g column, 70-100% EtOAc in hexanes) gave 6-fluoro-2,3′-bipyridine (581 mg, 3.34 mmol, 99% yield) as a pale yellow crystalline solid. m/z (ESI, +ve ion) 175.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.20 (1H, d, J=1.6 Hz); 8.67 (1H, d, J=3.9 Hz); 8.34 (1H, d, J=8.0 Hz); 7.90 (1H, q, J=8.0 Hz); 7.67 (1H, dd, J=7.5, 2.4 Hz); 7.42 (1H, dd, J=7.9, 4.8 Hz); 6.94 (1H, dd, J=8.0, 2.9 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]([F:13])[F:12])[C:3]=1[O:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][CH2:35][C:36]3=[O:41])O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:12][CH:11]([F:13])[O:10][C:4]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:2]([C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][CH2:35][C:36]3=[O:41])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COCOc1c(Br)ccc(OC)c1OC(F)F
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC(F)F
Temperature: 80 °C
Yield: 51.6 %

Procedure:
A solution of 1-bromo-3-(difluoromethoxy)-4-methoxy-2-(methoxymethoxy)benzene (3 g, 9.58 mmol) in dimethylformamide (50 mL) was purged with argon for 1 h, to this cesium carbonate (9.34 g, 28.74 mmol), tetrakis(triphenylphosphine) palladium (0) (1.1 g, 0.958 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (2.96 g, 11.49 mmol) were added and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was cooled to RT and filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 4-(3-(Difluoromethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one as a solid (1.8 g, 51.6%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[C:14]1([S:20]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([Cl:11])[C:10]=3[C:2]([Br:1])=[CH:3]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a slurry of the product from Method T (4.1 g/0.018 mol) in DMF (15 mL) and cooled to 0° C. was added 1.0 g (0.025 mol) of 60% sodium hydride in mineral oil and the resulting mixture stirred at 0° C. for 15 min. Benzenesulfonyl chloride (3.2 g/0.018 mol) was added, the reaction mixture warmed to room temperature and stirred for 2 h. Water was then added (15 mL) and the resulting solid removed by filtration and dried in vacuo affording 5.9 g (89%) of the title compound.
Reaction SMILES: ClC1N=C(C=[N:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=2[N+:22]([O-:24])=[O:23])C(N)=NC=1Cl.[N+](C1C=C([N+]([O-])=O)C=CC=1SCl)([O-])=O.[OH-].[NH4+]>>[N+:22]([C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[S:12][NH2:11])([O-:24])=[O:23]
Reactant: Nc1nc(Cl)c(Cl)nc1C=NSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccc(SCl)c([N+](=O)[O-])c1
Agent: [NH4+]
Agent: [OH-]
Product: NSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
5,6-Dichloro-3-[(2,4-dinitrophenyl)thioimino]methylpyrazinamine by the reaction of 2,4-dinitrobenzenesulfenyl chloride with ammonium hydroxide to form 2,4-dinitrobenzenesulfenamide, followed by the reaction of the latter with 3-amino-5,6-dichloropyrazinaldehyde.
Reaction SMILES: [CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1.Cl[C:48]1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][C:23]([CH3:48])([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@H:28]2[O:30][C@@H:29]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([Cl:46])[CH:39]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C\C[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Cryptophycin 289 (13.2 g, 20.2 mmol) in chloroform (43 mL) is stirred and treated with m-chloroperbenzoic acid (m-CPBA) (95% pure, 5.19 g, 30.1 mmol). After stirring overnight at room temperature, the solution is diluted with chloroform until clear, washed with sodium bicarbonate (saturated aqueous, 100 mL), sodium sulfite (saturated aqueous, 100 mL), sodium chloride (saturated aqueous, 100 mL), dried (magnesium sulfate), filtered, and the filtrate evaporated (40° C., 20 mm Hg) to provide 14 g of the Cryptophycin-292 as a mixture of epoxide isomers, as a white foam. The foam is dissolved in chloroform, cooled to −63° C., and treated with chlorotrimethylsilane (23.5 mL, 185 mmol) via syringe. The mixture is stirred at −63° C. for 5 hours, then allowed to stand in the freezer at −20° C. overnight. The mixture is again cooled to −63° C. and treated with sodium bicarbonate (saturated aqueous, 60 mL) with vigorous stirring. The cold bath is removed and the mixture allowed to warm to room temperature over a 1 hour period. The layers are separated and the aqueous layer extracted with chloroform. The organic layers are washed with sodium bicarbonate (saturated aqueous, 60 mL), sodium chloride (saturated aqueous, 100 mL), dried (magnesium sulfate), filtered, and the filtrate evaporated to 14 g of a white residue. The residue is chromatographed on silica gel (70×160 mm of silica gel, packed and eluted in 2:1:1 tBuOMe/CH2Cl2/hexanes) to provide 4.51 g of Cryptophycin 296 as a colorless foam (32%)
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[C:32](=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].O>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:49])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)[C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)[CH:33]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(C)cc1)c1ccc(C)cc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccc(C)cc1)(c1ccc(C)cc1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 0.373 g of fluorene (2.25 mmol) was dissolved in 60 ml of dehydrated diethylether in a nitrogen atmosphere. To the reaction solution, 1.6 ml of a n-butyl lithium/hexane solution (1.56M: 2.50 mmol) was gradually added dropwise in an ice bath and thereafter stirred at room temperature over night. To the reaction solution, a solution prepared by dissolving 1.10 g of 3-tert-butyl-1-methyl-6,6-di(p-tolyl)fulvene (3.36 mmol) in 60 ml of dehydrated diethyl ether was added and stirred under reflux for 10 days. To the reaction mixture, 30 ml of distilled water was gradually added dropwise in an ice bath, and thereafter the organic layer was separated by adding diethyl ether and washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate and then the drying agent was filtered off. The solvent was distilled off from the filtrate under reduced pressure to give a red brown liquid. The red brown liquid was purified by a column chromatography using 80 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The residue product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 0.140 g (0.282 mmol) as a pale yellow solid (yield: 13%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH:31][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: CN(C)CCCN
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)CCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 140 °C
Yield: 43.5 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.15 g), 3-dimethylaminopropylamine (1.26 g) and triethylamine (0.62 g) in NMP (6 mL) was stirred and heated at 140° C. for 48 hours. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 5-10%. The resultant product was repurified by preparative TLC, eluting with a mixture of methanol and DCM (10%) to give (1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.08 g) as an off white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14](N3CCCCC3)=[O:15])[CH:8]=[CH:9][C:2]1=2.[OH-:22].[Na+]>C(O)C.O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:15])=[O:22])[CH:8]=[CH:9][C:2]1=2
Reactant: O=C(COCCc1ccc2sccc2c1)N1CCCCC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)COCCc1ccc2sccc2c1
Yield: 74.6 %

Procedure:
In a mixture of 58 mL of ethanol and 6 mL of water is dissolved 6.40 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-1-piperidino-1-ethanone, to which is added 1.27 g of sodium hydroxide. The mixture is heated under reflux for 4 hours. After cooling the mixture, the deposited matter is collected by filtration. The deposited matter is added to a mixture of ethyl acetate and water, pH is adjusted to 1.5 with 2 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 3.72 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-acetic acid as a colorless crystalline product.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[CH2:13][CH2:12]1)=[O:10].CI>CN(C)C=O>[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[CH3:1])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H]1CC[C@H](N(C)Cc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium tert-butylate (35 mg, 0.31 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexanecarboxylic acid methyl ester (100 mg, 0.31 mmol, 1.0 eq) in N,N-dimethylformamide (4 mL), followed by methyl iodide (10 μL, 0.16 mmol, 0.5 eq). After 15 hours stirring at room temperature methyl iodide (10 μL, 0.16 mmol, 0.5 eq) is added again. After 4 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×5 mL) and water (5 mL). The combined organic layers are washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated to afford trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexanecarboxylic acid methyl ester as a brown oil (1.60 g, 98% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)=[N:4]1)[CH3:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)(=[O:27])=[O:26])[C:15]([C:17]4[CH:18]=[CH:19][C:20]([CH2:21][N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)=[CH:23][CH:24]=4)=[CH:16][C:9]=23)[C:5]([C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[N:4]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCn1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(CN4CCCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 4-[4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde (0.52 mmol) in tetrahydrofuran (5 mL) was added pyrrolidine (2.08 mmol) followed by sodium triacetoxyborohydride (2.08 mmol). After 1 h, the reaction mixture was quenched with water (5 mL) and diluted with ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (4×10 mL) and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% methanol/methylene chloride with 5% concentrated ammonoium hydroxide) to give the desired compound as a golden solid (93%). ESMS [M+H]+: 633.4
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:16][CH3:17])[CH2:11][C:12](OC)=[O:13])=[CH:5][CH:4]=1.[NH3:20]>CO>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:16][CH3:17])[CH2:11][C:12]([NH2:20])=[O:13])=[CH:5][CH:4]=1
Reactant: CC[C@H](CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reactant: N
Solvent: CO
Product: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 63 h
Yield: 48 %

Procedure:
403 mg (1.47 mmol) of methyl (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoate produced in Example 12 was dissolved in methanol (20 mL) and further mixed with a 28 wt % aqueous ammonia solution (30 mL) at room temperature. After stirring at the same temperature for further 63 hours, the reaction solution was concentrated under reduced pressure and subjected to extraction with ethyl acetate. The product was then dried with anhydrous magnesium sulfate. The residue obtained by removing the solvent by distillation under reduced pressure was purified on silica gel column chromatography to obtain (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid amide as a white solid (183 mg, isolated yield: 48%). The optical purity of the product was determined by HPLC analysis (column; Daicel Chiral Pack AD-H 4.6×250 mm: eluent; hexane/isopropanol=95/5: flow rate; 1.0 mL/min: column temperature; 30° C.: detector; UV 210 nm: retention time; (S) antipode=23.5 minutes, (R) antipode=24.8 minutes) to be 100% ee. 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.98 (3H, t), 1.65 (2H, m), 2.45 (2H, d), 3.76 (1H, m), 4.28 (1H, d), 5.58 (2H, brs), 6.64 (2H, d), 7.38 (2H, d)