Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([SiH](CC)CC)C>O1CCCC1>[O:10]=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCC(=O)Cl
Agent: CC[SiH](CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCC=O
Temperature: 25 °C

Procedure:
Into a 500-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 4-chloro-4-oxobutanoate (12 g, 72.91 mmol) in tetrahydrofuran (200 mL). The system was purged with nitrogen and palladium on carbon (2 g) was added to the reaction. This was followed by the addition of triethylsilane (16.5 mL, 103.20 mmol) dropwise with stirring at room temperature. The reaction mixture was stirred for 2 h at room temperature. The solids were filtered off and the filtrate was concentrated under reduced pressure to give 18 g (crude) of the title compound as a light yellow solid.
Reaction SMILES: C(OO)(=[O:3])C.OO.C(OC(=O)C)(=O)C.[Cl:15][CH2:16][CH2:17][N:18]([CH2:45][CH2:46][Cl:47])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:43])([CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:21]([CH3:44])[CH:20]=1>ClCCl>[C:30]([O:29][C:27](=[O:28])[CH2:26][C:25]([C:22]1[CH:23]=[CH:24][C:19]([N+:18]([O-:3])([CH2:45][CH2:46][Cl:47])[CH2:17][CH2:16][Cl:15])=[CH:20][C:21]=1[CH3:44])([CH2:34][NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH3:43])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1cc(N(CCCl)CCCl)ccc1C(C)(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CC(=O)OO
Agent: OO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+]([O-])(CCCl)CCCl)ccc1C(C)(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Adapting literature known protocols (Tercel, et al., J. Med. Chem. 1995, 38, 1247-1252; and U.S. Pat. No. 7,399,785), peracetic acid (H3CCO3H) is freshly prepared by adding hydrogen peroxide (H2O2) (1.5 mL of a 35 wt-% aqueous solution, 14.0 mmol) dropwise to acetic anhydride (Ac2O) (1.52 mL, 1.65 g, 16.0 mmol). When the reaction mixture is homogeneous, a solution of tert-butyl 3-[4-[bis(2-chloroethyl)amino]-2-methyl-phenyl]-4-(tert-butoxycarbonylamino)-3-methyl-butanoate (7o) (1.66 g, 3.29 mmol) in dichloromethane (DCM) (20 mL) is added with vigorous stirring at about room temperature for about 2 h. The reaction is followed by TLC and/or LC/MS to completion. The reaction is quenched with 2.0 N hydrochloric acid (HCl), and the aqueous layer separated and repeatedly washed with DCM until the organic extracts are colorless. The aqueous phase is evaporated to dryness under reduced pressure, dried over anhydrous sodium sulfate (Na2SO4), and partially reduced in volume. Diethyl ether (Et2O) is added to separate the title compound 4-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-1-methyl-3-oxo-propyl]-N,N-bis(2-chloroethyl)-3-methyl-benzeneamine oxide (25a). The material may be purified by silica gel column chromatography using ethyl acetate (EtOAc), methanol (MeOH), and hexane mixtures.
Reaction SMILES: [F-:1].[Cs+].[CH2:3]([C:8]12[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([N+]([O-])=O)[CH:19]=3)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)[CH2:4][CH2:5][CH2:6][CH3:7].C(C12CCC(CCC3C=CC(Br)=CC=3)(CC1)CC2)CCCC.[Cu](C#N)C#N>CN1CCCC1=O>[CH2:3]([C:8]12[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:1])[CH:19]=3)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC12CCC(CCc3ccc(C#N)c([N+](=O)[O-])c3)(CC1)CC2
Reactant: [F-]
Agent: N#C[Cu]C#N
Agent: CCCCCC12CCC(CCc3ccc(Br)cc3)(CC1)CC2
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCCCC12CCC(CCc3ccc(C#N)c(F)c3)(CC1)CC2

Procedure:
7.6 g of caesium fluoride are added to a mixture of 3.55 g of 1-[4-pentylbicyclo(2.2.2)octyl]-2-(4-cyano-3-nitrophenyl)ethane (obtainable by nitrating 1-[4-pentylbicyclo(2.2.2)octyl]-2-(4-bromophenyl)-ethane, reacting the product with copper cyanide in N-methylpyrrolidone and subsequently purifying the product by chromatography) and 25 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, and the mixture is heated at 120oC for 5 hours. Adding water and working up after extraction gives 1-[4-pentylbicyclo(2.2.2)octyl]-2-(4-cyano-3-fluorophenyl)-ethane.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.[OH-].[Na+]>ClCCCl.C(OCC)(=O)C>[F:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[CH2:6][CH2:7]2)[CH2:18][CH2:17]1
Reactant: Brc1ccc2c(c1)NCC2
Reactant: O=C1CCN(CCc2ccccc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccccc1CCN1CCC(N2CCc3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
Triacetoxylated sodium borohydride (15.0 g) was added under ice cooling to a liquid mixture of 6-bromoindoline (9.0 g), 1-(2-fluorophenethyl)piperidin-4-one (11.0 g) and acetic acid (12.5 ml) in 1,2-dichloroethane (140 ml). Then the reaction mixtures were stirred at room temperature overnight. The reaction mixtures were diluted with ethyl acetate (400 ml) and then an 8 N aqueous solution (70 ml) of sodium hydroxide was added thereto. The organic layer was separated, extracted with 5 N hydrochloric acid (100 ml) and then basified with an 8 N aqueous solution of sodium hydroxide. Then it was extracted with ethyl acetate and washed successively with water and brine. The ethyl acetate layer was dried over magnesium sulfate and the solvent was evaporated distilled off under reduced pressure to give the title compound (12.2 g) as a pale yellow solid (yield: 66.6%). 2.10(2H,dt,J=7.6,2.8 Hz), 2.48-2.53(2H,m), 2.77(2H,t, J=8.4 Hz), 2.83(2H,t,J=8.4 Hz), 2.96-3.03(2H,br-d), 3.37(2H,t,J=8.4 Hz), 3.34-3.43(1H,m), 6.57(1H,d,J=1.2 Hz), 6.61(1H,dd,J=7.6,1.2 Hz), 6.90(1H,d,J=7.6 Hz), 7.10-7.16(2H,m), 7.21-7.28(1H,m), 7.33(1H,dt,J=7.6,1.2 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[N:18](COCC[Si](C)(C)C)[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[NH2:7][CH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[NH:18][CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NC(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCC(N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.1 %

Procedure:
In a round-bottomed flask, (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclopentyl)-carbamic acid tert-butyl ester (80 mg, 0.125 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.4 ml, 5.0 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 h then concentrated. The residue was dissolved in dichloromethane (0.7 ml) and ethylenediamine (0.5 ml, 7.5 mmol) was added. The solution was stirred at room temperature for 2 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 40 mg (74%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclopentyl)-amide as an off-white powder. MS: (M+H)+=410; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.07 (s, 1H), 8.55 (d, J=8.7 Hz, 1H), 8.40 (s, 1H), 8.24 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.40 (d, J=9.1 Hz, 1H), 5.54 (br. s, 2H), 4.34-4.45 (m, 1H), 4.17 (s, 3H), 3.36-3.44 (m, 1H), 2.25-2.37 (m, 1H), 2.03-2.16 (m, 1H), 1.71-1.88 (m, 2H), 1.51-1.62 (m, 1H), 1.32-1.43 (m, 1H). The isolated product was determined to be a single diastereomer of unknown relative stereochemistry by NMR analysis.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36][CH2:37][O:38][CH3:39])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2[CH:32]=O)[CH3:21].O>CN(C)C=O>[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36][CH2:37][O:38][CH3:39])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2/[CH:32]=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH3:21]
Reactant: CCOP(=O)(CC(=O)N1CCCCC1)OCC
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(OCOC)c12
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
0.15 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide, to which 1.15 g of N-(diethoxyphosphoryl)acetylpiperidine was gradually added at room temperature. After stirring for 10 minutes, a solution of 800 mg of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde in N,N-dimethylformamide (10 ml) was gradually added. After stirring for 20 minutes, water was added, followed by extraction with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the resultant residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 1.1 g of the titled compound as pale yellow crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccncc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCl)c1ccncc1

Procedure:
The title compound was synthesized from chlorobutyryl chloride (141 mg), pyridine (2 ml), and AlCl3 (260 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([OH:11])=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22]COC)[N:4]=1>CO.Cl>[CH3:26][N:2]([CH3:1])[C:3]1[N:4]=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:6]([OH:11])=[C:7]([O:9][CH3:10])[N:8]=1
Reactant: COCOCCCCCCCCCCc1nc(N(C)C)nc(OC)c1O
Agent: Cl
Solvent: CO
Product: COc1nc(N(C)C)nc(CCCCCCCCCCO)c1O

Procedure:
To a stirred solution containing 20 mg (0.054 mmol) of 2-(dimethylamino)-4-methoxy-6-(10-(methoxymethoxy)decyl)pyrimidin-5-ol in 5 mL of methanol were added 2 drops of concentrated HCl. The reaction mixture was stirred at reflux for 16 h. The reaction mixture was concentrated under diminished pressure and the residue was purified by chromatography on a silica gel column (8×1 cm). Elution with 1:2 hexanes-ethyl acetate afforded the expected product as white solid: yield 7 mg (40%); mp: 104-105° C.; silica gel TLC Rf 0.15 (1:2 hexanes-ethyl acetate); 1H NMR (methanol-d4) δ 1.28-1.32 (br m, 10H), 1.49 (m, 2H), 1.64 (m, 2H), 2.76 (dd, 2H, J=7.6, 7.6 Hz), 3.22 (s, 6H), 3.51 (t, 2H, J=6.8 Hz) and 4.07 (s, 3H); 13C NMR (methanol-d4) δ 25.55, 27.49, 27.72, 29.02, 29.03, 29.17, 29.19, 29.31, 32.26, 37.20, 37.20, 54.45, 61.59, 128.10, 146.40, 151.34 and 162.67; mass spectrum (APCI+), m/z 326.2442 (M+H) (C17H32N3O3 requires 326.2444).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Al+3].[Li+].[Cl-].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([NH:23][C:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2[CH3:37].[OH-].[Na+]>O1CCCC1.O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[CH:22]=1)[N:19]=[CH:18][CH:17]=[C:16]2[CH3:37]
Reactant: COc1cc(NC(=O)CCCCCN2CCNCC2)c2nccc(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NCCCCCCN2CCNCC2)c2nccc(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A cold (-40°) slurry of 3.8 g (0.0285 mole) of anhydrous aluminum chloride in 60 ml of tetrahydrofuran was added to an equally cold suspension of 3.2 g (0.087 mole) of lithium aluminum chloride in 40 ml of tetrahydrofuran. The mixture was allowed to warm to -20° and to it was added portionwise a suspension of 7.8 g (0.021 mole) of N-(6-methoxy-4-methyl-8-quinolinyl)-1-piperazinehexanamide in 300 ml of tetrahydrofuran. The mixture was allowed to stir overnight as it warmed to room temperature, and then was treated with 13.5 ml of 30% sodium hydroxide solution, and with enough water to clarify the supernatant. The supernatant was separated from the sticky precipiate, concentrated in vacuo to remove most of the tetrahydrofuran, diluted with dichloromethane, washed with water, dried and concentrated to dryness in vacuo. The residue was chromatographed over 200 g of silica gel first with 1 liter of ethyl acetate and then with the following solutions of methanol in ethyl acetate: 5% (1 liter), 10% (1 liter), 15% (1 liter), 20% (1 liter) and 25% (4 liters). The eluant containing product, Rf(silica--75 parts ethyl acetate:25 parts of methanol:1 part triethylamine)=0.05, was concentrated to dryness in vacuo to afford 4.4 g (59%) of the desired product of sufficient purity to use in the next step.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19]>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH:19][S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3]
Reactant: Nc1c(F)cccc1F
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (1.0 g, 4.02 mmol) in N,N-dimethylacetamide (6 mL) was added 2,6-difluoroaniline (2.03 g, 15.8 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 5 hours and then diluted with ethyl acetate (40 mL). The organic solution was washed with 1 N HCl (2×15 mL and 3×30 mL) and saturated NaCl (30 mL). The organics were concentrated, ethanol (10 mL) was added, and the mixture was concentrated to give ethyl 3-{[(2,6-difluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: C([CH:3]([C:33]([OH:35])=[O:34])[N:4]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:21]([C:31]#[N:32])[CH:20]=1)[C:5]([C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+]>C(O)C>[C:31]([C:21]1[CH:20]=[C:19]([N:4]([C:5]([C:7]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)=[O:6])[CH2:3][C:33]([OH:35])=[O:34])[CH:24]=[CH:23][C:22]=1[N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)#[N:32]
Reactant: CCC(C(=O)O)N(C(=O)c1cccn1-c1ccc(F)cc1)c1ccc(N2CCCCC2)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc(N(CC(=O)O)C(=O)c2cccn2-c2ccc(F)cc2)ccc1N1CCCCC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
Ethyl N-(3-cyano-4-piperidinophenyl)-N-[1-(4-fluorophenyl)pyrrol-2-ylcarbonyl]glycine (1.0 g) was added to ethanol (10 ml), and 10% aqueous sodium hydroxide solution (10 ml) was added. The mixture was stirred at a refluxing temperature for 30 min. The solvent was evaporated under reduced pressure. Dilute hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of toluene-diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.5 g), melting point: 117–120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2-methoxy-4-nitroaniline (5 g) in pyridine (25 ml) at 0° C. was added dropwise methanesulfonyl chloride (3.5 ml). The mixture was left at 0° C. for 1 hour, then brought to RT for 2 h. The mixture was poured onto ice (100 g) and dilute hydrochloric acid (3M, 100 ml), the solid formed was filtered then washed with water and dried to give 2-methoxy-4-nitro-methanesulfonylaminobenzene (7.32 g, 98%) as an off-white crystalline solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:33])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nc1cccc2c1cnn2CCN1CCCC1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine and (4-phenoxy-phenyl)-acetic acid were processed as describe in Example 3 to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.61 (m, 4 H), 2.43 (m, J=5.43 Hz, 4 H), 2.86 (t, J=6.78 Hz, 2 H), 3.78 (s, 2 H), 4.47 (t, J=6.61 Hz, 2 H), 6.99 (m, 4 H), 7.12 (m, 1 H), 7.29 (m, 1 H), 7.39 (m, 5 H), 7.65 (m, 1 H), 8.27 (m, 1 H), 10.17 (m, 1 H); MS (DCI/NH3) m/z 441 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl.Cl[CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:3]=1
Reactant: CN(C)CCCCl
Reactant: Cc1ccc2c(I)n[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(I)nn(CCCN(C)C)c2c1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A mixture of 3-iodo-6-methyl-1H-indazole (2.58 g, 10 mmol), 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (2.37 g, 15 mmol) and potassium carbonate (4.14 g, 30 mmol) in 50 ml, of DMF was heated to 85° C. for 3 hours. After cooling to room temperature, 100 mL of water was added and the mixture was extracted with ethyl acetate (4×100 mL). Then the combined organic phases were added with 20 mL of 6N HCl, and the solution was extracted with dichloromethane (4×50 mL). The combined organic phases were dried with sodium sulfate, concentrated to give 3-(3-iodo-6-methyl-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (1.74 g, 50.6%). LCMS: (M+H)+=344; 1H NMR (300 MHz, CDCl3): δ 7.33 (d, 1H, J=8.4 Hz), 7.21 (s, 1H), 7.03 (d, 1H, J=8.4 Hz), 4.43 (t, 2H, J=6.6 Hz), 2.51 (s, 3H), 2.27-2.23 (m, 8H), 2.09-2.07 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH: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([CH2:36][CH2:37][O:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([C:49](O)=O)=[CH:41][CH:40]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([N:3]([CH2:49][C:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:39]([O:38][CH2:37][CH2:36][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:40][CH:41]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c2ccccc12
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c2ccccc12)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 87.8 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (60 mg) and 4-(2-piperidin-1-ylethoxy)naphthalene-1-carboxylic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 152, the title compound (78 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH3:33])[C@H:10]([O:14][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]/[CH:25]=[CH:24]\[CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCC/C=C\CCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCC/C=C\CCCC

Procedure:
Compound VI-13 (119 mg, 49.5%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 80.0 mg, 0.414 mmol) and (Z)-tetradec-9-enyl methanesulfonate (Nu-Chek Prep, Inc; 301 mg, 1.04 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=O.[CH3:18][C:19]([S:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[N:24][S:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23]
Reactant: CC(C)(C)S(N)=O
Reactant: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Temperature: 75 °C

Procedure:
A mixture of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (20 g, 64.4 mmol), 2-methyl-2-propanesulfinamide (23.42 g, 193 mmol) and titanium (IV) ethoxide (45.3 mL, 219 mmol) in dry THF 250 mL was heated at 75° C. overnight. The mixture was cooled to RT, then brine was added while stirring. The resulting suspension was filtered through celite, and the solid was washed with EtOAc. The filtrate was washed with brine, dried over sodium sulfate and concentrated. The crude material was purified by column chromatography with gradient of 0-30% EtOAc/Hexane to give the desired product as an orange solid. MS m/z=415.0 [M+H]+.
Reaction SMILES: C(OC1C=CC=CC=1C([O-])=O)(C)C.[CH:14]([O:17][C:18]1[CH:19]=[C:20]([CH:27]=[C:28]([O:30][CH:31]([CH3:33])[CH3:32])[CH:29]=1)[C:21]([O:23]C(C)C)=[O:22])([CH3:16])[CH3:15].[OH-].[Li+].Cl>C1COCC1.O>[CH:31]([O:30][C:28]1[CH:27]=[C:20]([CH:19]=[C:18]([O:17][CH:14]([CH3:16])[CH3:15])[CH:29]=1)[C:21]([OH:23])=[O:22])([CH3:33])[CH3:32]
Reactant: CC(C)OC(=O)c1cc(OC(C)C)cc(OC(C)C)c1
Agent: CC(C)Oc1ccccc1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(OC(C)C)cc(C(=O)O)c1
Yield: 55 %

Procedure:
Crude isopropoxybenzoate from above (compound E) was dissolved in 200 mL THF/H2O (1:1) in a 500 mL flask. Excess lithium hydroxide (10 g) was added and the reaction refluxed for over 48 hours. The mixture was cooled, acidified with HCl to pH 2, then extracted with several portions of diethyl ether. The organic layers were washed with brine, dried over MgSO4, and concentrated to a white solid in 55% yield over 2 steps: IR (cm−1): 3064, 2978, 2933, 2639, 1693, 1594, 1300, 1158, 1114, 1040, 767; 1H NMR (250 MHz, CD3OD): δ 1.30 (dd, J=2.3, 5.9 Hz, 12H), 4.59 (qn, J=6.2 Hz, 2H), 6.61 (t, J=2.3 Hz, 1H), 7.10 (d, J=2.5 Hz, 2H); 13C NMR (63 MHz, CD3OD): 22.2 (4C), 71.2 (2C), 109.8, 109.9, 133.8, 160.3 (2C), 169.7.