Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(#N)C>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(OC)c(OC)c2)cc1

Procedure:
As described under 1.2., 10.3 g (0.05 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 11.37 g (0.055 mol) of 4-methoxyphenylsulfonic acid chloride in the presence of 7.6 g of triethylamine. After recrystallisation of the crude product from ethyl acetate/hexane, 3.26 g (17%) of α-(4-methoxy-phenylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of yellowish crystals having a melting point of 161-167° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 349 nm (ε=11700) that extends to 435 nm. Elemental analysis: C17H16N2O6S (376.38)
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1>>[C:2]([C:1]([N:14]([C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1)[C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:5])(=[O:3])[CH3:4]
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reactant: CC(=O)C(=O)O
Product: CC(=O)C(=O)N(c1ccc(Cl)cc1)[C@H](C(=O)O)C(C)C

Procedure:
Following the procedure of Example 47, the m-phenoxybenzyl ester of N-acetylformyl,N-(4-chlorophenyl)valine [MS m/e 479 (M+, 0.5), 183 (100)] is prepared by the reaction of the acid chloride of pyruvic acid with the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]1=2.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.Cl>C1COCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([B:21]([OH:26])[OH:22])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.38 g (80.0 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 38.4 ml (96.0 mmol) of n-butyllithium (2.5 M in hexane) are added dropwise, at −78° C., and the mixture is stirred for one hour. 27.7 ml (120.0 mmol) of triisopropyl borate are added dropwise at this same temperature and the mixture is stirred for 2 hours. 350 ml of hydrochloric acid (1 N) are added at −50° C. and the mixture is allowed to warm to room temperature. The reaction medium is extracted with dichloromethane and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 18.60 g (100%) of the expected boronic acid are collected in the form of an oil which crystallizes slowly. Melting point 190–192° C.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:19])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)c1cccc2cnccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2cnccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
Isoquinoline-5-carboxylic acid (5.6 g, 32.36 mmol) obtained in Step (2) above and methanol (90 mL) were mixed and stirred. The reaction solution was slowly added with sulfuric acid (15 mL, 259 mmol) and refluxed for about 20 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled under reduced pressure. The concentrate was added with distilled water and adjusted to have a pH value in a range of 10˜11 by adding DIPEA. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (5.8 g, 96%).
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(=O)=O.CC(C)=O.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1/[CH:31]=[C:32](\[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)/[C:33]([O:35]CC)=O>O1CCCC1>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1/[CH:31]=[C:32](\[C:38]1[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=1)/[C:33](=[O:35])[CH3:4]
Reactant: CCOC(=O)/C(=C/c1ccco1)c1ccncc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(=O)/C(=C/c1ccco1)c1ccncc1
Reaction time: 1 h
Yield: 24.7 %

Procedure:
Under a nitrogen atmosphere, a 3.0M solution of methylmagnesium bromide in diethyl ether (3.7 ml, 11.1 mmol) was added dropwise over 5 minutes to a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (22 ml, 22 mmol) at −50° C. (dry ice-acetone bath), followed by stirring as it was for 1 hour. Then, a solution of ethyl (E)-3-(2-furyl)-2-(4-pyridyl)-2-propenoate (2.4 g, 9.87 mmol) in tetrahydrofuran (20 ml) was added dropwise thereinto over 5 minutes. The reaction mixture was stirred for 30 minutes while elevating to room temperature, and then the reaction was terminated by adding hydrochloric acid. After diluting with a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=1:1 to 4:1), to give the title compound (0.52 g, 23%).
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)O1>>[N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:2]3[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Reactant: O=C1C=C(Br)CCC1
Product: O=C1C=C(c2ccc3ncccc3c2)CCC1
Yield: 88 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (40 to 100% ethyl acetate/hexanes) yielded the product (164 mg, 88%) as a white powder. 1H NMR (CDCl3, 300 MHz): δ 8.92 (dd, J=4.2, 1.5 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.86 (dd, J=9.0, 2.4 Hz, 1H), 7.43 (dd, J=8.4, 4.5 Hz, 1H), 6.54 (s, 1H), 2.89 (t, J=6.3 Hz, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.21 (pent, J=6.3 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 199.4, 158.3, 151.2, 148.6, 136.7, 136.5, 129.9, 127.8, 126.8, 126.3, 125.7, 121.7, 37.3, 28.2, 22.8. LCMS (ESI): mass calcd for (C15H13NO) m/z 223.10; measured [M+H]+: m/z 224.80.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=[O:6].[CH2:16]([Mg]Br)[CH:17]=[CH2:18]>C1COCC1>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]([OH:6])[CH2:18][CH:17]=[CH2:16]
Reactant: C=CC[Mg]Br
Reactant: COc1c(C)c(C)c(OC)c(C=O)c1C
Solvent: C1CCOC1
Product: C=CCC(O)c1c(C)c(OC)c(C)c(C)c1OC
Reaction time: 0.25 h

Procedure:
A stirred solution of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde (6.34 g) in 125 mL THF was cooled to 0° C. and treated with 34 mL 1.0 M allyl magnesium bromide (1.0 M in THF, 1.1 equiv.) slowly over 0.25 h via dropping funnel. The solution was stirred for and additional 0.25 h and quenched by the addition of 40 mL 1.0 M aqueous citric acid and stirring until the layers clarified. The layers were separated and the aqueous layer extracted 3×50 mL EtOAc. The combined organics were washed 2×25 mL saturated aqueous NaCl, dried over Na2SO4 and concentrated to yield 9.8 g of 1-(2,5-dimethoxy-3,4,6-trimethylphenyl)but-3-en-1-ol as a brown oil. M+−H2O=233.4 m/z; 1H NMR (400 MHz, CDCl3) δ=5.90 (m, 1 H), 5.15 (m, 1 H), 5.10 (m, 1 H), 4.98 (m, 1 H), 3.78 (s, 3 H), 3.65 (s, 3 H), 2.66 (s, 1 H), 2.48 (s, 1 H), 2.25 (s, 3 H), 2.18 (s, 6H) ppm.
Reaction SMILES: O[C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4](O)[C:3]=1[C:10](=[O:12])[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:22][O:23]CCl>O1CCCC1>[CH3:22][O:23][CH2:11][C:10]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:12]
Reactant: COCCl
Reactant: CC(=O)c1c(O)cc(O)cc1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 200 ml of anhydrous tetrahydrofuran were dissolved 30 g of 2',4',6'-trihydroxyacetophenone and 115.0 g of N,N-diisopropylethylamine, and 50.2 g of chloromethyl methyl ether was gradually added to the solution under ice cooling over a period of 20 minutes and the reaction mixture was stirred under ice cooling for 1 hour and at room temperature for 4 hours to effect reaction. After the reaction, the reaction mixture was extracted with 3 l of ether, and the ether layer was washed with water (500 ml×3 times), shaken with a saturated aqueous solution of sodium chloride (300 ml×2 times), dried with anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from a mixed solvent of methanol and water to obtain 18.9 g (yield=41.4%) of 2'-hydroxy-4',6'-bis(methoxyacetophenone in the form of a colorless prism.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.C(=CCO[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[N:51]=[C:52]=[O:53])=O>>[C:7](=[CH:6][CH2:5][O:39][N:51]([C:46]1[CH:45]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:52]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:53])=[O:8]
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C=CCOc1ccccc1N=C=O
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)N(OCC=C=O)c3ccccc3)CN2C1=O
Yield: 27.1 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 2-carbonylethoxyphenyl isocyanate (102 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 18 mg (14%) of 18-(2-carbonylethoxyphenylaminocarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.9% pure (HPLC), MS m/z 758 (M−H)−, HRMS: calcd. 760.3228 and found 760.3226 (M+NH4)+, mp 148-150° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([S:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:6]=1)[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([NH:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([S:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Yield: 101.4 %

Procedure:
A mixture of N-ethyl-3-(2,4-difluorophenylthio)4-nitrobenzamide (0.92 g), iron powder (0.92 g) and ammonium chloride (92 mg) in ethanol (10 ml) and water (5 ml) was stirred and refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried, and evaporated to give an oil of N-ethyl4-amino-3-(2,4-difluorophenylthio)benzamide (0.85 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][CH2:22][OH:23])[CH:18]=3)[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(NC1Cc2ccc(CCO)cc2C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
[2-[(4-Chlorophenyl)sulfonylamino]indan-5-yl]acetic acid (600 mg) is dissolved in tetrahydrofuran (20 ml) and thereto is added dropwise 7.8 M borane-1,4-oxathiane complex (1 ml). The mixture is stirred at room temperature for one hour and thereto is added methanol to terminate the reaction, and then, the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution and saline solution, dried and then distilled under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform) to give 2-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]ethanol (542 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O.C(O)(=O)C>[N:9]1([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:2]3[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: Nc1cc(Cl)ncn1
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Nc2ccc(OCCN3CCOCC3)cc2)ncn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-chloro-pyrimidin-4-ylamine (194 mg, 1.5 mmol, 1.3 equiv), 4-(2-morpholin-4-yl-ethoxy)-phenylamine (256 mg, 1.15 mmol) in H2O (1 mL) and glacial acetic acid (5 mL) is stirred for 16 h at 100° C. After solvent evaporation, the residue is taken up in DCM and diluted with a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is triturated in EtOAc to provide the title compound as a grey solid: ESI-MS: 316.2 [MH]+; tR=1.00 min (purity: 95%, system 1); TLC: Rf=0.22 (DCM/MeOH+1% NH3aq, 93:7).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C@H:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[CH:23]=2)[C:18]([OH:20])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:37][C:34]1[N:35]=[CH:36][C:31]([NH:30][C:18](=[O:20])[C:17]2[CH:21]=[C:22]([O:24][C@H:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[CH:23]=[C:15]([O:14][CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:16]=2)=[N:32][CH:33]=1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCOC3)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Oxalyl chloride (1.9 mL, 22.2 mmol) and DMF (1 drop) were added to a solution of 3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (5.8 g, 18.5 mmol) in DCM (100 mL) and the mixture stirred at RT for 16 hours. The mixture was evaporated in vacuo to a residue which was redissolved in DCM (25 mL) and added to a stirred mixture of 2-amino-5-methylpyrazine (2.22 g, 20.35 mmol) and pyridine (1.81 mL, 22.2 mmol) in DCM (100 mL) at 5° C.-10° C. The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo to give a residue which was partitioned between water (50 mL) and ethyl acetate (125 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 60% ethyl acetate in isohexane, to give the desired material (5.1 g). 1H NMR δ (CDCl3): 2.1-2.2 (m, 2H), 2.5 (s, 3H), 3.8-3.95 (m, 4H), 4.9 (m, 1H), 5.0 (s, 2H), 6.6 (s, 1H), 6.95 (s, 1H), 7.05 (s, 1H), 7.35 (m, 5H), 8.05 (s, 1H), 8.3 (s, 1H), 9.5 (s, 1H); m/z 406 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[O:19]1[CH2:23][CH2:22][C:21](=O)[CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[O:19]1[CH2:23][CH2:22][CH:21]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:4][CH2:3]2)[CH2:20]1
Reactant: O=C1CCOC1
Reactant: N[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](NC2CCOC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of benzyl trans-4-aminocyclohexylcarbamate (396 mg, 1.595 mmol) in CH2Cl2 (9 ml) was added dihydrofuran-3(2H)-one (151 mg, 1.754 mmol) followed by acetic acid (150 μL, 2.62 mmol) and sodium triacetoxyborohydride (439 mg, 2.073 mmol) under Argon. Stirred at 25° C. for 16 h, then concentrated in vacuo. The resulting residue was partitioned between EtOAc and 1M NaOH. The organics were combined, then washed with 1M NaOH (×2), water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure to give racemic benzyl trans-4-(tetrahydrofuran-3-yl-amino)cyclohexylcarbamate (495 mg). The resulting residue was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:20]([NH:21][C:22](=[O:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=[C:17]([Cl:30])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.IC.[CH3:33]N(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:20]([N:21]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:33])=[CH:19][CH:18]=[C:17]([Cl:30])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CN(C)C=O
Reactant: COC(=O)CCC(=O)Nc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)CCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 2 h

Procedure:
To a mixture of 8-[2,6-dichloro-3-(3-methoxycarbonylpropionylamino)benzyloxy]-2-methylquinoline (447 mg), iodomethane (0.1 ml) and dimethylformamide (5.0 ml) was added sodium hydride (60% in oil, 44 mg) under ice-water cooling. After stirring for 2 hours at the same temperature, the reaction mixture was diluted with ethyl acetate and washed with water twice. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a column chromatography eluted with chloroform to give 8-[2,6-dichloro-3-[N-(3-methyoxycarbonylpropionyl)-N-methylamino]benzyloxy]-2-methylquinoline (310 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:19]([CH3:29])[CH:18]=3)=[C:14]([C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([CH:39]4[CH2:43][CH2:42][C:41](=[O:44])[N:40]4[CH3:45])=[O:38])=[CH:32][CH:31]=3)[S:13][C:12]=2[CH:46]=1.[H-].[Na+].CI.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:19]([CH3:29])[CH:18]=3)=[C:14]([C:30]3[CH:35]=[CH:34][C:33]([N:36]([CH3:1])[C:37]([CH:39]4[CH2:43][CH2:42][C:41](=[O:44])[N:40]4[CH3:45])=[O:38])=[CH:32][CH:31]=3)[S:13][C:12]=2[CH:46]=1
Reactant: Cc1cc(Cc2c(-c3ccc(NC(=O)C4CCC(=O)N4C)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Agent: O=C(O)C(=O)O
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1cc(Cc2c(-c3ccc(N(C)C(=O)C4CCC(=O)N4C)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A 0° C. solution of 6-hydroxy-3-[3-methyl-4-(1-pyrrolidinylmethyl)benzyl]-2-[4-(1-methyl-5-oxopyrrolidin-2-ylcarbonylamino)phenyl]benzo[b]thiophene from Example 29, Part B (150 mg; 0.264 mmol) in 5 mL of dry DMF was treated with NaH (16 mg; 0.37 mmol). After 1 hr, methyl iodide (0.017 mL; 0.264 mmol) was quickly added via a syringe. The resulting mixture was stirred at 0° C. for 30 min, then it was allowed to warm to ambient temperature. The reaction mixture was poured into saturated aqueous NH4Cl and EtOAc (25 mL each). The aqueous layer was extracted with 5% MeOH/EtOAc (2×25 mL). The combined organics were dried over K2CO3, filtered and concentrated in vacuo. The crude residue was purified by radial chromatography (SiO2; gradient of 0.5% to 2% MeOH in CHCl3, saturated with NH4OH) afforded 37 mg (24%) of the title product as a yellow oil.