Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[F:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH2:17][C:18](OCC)=[O:19])[CH:12]=[CH:13][C:14]=1[F:15]>N1C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[N:4]3[N:3]=[C:2]([CH3:1])[CH:6]=[C:5]3[NH:7][C:18](=[O:19])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CCOC(=O)CC(=O)c1ccc(F)c(F)c1
Reactant: Cc1cc(N)[nH]n1
Solvent: c1ccncc1
Product: Cc1cc2[nH]c(=O)cc(-c3ccc(F)c(F)c3)n2n1
Temperature: 25 °C
Yield: 64 %

Procedure:
3-Methylpyrazol-5-amine (670 mg) and ethyl 3-(3,4-difluorophenyl)-3-oxopropanoate (1.12 g) are stirred overnight in a pyridine (30 mL) solvent at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and the target compound (821 mg) is yielded by column chromatography. 1H NMR (CDCl3, 300 MHz) δ 10.80 (br, 1H), 8.01 (m, 1H), 7.54 (m, 1H), 7.30 (m, 1H), 6.45 (s, 1H), 5.88 (s, 1H), 2.31 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([C:17]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[O:19][N:18]=1)[O:12][Si](C)(C)C)[CH2:9][CH3:10])(C)(C)C.[ClH:26]>ClCCl.O1CCOCC1>[ClH:26].[NH2:7][CH:8]([CH2:9][CH3:10])[CH:11]([C:17]1[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[O:19][N:18]=1)[OH:12]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O[Si](C)(C)C)c1cc(C(C)C)on1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(N)C(O)c1cc(C(C)C)on1
Temperature: 25 °C
Reaction time: 22 h
Yield: 99 %

Procedure:
To a solution of {1-[(5-Isopropyl-isoxazol-3-yl)-trimethylsilanyloxy-methyl]-propyl}-carbamic acid tert-butyl ester in dry dichloromethane (5 mL) under N2 is added a 4M solution of HCl in dioxane (5.0 mL, XS). The mixture is stirred at room temperature for 22 h, then concentrated in vacuum to afford the amine salt (475 mg, 99%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](O)(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.O=S(Cl)[Cl:18]>CN(C=O)C>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([Cl:18])(=[O:11])=[O:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(S(=O)(=O)O)c([N+](=O)[O-])cc1F
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)Cl)c([N+](=O)[O-])cc1F
Yield: 99 %

Procedure:
In a similar fashion using route 39 general procedure 96, 4-fluoro-5-methyl-2-nitro-benzenesulfonic acid 452 (1.5 g, 6.38 mmol), SOCl2 (15 ml) and DMF (0.1 ml) gave the title compound (1.6 g, 99%) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:32][C:33](=[O:43])[CH:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O>>[C:1]([C:9]1[O:10][C:11]2[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:34]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:33]([OH:43])=[O:32])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(O)cc2)cc1
Product: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzoyl-benzofuran-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a yellow solid, mp 159-161° C.; MS m/e 538 (M+);
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:20])[C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][N:38]=[C:37]2Cl)=[O:31]>C(#N)C>[CH3:28][O:29][C:30]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][N:38]=[C:37]2[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH3:20])[CH:4]=1)=[O:31]
Reactant: COc1ccc(C(=O)N(C)c2cccc(CN)c2)cc1
Reactant: COC(=O)c1cccc2c(Cl)ncnc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2c(NCc3cccc(N(C)C(=O)c4ccc(OC)cc4)c3)ncnc12
Reaction time: 8 h

Procedure:
101 mg (0.37 mmol) N-(3-Aminomethyl-phenyl)-4-methoxy-N-methyl-benzamide were dissolved in 3 ml acetonitrile and 260 μl (1.87 mmol) triethylamine. 130 mg (0.37 mmol) 4-Chloro-quinazoline-8-carboxylic acid methyl ester were added and the mixture was stirred overnight. The solvent was removed, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:31]=[CH:30][C:20]([C:21]([O:23][CH2:24][CH2:25]CCCC)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.OC1C=CC(C(OCCCCCC)=O)=CC=1>>[CH3:32][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:30][CH:31]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: CCCCCCOC(=O)c1ccc(O)cc1
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
n-Hexyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzoate-Using n-hexyl 4-hydroxybenzoate, the title compound was synthesized as a colorless oil. PMR (CDCl3): δ 0.92 (3H, m), 1.33 (6H, s), 1.35 (6H, s), 1.42 (6H, m), 1.74 (4H, s), 1.77 (2H, m), 4.34 (2H, t, J~6.7 Hz), 7.30 (2H, d, J~8.8 Hz), 7.46 (1H, d, J~8.3 Hz)), 7.95 (1H, dd, J~8.3 Hz, 1.9 Hz), 8.14 (2H, d, J~8.8 Hz), 8.17 (1H, d, J~1.9 Hz).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH:2]=[CH2:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[C:25]1([Se:31]Cl)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:1]([CH:4]1[CH2:8][CH2:7][CH:6]([Se:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]1=[O:9])[CH:2]=[CH2:3]
Reactant: Cl[Se]c1ccccc1
Reactant: C=CCC1CCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1CCC([Se]c2ccccc2)C1=O
Temperature: -65 °C
Yield: 70.5 %

Procedure:
While under a nitrogen, a solution of 2-allylcyclopentanone (12.4 g, 100 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to −70° C. and treated with 1 N lithium bis(tri-methylsilyl)amide/tetrahydrofuran (200 mL, 200 mmol) at a rate to keep pot temperature below −55° C. Once the addition was complete, the mixture was stirred at −60 to −70° C. for one additional hour. A second solution of phenylselenyl chloride (19.5 g, 102 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise and the mixture stirred at −60 to −70° C. for 30 min, then allowed to warm to 0° C. The reaction was quenched by addition of the solution to a rapidly stirred mixture of ethyl acetate (500 mL) and 5% aqueous citric acid (200 mL), and the organic layer was separated. The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic solution was washed with saturated aqueous sodium chloride (200 mL), dried (MgSO4), and concentrated in vacuo. The residue was dissolved in heptane and loaded onto a silica gel column (˜600 cc) and eluted with 2:1 heptane/dichloromethane, then with 1:1 heptane/dichloromethane to afford 2-allyl-5-(phenylselanyl)cyclopentanone (19.7 g, 71%) as a pale yellow oil. NMR (CDCl3): δ 7.40-7.50 (m, 2 H), 7.05-7.25 (m, 3 H), 5.50-5.70 (m, 1 H), 4.80-4.95 (m, 2 H), 3.45-3.75 (m, 1 H), 2.30-2.50 (m, 1 H), 1.80-2.25 (m, 5 H), 1.50-1.75 (m, 1 H). MS (M+1): 279.1/280.9 (for 2 major isotopes of Se).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])[CH2:3][CH2:2]1.[CH3:13][C:14]1([O:17][CH2:16]1)[CH3:15]>C(O)C>[CH2:10]([O:9][C:8](=[O:12])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]1)[CH3:11]
Reactant: CC1(C)CO1
Reactant: CCOC(=O)NC1CCNCC1
Solvent: CCO
Product: CCOC(=O)NC1CCN(CC(C)(C)O)CC1
Yield: 96.8 %

Procedure:
A mixture of commercially available ethyl piperidin-4-ylcarbamate (2.067 g, 12 mmol) and isobutylene oxide (868 mg, 12 mmol) in ethanol (15 mL) was irradiated in a microwave apparatus at 110° C. for 90 min. Purification by silica gel column chromatography with ethyl acetate gave the title compound as a colorless oil (2.838 g, 97%); MS: m/e=245.3 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:7])[CH3:6])C.[H][H]>C(O)C.[Pd]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:29])=[O:3])=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(Oc1ccc(O)cc1-c1ccccc1)C(=O)O

Procedure:
A solution of 2-(5-benzyloxy-biphenyl-2-yloxy)-2-methyl-propionic acid ethyl ester (3.58 g, 7.63 mmol maximum) in ethanol (75 mL) was treated with 5% Pd/C (3.0 g) and hydrogen (balloon, room temperature, 16 h). The mixture was filtered and concentrated to a viscous colorless oil (2.44 g, 107%): 1H NMR (400 MHz, CDCl3) δ1.25 (t, 3H, J=7.1 Hz), 1.27 (s, 6H), 4.20 (q, 2H, J=7.3 Hz), 4.95 (brs, 1H), 6.67 (dd, 1H, J=3.4, 8.8 Hz), 6.81 (d, 1H, J=3.4 Hz), 6.88(d, 1H, J=8.8 Hz), 7.30(dt, 1H, J=1.5, 7.3 Hz), 7.37 (dt, 2H, J=1.5, 7.3 Hz), 7.52 (dd, 2H, J=1.5, 6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH2:7][CH:8]3[CH:12]([NH2:13])[C:11]([CH3:14])([C:5]=2[CH:4]=1)[CH:10]=[CH:9]3.[H][H]>[Pt]=O.C(O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH2:7][CH:8]3[CH:12]([NH2:13])[C:11]([CH3:14])([C:5]=2[CH:4]=1)[CH2:10][CH2:9]3
Reactant: COc1ccc2c(c1)C1(C)C=CC(C2)C1N
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc2c(c1)C1(C)CCC(C2)C1N

Procedure:
A solution of 8,9-dihydro-3-methoxy-5-methyl-5,8-methano-5H-benzocyclohepten-10-amine [1.0 g. of α,β-amine mixture (9:1)] in 100 ml. of ethanol is hydrogenated over 150 mg. of platinum oxide catalyst under 48 psi hydrogen pressure in a Parr apparatus. Uptake of hydrogen is complete in one-half hour. The catalyst is filtered and the filtrate is concentrated. Gas chromatography of the residue identified it as a 9:1 mixture of α/β 6,7,8,9-tetrahydro-3-methoxy-5-methyl-5,8-methano-5H-benzocycloheptene-10-amine.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18].O>C(#N)C>[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]([OH:18])[CH:4]([N+:1]([O-:3])=[O:2])[CH3:5]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C(O)c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Reaction time: 4 h

Procedure:
To a stirred solution of nitroethane (8.3 g, 0.11 mol) in acetonitrile (150 ml) was added anhydrous potassium phosphate (1.0 g, 4.6 mmol) followed by 2,4-dichloro-benzaldehyde (17.5 g, 0.10 mol). The reaction mixture was stirred for 4 hours. Water (300 ml) was added and the reaction mixture was extracted with diethyl ether (200 ml). The organic extract was washed with water and dried over anhydrous Na2SO4, the solvent was removed and the resulting residue was purified by flash chromatography over silicagel (eluent:cyclohexane/ethylacetate 9:1). 20.7 g (82.5% of theory) of a threo/erythro-mixture of 1-(2,4-dichlorophenyl)-2-nitro-propan-1-ol was obtained. Crystallisation from cyclohexane yielded pure erythro 1-(2,4-dichlorophenyl)-2-nitro-propan-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[CH2:15][CH2:14]2)[CH3:12])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(Br)cc1
Reactant: BrCCCCCCBr
Product: CN([C@H]1CC[C@H](OCCCCCCBr)CC1)S(=O)(=O)c1ccc(Br)cc1

Procedure:
In analogy to example 11.11, trans-4-Bromo-N-(4-hydroxy-cyclohexyl)-N-methyl-benzenesulfonamide and 1,6-dibromohexane were reacted to yield trans-4-Bromo-N-[4-(6-bromo-hexyloxy)-cyclohexyl]-N-methyl-benzenesulfonamide as off-white solid, MS: 510 (MH+, 1Br).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[O:24][CH:23]=[CH:22][C:21]=12)=[O:15])=O)(C)(C)C.[ClH:25]>CC(O)C>[ClH:25].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[O:24][CH:23]=[CH:22][C:21]=12)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CNC(=O)c1cccc2occc12
Agent: Cl
Solvent: CC(C)O
Product: O=C(NC[C@@H]1CCN1)c1cccc2occc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
To a solution of (2S)-{[(benzofuran-4-carbonyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (170 mg) in 2-propanol (4 mL) was added 5-6M HCl in 2-propanol (2 mL). The resulting reaction mixture was stirred at RT under nitrogen for 20 h and concentrated in vacuo to yield 120 mg (85%) of the title compound as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1)[CH3:39]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(CC)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CC)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M141) (0.33 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (230 mg, 88%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(F)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cc(F)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 11.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (3.1 g, 8.5 mmol) and DMAP (0.54 g) in dry CH2Cl2 (45 mL), Et3N (2.58 g, 3.6 mL) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (4.0 g, 43 mmol, 5 eq) in dry CH2Cl2 (50 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. The reaction was quenched with water (50 mL). The aqueous layer was extracted with CH2Cl2 (3×30 mL), the combined organic layers were washed with 10% citric acid (2×50 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (400 mg, HPLC≧98%). 1H NMR (CDCl3) δ 7.2 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 4.4 (m, 1H), 4.1 (m, 1H), 3.7 (m, 1H), 3.6 (s, 3H), 3.2 (m, 2H), 2.9 (m, 2H), 2.3 (s, 3H), 1.75 (m, 1H), 1.6 (m, 1H), 1.4 (s, 9H), 1.25 (m, 2H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]([C:8]1([NH:13][C:14]([CH:16]2[CH2:20][CH:19]([O:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24][N:23]=3)[CH2:18][NH:17]2)=[O:15])[CH2:10][CH:9]1[CH:11]=[CH2:12])=[O:7])[CH3:4].[CH2:34]([O:37][CH2:38][CH2:39][CH2:40][CH:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:42](O)=[O:43])[CH:35]=[CH2:36].C(OCCC[C@H](NC(OC(C)(C)C)=O)C(O)=O)C=C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:3]([O:5][C:6]([C:8]1([NH:13][C:14]([CH:16]2[CH2:20][CH:19]([O:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24][N:23]=3)[CH2:18][N:17]2[C:42](=[O:43])[CH:41]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:40][CH2:39][CH2:38][O:37][CH2:34][CH:35]=[CH2:36])=[O:15])[CH2:10][CH:9]1[CH:11]=[CH2:12])=[O:7])[CH3:4]
Reactant: C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1)C(=O)OCC
Agent: C=CCOCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CN1CCOCC1
Product: C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc2nccc3cc(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A solution of 1-{[4-(6-Methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester dihydrochloride (Example 22)(3.60 g, 7.25 mmol) and 5-allyloxy-2-tert-butoxycarbonylamino-pentanoic acid (the product of step 26E, 1.98 g, 7.25 mmol) in 75 ml of DMF was treated with HATU (3.31 g, 8.7 mmol) and N-methylmorpholine (2.79 ml, 25.4 mmol). The reaction mixture was stirred at rt under N2 for 4 h, and then quenched with pH 4 buffer (biphthalate). The resulting mixture was extracted with EtOAc. The organic phase was washed with sat. aq. NaCl, dried (MgSO4), and concentrated in vacuo to give the crude product. Flash chromatography (silica gel, 10–60% ethyl acetate/hexane) gave 3.91 g (˜79%) of 1-{[1-(5-Allyloxy-2-tert-butoxycarbonylamino-pentanoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester as a yellow collapsed foam: 1H NMR (500 MHz, METHANOL-D4) δ 1.05–1.16 (m, 1H), 1.32 (s, 9H), 1.37–1.50 (m, 3H), 1.51–1.67 (m, 3H), 1.68–1.84 (m, 2H), 2.17–2.30 (m, 1H), 2.32–2.50 (m, 1H), 2.58–2.73 (m, 1H), 2.80 (s, 1H), 3.33–3.52 (m, 2H), 3.86–3.95 (m, 5H), 4.00–4.06 (m, 1H), 4.07–4.22 (m, 3H), 4.23–4.38 (m, 1H), 4.58–4.67 (m, 1H), 5.04–5.17 (m, 2H), 5.18–5.34 (m, 2H), 5.65–5.94 (m, 3H), 7.07–7.28 (m, 3H), 7.82–7.92 (m, 1H), 7.96–8.13 (m, 1H). LC-MS (Method B, retention time: 1.75 min), MS m/z 681 (M++1).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[CH2:14]([N:16]([CH2:20][CH3:21])[CH2:17][CH2:18][NH2:19])[CH3:15]>C(O)C>[CH2:14]([N:16]([CH2:17][CH2:18][NH:19][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12])[CH2:20][CH3:21])[CH3:15]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: CCN(CC)CCN
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(Br)cc(C)c1N
Temperature: 78 °C
Yield: 83.8 %

Procedure:
To a 100 mL round-bottom flask, 0.1 mol of 2-amino-3-methyl 5-bromobenzoic acid methyl ester having the structural formula of VIII-2, 100 mL of ethanol, 0.3 mol of N,N-diethyl ethylenediamine were added, heated to 78° C. and reacted for 4 hours, after treatment 27.5 grams of N-diethylaminoethyl-2-amino-3-methyl-5-bromobenzamide having a structural formula of III-2 was obtained, and the yield was 84.2%;
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH2:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:26]([C:25]([NH:24][C:17]1[CH:16]=[C:15]([CH:12]2[CH2:11][C:10]([CH3:22])([CH3:23])[C:9]3[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[CH:7][CH:8]=3)[NH:13]2)[CH:20]=[CH:19][CH:18]=1)([CH3:30])[CH3:29])([OH:28])=[O:27]
Reactant: COC(=O)c1cccc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cccc(C(=O)O)c3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 24.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (374 mg, 1.0 mmol), copper(I) iodide (57 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309 mg, 3.0 mmol) and potassium carbonate (415 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (95.3 mg, 25.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 383.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([C:8]1[CH:9]=[C:10]([CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)(=[O:34])[CH3:33]
Reactant: COc1ccc2cccc(CONC(C)=O)c2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C(C)=O)cc(CONC(C)=O)c2c1
Reaction time: 2 h

Procedure:
Starting with a solution of the compound of Example 1 and AlCl3, in a solvent such as nitrobenzene, acetyl chloride is added dropwise at 12° C. and under nitrogen. The reaction is allowed to proceed for 2 hours at 12° C. and the reaction mixture is poured over ice. The crude mixture is extracted, dried, concentrated and chromatographed on silica. The title compound is obtained.