Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[Br:11]N1C(=O)CCC1=O.ClCCl>O>[Br:11][CH:9]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])[CH3:10]
Reactant: CCc1ncnc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC(Br)c1ncnc(Cl)c1F
Temperature: 25 °C
Yield: 107.5 %

Procedure:
A stirred mixture of the compound of part (v) (38.5 kg), azoisobutyronitrile (AIBN) (1.92 kg), N-bromosuccinimide (49 kg) and dichloromethane (198 L) was heated under reflux under nitrogen for 12 hours. The mixture was cooled to 25° C. and water (239 L) added. The layers were separated and the aqueous layer extracted with dichloromethane (120 L). The combined organic layers were washed with a solution of sodium metabisulphite (22.8 kg) in water (239 L), followed by water (239 L). The organic layer was concentrated under reduced pressure, toluene (240 L) was added and the resulting solution concentrated under reduced pressure to give the product as an oil (61.7 kg).
Reaction SMILES: Cl[CH:2]([B:5]1[O:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:10])[C:7]([CH3:24])([CH3:23])[O:6]1)[CH2:3][CH3:4].C[Si]([N-:29][Si](C)(C)C)(C)C.[Li+].FC(F)(F)C(O)=O>O1CCCC1>[NH2:29][CH:2]([B:5]1[O:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:10])[C:7]([CH3:24])([CH3:23])[O:6]1)[CH2:3][CH3:4]
Reactant: CCC(Cl)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCC(N)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -78 °C
Reaction time: 8 h
Yield: 129.1 %

Procedure:
0.82 g (2.27 mmol) of tert-butyl 5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 10 ml of tetrahydrofuran and then cooled to −78° C. under a nitrogen atmosphere. 2.3 ml (2.3 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise. The solution was then stirred overnight while slowly warming to room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 0.52 ml (6.8 mmol) of trifluoroacetic acid was added and the solution was stirred at 0° C. for 30 minutes. The solution was evaporated and the residue was co-evaporated with toluene to give 1 g of tert-butyl 5-[2-(1(RS)-aminopropyl)-4(RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in the next step without purification.
Reaction SMILES: [CH:1]1([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.N>ClCCl>[CH:1]1([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:20])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Agent: N
Solvent: ClCCl
Product: NC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
(2R)-2-Cyclohexyl-2-hydroxy-2-phenylacetic acid (preparation 36, 4.87 g, 20.8 mmol) was dissolved in dichloromethane (150 mL) and carbonyldiimidazole (3.37 g, 20.8 mmol) added in one portion. After stirring for 1 hour at room temperature, 0.880 ammonia (21 mL) was added and stirring continued at room temperature for 18 hours. The organic layer was separated, washed with brine (50 mL), dried over magnesium sulphate, filtered and the solvent removed in vacuo to furnish the title compound as a white foam in 92% yield, 4.56 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.C(OP([CH2:46][C:47]#[N:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:46]/[C:47]#[N:48])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C#N)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
To a mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-4-carbaldehyde (580 mg), diethylphosphonoacetonitrile (230 mg) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 56.0 mg) at 0° C., and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenonitrile (460 mg, yield 76%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from acetone-hexane. melting point: 184-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:3]=1
Reactant: Nc1cccc(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
1.26 g (10.2 mmol) of 2-amino-6-hydroxymethylpyridine (Journal of Heterocyclic Chemistry, 2001, 38, 173) was dissolved in 5.1 mL of dimethylformamide and 1.7 g (25 mmol) of imidazole was added thereto. Under cooling with ice, 1.8 g (12 mmol) of tert-butyldimethylsilyl chloride was added thereto followed by stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and brine. This was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography to give 1.9 g of the title compound as an orange-colored oil.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:34])([CH3:33])[C:8]12[O:15][C:12]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH:13]=[CH:14]1)[CH2:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9]2)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([SiH2:5][O:6][C:7]([CH3:34])([CH3:33])[C:8]12[O:15][C:12]([C:16]([CH3:23])([CH3:24])[O:17][SiH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])([CH:13]=[CH:14]1)[CH2:11][C:10]([C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1)=[CH:9]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)C12C=CC(C(C)(C)O[SiH2]C(C)(C)C)(CC(OS(=O)(=O)C(F)(F)F)=C1)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)[SiH2]OC(C)(C)C12C=CC(C(C)(C)O[SiH2]C(C)(C)C)(CC(c3ccc(N)cc3)=C1)O2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of trifluoromethanesulfonic acid 1,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-8-oxa-bicyclo[3.2.1]octa-2,6-dien-3-yl ester (as prepared in the previous step, 1.22 g, 2.24 mmol), Pd(PPh3)4 (259 mg, 0.224 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (540 mg, 2.46 mmol) in 20 mL of 1,4-dioxane was added 2.0 M aqueous Na2CO3 solution (9.0 mL, 18 mmol). The resulting mixture was stirred at 80° C. for 2 h and then cooled to RT. Treated with 100 mL of EtOAc, the mixture was washed with H2O (3×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1:1 hexane/DCM-DCM) gave 802 mg (73% for two steps) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C27H45NO3Si2, 488.3 (M+H), found 488.4.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:20])[CH2:19][NH:18][CH2:17][CH2:16][NH:15]1.C(N(C(C)C)C(C)C)C>CC(N(C)C)=O>[CH3:13][C:14]1([CH3:20])[NH:15][CH2:16][CH2:17][N:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:19]1
Reactant: CC1(C)CNCCN1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCNC(C)(C)C2)cc1
Temperature: 200 °C
Yield: 55.3 %

Procedure:
Ethyl 4-fluorobenzoate (0.151 mL, 1 mmol), 2,2-dimethylpiperazine (0.137 g, 1.20 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.349 mL, 2.00 mmol) were dissolved in DMA (2 mL) and sealed into a microwave tube. The reaction was heated to 200° C. for 4 h in the microwave reactor and cooled to room temperature. The crude mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5M ammonia in methanol, fractions were evaporated to dryness to afford an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(3,3-dimethylpiperazin-1-yl)benzoate (0.145 g, 55.3%) as a white solid. 1H NMR (399.9 MHz, CDCl3) δ 1.15 (6H, d), 1.37 (3H, t), 2.38 (1H, d), 2.41 (1H, d), 2.96-3.04 (2H, m), 3.65-3.69 (2H, m), 4.33 (2H, q), 6.84-6.87 (2H, m), 7.89-7.93 (2H, m). MS: m/z 266 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[N:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)=[N+:18]=[N-:19]>C(O)(C)C>[ClH:1].[N:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1)=[N+:18]=[N-:19]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(N=[N+]=[N-])cc3)c2cc1OC

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.12 mmol) and 4-azidoaniline hydrochloride (200 mg, 1.11 mmol) were refluxed in 10 mL of isopropyl alcohol for 0.5 hour, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo, at 70° C., 392 mg (98%); mp 200°-205° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][CH:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]4[C:18]5([CH2:23][NH:22][CH2:21]5)[O:19][CH2:20][C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40]([CH2:43][C:44](O)=[O:45])(=[O:42])=[O:41].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][CH:12]=[C:11]([C:14]3[CH:25]=[CH:24][C:17]4[C:18]5([CH2:23][N:22]([C:44](=[O:45])[CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21]5)[O:19][CH2:20][C:16]=4[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc3c(c2)COC32CNC2)=CO1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a stirred solution of hydrochloride salt of 5′-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl]-3′H-spiro[azetidine-3,1′-[2]benzofuran](Preparation 16, 0.5 g, 1.04 mmol) in THF (6 mL) was added DIPEA (1.82 mL, 10.45 mmol) at room temperature and stirred for 10 minutes at room temperature. Methane sulfonyl acetic acid (0.289 g, 2.09 mmol) and T3P (50% solution in ethyl acetate, 3.1 mL, 5.22 mmol) were added at room temperature. Resulting reaction mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (5×25 mL). Combined organic layer was washed with saturated solution of NaHCO3 (2×100 mL), dried over sodium sulphate and concentrated in vacuo to get pale yellow oil (0.62 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product gets eluted in 0.7% MeOH in DCM to afford white semisolid (0.36 g), which was triturated with DCM: n-pentane (1:10; 2×5 mL) to afford off white solid (0.295 g, 50.18%). 1H NMR (400 MHz, CDCl3) δ: 3.17 (s, 3H), 3.21 (d, J=8.4 Hz, 1H), 3.31 (d, J=17.32 Hz, 1H), 3.84 (s, 2H), 4.31 (d, J=10.96 Hz, 1H), 4.41 (d, J=11.24 Hz, 1H), 4.58-4.64 (m, 2H), 5.08 (s, 2H), 7.15 (s, 1H), 7.33 (d, J=7.76 Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (d, J=1.12 Hz, 2H). LC-MS (m/z): 559.7 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C.C1COCC1>[Cl:21][C:6]1([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:12])[O:11]1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
THF (25 mL) was added to 2-(4-chlorobenzoyl)benzoic acid (1 g, 3.8 mmol) followed by thionyl chloride (0.55 mL, 7.6 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature and monitored by TLC. Removal of the solvent gave 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one as a colourless oil (1.06 g, 3.8 mmol, 100%).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C@@H:18]2[CH2:20][O:19]2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].O>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C@@H:18]([OH:19])[CH2:20][S:3][CH2:1][CH3:2])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
Ethanethiol (312 μL, 4.2 mmol) was dissolved in THF (1.0 mL), and the mixture was cooled to 0° C. NaH (50.6 mg, 2.1 mmol) was slowly added in four portions and the mixture was stirred at room temperature for 10 minutes. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (300 mg, 1.4 mmol) was dissolved in THF (0.4 mL) and added to the mixture. The resulting solution was placed in a microwave reactor for 30 minutes at 100° C., then cooled to room temperature. Hexanes (3×10 mL) was added, followed by water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to yield the title compound as a clear oil (315 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:25][O:24][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[N:10]=[CH:9]3)=[C:4]2[NH:3]1.[H-].[Na+].IC.[CH3:30]N(C)C=O>O1CCCC1>[CH3:30][N:3]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:15])[N:10]=[CH:9]3)[O:24][CH2:25][C:2]1=[O:1]
Reactant: CC(Cn1ncc2ccc3c(c21)NC(=O)CO3)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](Cn1ncc2ccc3c(c21)N(C)C(=O)CO3)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of the product from Example 2, Step F (0.22 g, 0.64 mmol) in anhydrous tetrahydrofuran (30 mL) was added sodium hydride (60% dispersion, 28 mg, 0.70 mmol) and this mixture was stirred under a nitrogen atmosphere for 10 min. Iodomethane (99 mg, 44 uL, 0.70 mmol) was added and the mixture was stirred for 1 h followed by the addition of anhydrous dimethylformamide (20 mL); this mixture was stirred for 4 h, poured into ice water, and the solution was extracted with ethyl acetate (3×50 mL). The combined extracts were evaporated to a residue that was purified by chromatography (gradient, 20% to 50% ethyl acetate in hexane to give an oil (0.14 g, 57%): LC/MS (+APCI) m/z 361 (M+H).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@@:11]3([O:24][CH3:25])[CH:12]=[CH:13][C:14](=[O:23])[CH2:15]4>C(OCC)C.C(Cl)Cl.[Cu](I)I>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([CH3:22])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@@:11]3([O:24][CH3:25])[C@@H:12]([CH3:1])[CH2:13][C:14](=[O:23])[CH2:15]4
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)C=CC(=O)C3
Reactant: [Li]C
Agent: I[Cu]I
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A slurry of copper iodide (8.63 g, 0.045 mol) in 250 ml of anhydrous diethyl ether was cooled at -20° to -25° C. in a dry ice/carbon tetrachloride bath while being held under a nitrogen atmosphere. Methyl lithium (49.3 ml of a 1.84 M solution in ether, 0.091 mol) was cannulated into a calibrated dropping funnel and quickly added to the slurry. This complex was cooled an additional 10 minutes at -25° C. before a solution of 7,8-didehydro-3,14-dimethoxy-17-methylmorphinan-6-one (3) (9.47 g, 0.032 mol) in 60 ml of dry methylene chloride was added dropwise and washed in with an additional 30 ml of dry diethyl ether. After stirring at -20° C. for 21/2 hours, the reaction mixture was quenched with 60 ml of 20% ammonium hydroxide and made basic by the addition of 50% sodium hydroxide. The resultant copper salts were removed by suction filtration and the filter cake was washed several times with diethyl ether and water. The layers were separated and the aqueous phase extracted with two additional portions of ether. The ethereal extracts were combined, washed with saturated sodium chloride solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography on Flosisil (eluted with graded methanol/chloroform) yielded 4.6 g (46% theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.Br[CH2:18][CH2:19][CH3:20].CC(C)([O-])C.[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][CH2:18][CH2:19][CH3:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CCCBr
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
A mixture of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1 (2H)-yl)ethanone (0.150 g, 0.528 mmol), 1-bromopropane (0.24 mL, 2.64 mmol), and potassium tert-butoxide (0.296 g, 2.64 mmol) in N,N-dimethylformamide (3.0 mL) was heated at 80° C. After 24 h, a second portion of 1-bromopropane (0.24 mL, 2.64 mmol) and potassium tert-butoxide (0.296 g, 2.64 mmol) was added and the mixture was heated at 100° C. for 24 h. The reaction mixture was cooled to rt and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.100 g, 58%) as a colorless oil. MS (ESI, pos. ion) m/z 326, 328 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[C:39]([O:38][CH2:37][C@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)COC(C)(C)C
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](COC(C)(C)C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 45.4 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-3-tert-butoxy-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-24) 65 mg (0.15 mmol) to obtain the title compound 20 mg (22%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[O:25][C:22]2=[CH:23][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:5]([O:4][C:2]([N:31]1[CH2:32][CH2:33][CH:28]([C:26]2[O:25][C:22]3=[CH:23][N:24]=[C:19]([C:10]4[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=4[F:8])[CH:20]=[C:21]3[CH:27]=2)[CH2:29][CH2:30]1)=[O:3])([CH3:7])[CH3:6]
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isopropyl chloroformate (1 mol/L in toluene; 0.30 mL) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (75 mg) and N,N-diisopropyl-ethylamine (0.10 mL) in tetrahydrofuran (1 mL) chilled in an ice bath. The solution is stirred at room temperature for 3 h. The solution is concentrated and the residue is taken up in water and dichloromethane. The resulting mixture is extracted with dichloromethane and the combined extracts are dried (Na2SO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. Mass spectrum (ESI+): m/z=461 [M+H]+.