Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:29]3[CH2:28][CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCc1ccccc1
Reaction time: 10 h
Yield: 78.6 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.29 ml (0.016 mol) of 3-phenylpropylamine were added thereto and the mixture was boiled for 20 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 70° and 80 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. There were obtained 4.02 g (76%) of oily rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-phenyl-propyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[NH4+]=[S:12]>CO.O>[F:1][C:2]1[C:3]([C:9](=[S:12])[NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1ncc(F)cc1F
Solvent: O
Solvent: CO
Product: NC(=S)c1ncc(F)cc1F
Temperature: 0 °C
Reaction time: 14 h

Procedure:
3,5-Difluoropicolinonitrile (1.00 g) was partially dissolved in methanol (5 mL) and cooled to 0° C. A solution of ammonium sulfide in water (1.1 mL, 45% weight) was added slowly and the reaction was stirred 14 hours. The reaction was decanted and this solution was concentrated and then purified by column chromatography using dichloromethane as the eluant to obtain the title compound (0.17 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)/[CH:5]=[C:6](\[C:10](=[O:13])[CH2:11][CH3:12])/[C:7](=[O:9])[CH3:8].ClC1C=C(C=C(Cl)C=1)/C=C(/C(=O)CC)\C(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[CH2:5][CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[C:7](=[O:9])[CH3:8]
Reactant: CCC(=O)/C(=C\c1cc(Cl)cc(Cl)c1)C(C)=O
Agent: CCC(=O)/C(=C/c1cc(Cl)cc(Cl)c1)C(C)=O
Product: CCC(=O)C(Cc1cc(Cl)cc(Cl)c1)C(C)=O

Procedure:
The title compound was prepared by a similar method to that of Preparation 6 using (3Z)-3-(3,5-dichlorobenzylidene)-2,4-hexanedione and (3E)-3-(3,5-dichlorobenzylidene)-2,4-hexanedione of Preparations 18 and 19 and was obtained as yellow oil (300 mg).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2C=CC=[CH:16][C:11]=2N=N1.[Br:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[C:31]([NH:38][C:39]([O:41]CC)=O)[CH:30]=1.CN1CCOCC1.C(N)C=C.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:12]([N:8]1[C:33](=[O:35])[C:32]2[C:31](=[CH:30][C:29]([Br:28])=[CH:37][CH:36]=2)[NH:38][C:39]1=[O:41])[CH:11]=[CH2:16]
Reactant: CCOC(=O)Nc1cc(Br)ccc1C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C=CCN
Solvent: CN1CCOCC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCn1c(=O)[nH]c2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
BOP (8.47 g, 19.16 mmol) was added to a solution of 4-bromo-2-[(ethoxycarbonyl)amino]benzoic acid (4.6 g, 15.97 mmol), N-methylmorpholine (3.51 ml, 31.9 mmol) and allylamine (1.434 ml, 19.16 mmol) in DMF (50 ml) at room temperature. The mixture was allowed to stir at room temperature for 4 hrs. DBU (24.07 ml, 160 mmol) was added to the reaction and the temperature was raised to 60° C. The mixture let was allowed to stir at 60° C. for 1 hr. The mixture was quenched into 0.5 N HCL (200 mL), and the pH was adjusted to 1.5 with 3N HCL. Thick white solids were observed. The reaction was diluted to ˜400 mL with water let stir 10 min and solids filtered. The solids were washed with 0.5 N HCL (50 mL) and then slurry washed with water and sucked dry overnight to give the title compound (4.5 gm, 100%) as a solid. LCMS (ES+) m/z 280.87 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:39](Br)[CH3:40])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>C(#N)C.C(=O)(O)[O-].[Na+]>[F:27][C:28]([F:42])([F:43])[C:29]1[CH:30]=[C:31]([CH:39]([NH:1][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH3:40])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1
Reactant: COC(=O)[C@@H]1CC[C@H](N)[C@H]1c1ccc(F)cc1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H]1CC[C@H](NC(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Yield: 37.3 %

Procedure:
A solution of 200 mg of amine from Example 62, 0.3 mL of DIPEA and 350 mg of 1-(RS)-(3,5-bis(trifluoromethyl)phenyl)ethyl bromide (prepared in Example 24) in 2 mL of acetonitrile was heated at 50° C. in a sealed vial for 40 h. The reaction was diluted with saturated sodium bicarbonate and extracted twice with methylene chloride. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 10 to 15% ethyl acetate in hexanes to obtain 150 mg of title compound as a mixture of methyl isomers. Mass spec (NH3 /CI): 478 (M+1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](OCC)=[O:4].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[CH3:13]>C1COCC1>[CH2:12]([O:14][C:15](=[O:30])[CH:16]([C:3](=[O:4])[C:2]([F:9])([F:8])[F:1])[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[CH3:13]
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C

Procedure:
THF (3.0 mL) and ethyl trifluoroacetate (1.32 mL, 1.58 g, 11.1 mmol) were added to sodium hydride (442 mg of 60% oil dispersion, 11.1 mmol) in a flask fitted with a mechanical stirrer and a reflux condenser. 1-(tert-butoxycarbonyl)-4-piperidineacetic acid ethyl ester (1.50 g, 5.52 mmol) dissolved in THF (2.0 mL) was added over 30 min, with additional THF (2×1 mL) to complete the transfer. The mixture was warmed to 45° C. overnight. An additional portion of ethyl trifluoroacetate (1.0 mL, 1.19 g, 8.4 mmol) was added the temperature was increased to 70° C. for 17 h. After cooling to RT, the mixture was partitioned between EtOAc (50 mL) and a mixture of saturated aq. NaCl (25 mL) and 2 N aq. HCl (10 mL). The aqueous layer was extracted with EtOAc (25 mL). The organic layers were washed in succession with saturated aq. NaCl (2×10 mL), dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 90:10 to 85:15 v/v hexanes/EtOAc to give the title compound as a colorless oil. For the title compound: 1H NMR (500 MHz, CDCl3) showed an apparent mixture of tautomers; ESI-MS 268.2 (M+H−100); HPLC A: 3.3 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][C:9](=[O:12])[C:8]([NH:13][C:14](=[O:16])[CH3:15])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>>[N:1]1([C:2]2[C:11]3[O:10][C:9](=[O:12])[C:8]([NH:13][C:14](=[O:16])[CH3:15])=[CH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: CC(=O)Nc1cc2cccc(N)c2oc1=O
Reactant: ClCCNCCCl
Product: CC(=O)Nc1cc2cccc(N3CCNCC3)c2oc1=O

Procedure:
Step 4 was the alkylation of N-(8-amino-2-oxo-2H-1-benzopyran-3-yl)-acetamide (4*) with bis-chloroethylamine yielding N-(8-(1-piperazinyl)-2-oxo-2H-1-benzopyran-3-yl-)acetamide (5*).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=3)[CH:8]=[CH:9][C:2]1=2.[OH-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:11]=3)[CH:8]=[CH:9][C:2]1=2
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2sccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2sccc2c1
Yield: 81.3 %

Procedure:
2 This compound was prepared according to general method D from methyl 2-(4-(benzo[b]thiophen-5-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.047 g; 0.113 mmol), sodium hydroxide 10N (0.113 mL; 1.13 mmol) in methanol (1.1 mL) to afford 0.037 g (79%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:16])[CH:9]=[C:8]2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CCO>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH3:16])[CH:9]=[C:8]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cccc(C)c2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc2cc(C(=O)O)n(Cc3ccc(Cl)cc3)c12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
ethyl 1-(4-chlorobenzyl)-7-methyl-1H-indole-2-carboxylate (212 mg, 0.647 mmol) was dissolved in EtOH (10 mL) and 10% aq. KOH (10 mL) was added. The reaction stirred for 4 h at 70° C., after which time as much solvent was stripped off as possible. The mostly aqueous mixture was cooled in an ice bath and acidified with concentrate HCl to obtain a precipitate that was collected over a filter and washed with 1M HCl and water. The title compound was not purified or characterized further. (Yield: 182 mg, 0.607 mmol, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[ClH:21].[CH3:22][NH2:23].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:21].[ClH:21].[CH3:22][NH:23][CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:16]1
Reactant: O=C1CCN(CCCOCCc2ccc(F)cc2)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CNC1CCN(CCCOCCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 14.7 g (52.6 mmol) of the preceding ketoamine (22.2) in 150 ml of CH2Cl2 is treated with 3.5 g (52.6 mmol) of methylamine hydrochloride and then methanol is added until dissolution is complete. After stirring for 3 h at 25° C., the mixture is cooled on an ice bath and 14.5 g (68.5 mmol) of sodium triacetoxyborohydride are added portionwise and, finally, 3 ml of acetic acid are added dropwise. Stirring is continued overnight at 25° C. The reaction mixture is poured into ice and basified to pH 12-13. The base released is extracted in the usual way to give a greenish oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:12][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
Using a procedure similar to Example 1B except starting with 4-methoxycarbonyl-1,2-benzenediamine and 4-t-butylbenzoyl chloride, the title compound was obtained as a solid (10.8 g, 65%); MS(FD): 326.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:28][N:29]([CH2:40][C:41]2[C:46]([NH2:47])=[CH:45][CH:44]=[CH:43][N:42]=2)[C@@H:30]2[C:39]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:33][CH2:32][CH2:31]2)=[C:24]([CH2:26][OH:27])[CH:25]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.C1COCC1>[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:28][N:29]([CH2:40][C:41]2[C:46]([NH:47][C:4](=[O:6])[C:3]3[C:7]([Cl:11])=[CH:8][N:9]=[CH:10][C:2]=3[Cl:1])=[CH:45][CH:44]=[CH:43][N:42]=2)[C@@H:30]2[C:39]3[N:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:33][CH2:32][CH2:31]2)=[C:24]([CH2:26][OH:27])[CH:25]=1
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: NCc1ccc(CN(Cc2ncccc2N)[C@H]2CCCc3cccnc32)c(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NCc1ccc(CN(Cc2ncccc2NC(=O)c2c(Cl)cncc2Cl)[C@H]2CCCc3cccnc32)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
To a stirred suspension of 3,5-dichloro-isonicotinic acid (85 mg, 0.44 mmol) in CH2Cl2 (3 mL) was added DMF (1 drop) and oxalyl chloride (0.12 mL, 1.4 mmol). The suspension was stirred at room temperature for 2 h, then concentrated under reduced pressure. A solution of (5-aminomethyl-2-{[(3-amino-pyridin-2-ylmethyl)-((S)-5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (88 mg, 0.22 mmol) in THF (3 mL) was added to the acid chloride followed by Et3N (0.04 mL, 0.3 mmol). The mixture was stirred for 1 h, then diluted with CH2Cl2 (10 mL) and washed with water (10 mL). The aqueous layer was extracted with CH2Cl2 (3×8 mL), and the combined organic layers were washed with saturated NaHCO3 (20 mL), then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified using flash chromatography on silica gel (97:2:1 CH2Cl2/MeOH/NH4OH) to give COMPOUND 407 (21 mg, 17%), as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[C:7]=3[C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.O(Cl)[Cl:22]>>[Cl:22][C:8]1[C:7]2[C:13](=[O:20])[C:14]3[C:19]([C:6]=2[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1ccccc1-3
Reactant: ClOCl
Product: Cc1ccc2c3c(c(Cl)nc2c1)C(=O)c1ccccc1-3
Yield: 73.4 %

Procedure:
A mixture of 3-methyl-5H-indeno[2,1-c]quinoline-6,7-dion obtained in reference example 5 (700 mg, 2.7 mmol) and phophorous oxychloride (10 ml, 107 mmol) was refluxed with heat for 1.5 hours. The reaction mixture was distilled to dryness. To the residue was added water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and dissolved in chloroform to filter off undissolved substances. Recrystallization from benzene to give 550 mg (yield 73.4%) of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(CCN(C)C)C.N[C@H](C(O)=O)C[SeH].[Li]CCCC.[CH3:33][C:34]1[C:38]([C:39]2[CH:40]=[C:41]([CH:58]=[O:59])[C:42]3[N:46]=[C:45]([O:47][CH2:48][CH3:49])[N:44](C(OC(C)(C)C)=O)[C:43]=3[CH:57]=2)=[C:37]([CH3:60])[O:36][N:35]=1>CC1OCCC1>[CH3:33][C:34]1[C:38]([C:39]2[CH:40]=[C:41]([CH:58]([OH:59])[CH:12]3[CH2:11][CH2:10][CH2:9][N:8]3[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:42]3[N:46]=[C:45]([O:47][CH2:48][CH3:49])[NH:44][C:43]=3[CH:57]=2)=[C:37]([CH3:60])[O:36][N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: CCOc1nc2c(C=O)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: CC1CCCO1
Product: CCOc1nc2c(C(O)C3CCCN3C(=O)OC(C)(C)C)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 29.8 %

Procedure:
N-Boc-pyrrolidine (150 mg, 0.39 mmol) and TMEDA (0.2 mL, 158 mg, 1.36 mmol) was dissolved in dry MeTHF (2.6 mL) under Ar and cooled to −78° C. Sec-BuLi (1.4M, 0.97 mL, 1.36 mmol) was added dropwise and the reaction was allowed to stir at −78° C. for 40 mins. tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate (150 mg, 0.39 mmol) was dissolved in MeTHF (0.5 mL) and added dropwise via syringe to the reaction and allowed to stir at −78° C. for 10 minutes. The reaction was quenched with water and extracted three times with EtOAc, combined organic layers were washed once with brine, concentrated, and purified by reverse-phase HPLC to give tert-butyl 2-((6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(hydroxy)methyl)pyrrolidine-1-carboxylate (53 mg, 30%) as a white powder. The solid (50 mg, 0.11 mmol) was dissolved in EtOH (5 mL) and HCl (1 mL) and heated for 12 hours at 65° C. The reaction was cooled and concentrated to afford the desired product as a white powder.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3].C([N-]C(C)C)(C)C.[Li+].[Br:19][C:20]1[C:21](=O)[CH2:22][CH2:23][CH2:24][C:25]=1[O:26]C>C1C=CC=CC=1.C1COCC1>[Br:19][C:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]=1[CH:6]1[CH2:7][CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:10]
Reactant: CCCN1CCCCC1=O
Reactant: COC1=C(Br)C(=O)CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCN1CCCC(C2=C(Br)C(=O)CCC2)C1=O

Procedure:
A solution of 1-propyl-2-piperidone (50 mM) in benzene (40 ml) was added dropwise to a solution of lithium di-isopropylamide [ex n-butyl lithium in hexane (32.3 ml, 50 mM), di-isopropylamine (7 ml, 50 mM) and THF (33 ml)]. A solution of 2-bromo-3-methoxycyclohex-2-en-1-one (10.25 g, 50 mM) in THF (40 ml) was added, and after 5 minutes the mixture was quenched by pouring on to excess aqueous hydrochloric acid. Ether extraction followed by passage through a short silica pad using ethyl acetate as eluant gave the title compound as a colourless oil (10.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:35](O)=[O:36])[CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:35]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][CH2:7][C:6]1[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[O:15])=[O:36])[CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cncn1)[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred solution of N-[5-chloro-2-(1H1,2,4-triazol-1-yl)benzyl]-L-prolinamide (Example 27, Step B, 0.046 g, 0.121 mmol), N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (30 mg, 0.121 mmol), and HOBt hydrate (20 mg, 0.145 mmol) in DMF (3 mL) was added EDC (0.028 g, 0.145 mmol). Diisopropylethylamine (0.083 mL, 0.484 mmol) was added and the mixture was stirred at ambient temperature for 18 hours, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 10% aqueous Na2CO3. The EtOAc layer was separated, washed with water and brine, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure to give N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanyl-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide as a gum (0.058 g). HPLC RT=2.18 min, Method B; LCMS (M+H): 517, 519.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[NH:31][C@@H:30]([CH2:32][OH:33])[CH2:29][O:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+].[Cl-].[NH4+]>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]2[CH2:27][O:28][CH2:29][C@H:30]([CH2:32][OH:33])[N:31]2[C:2]([O:4][CH2:5][CH:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:3])=[CH:24][CH:25]=1
Reactant: OC[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1[C@@H](CO)COC[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
9-Fluorenylmethyl chloroformate (122 mg) was added to a mixed solution of [(3S,5R)-5-(4-chlorophenyl)morpholin-3-yl]methanol (86 mg) in methylene chloride (3 mL) and a saturated sodium bicarbonate solution (3 mL). The reaction solution was stirred at room temperature for eight hours. Then, chloroform and a saturated ammonium chloride solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system) to obtain 153 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=2)[OH:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[O:32]=[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47](O)=[O:48])[C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:38][C:35]([CH3:39])([CH2:36][CH3:37])[C:34](=[O:40])[C:33]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47]([O:16][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:18]=1)[CH2:14][CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:48])=[O:32]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Reactant: COc1cc(CC[C@@H](O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1cc(OC)c(OC)c(OC)c1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of alcohol 14 (650 mg, 1.5 mmol) in CH2Cl2 (5 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 382 mg, 1.5 mmol, followed by 1,3-dicyclohexylcarbodiinide (370 mg, 1.8 mmol), and 4-(dimethylamino)-pyridine (128 mg, 1.0 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20-30% EtOAc/hexanes) to give (1R)-3-(3,4,5-trimethoxyphenyl)-1-[3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (776 mg, 78%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.30-6.80 (m, 4H), 6.37 (s, 2H), 5.82 (t, J=6.1 Hz, 1H), 5.33 (d, J=5.2 Hz, 1H), 4.54 (s, 2H), 3.85 (s, 6H), 3.83 (s, 3H), 3.38 (d, J=12.6 Hz, 1H), 3.16 (td, J=12.8, 3.1 Hz, 1H), 2.60 (m, 2H), 2.45-2.05 (m, 3H), 1.70 (m, 6H), 1.50 (s, 9H), 1.45 (m, 2H), 1.25 (s, 3H), 1.23 (s, 3H), 0.90 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75MHz) (single diastereomer, mixture of rotamers) 208.2, 175.1, 170.1, 168.2, 167.6, 158.5, 153.6, 141.7, 137.0, 130.1, 120.9, 120.2, 114.6, 113.7, 105.7, 82.7, 66.2, 61.2, 56.5, 51.7, 47.1, 44.6, 38.2, 32.9, 32.4, 28.4, 26.8, 25.3, 23.9, 23.5, 21.6, 9.1.