Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH2:20][NH:21][CH3:22])=[CH:7]2.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH2:20][N:21]([CH3:22])[C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][N:28]3[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[CH:7]2
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CNCc1cc2cccc(C)c2c(=O)n1-c1ccccc1C
Solvent: CCO
Product: Cc1ccccc1-n1c(CN(C)c2ncnc3c2ncn3C2CCCCO2)cc2cccc(C)c2c1=O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
8-Methyl-3-((methylamino)methyl)-2-o-tolylisoquinolin-1(2H)-one (233 mg, 0.8 mmol) (4001) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4002) (238 mg, 1.0 mmol) were dissolved in EtOH (50 mL) and the resulting mixture was stirred at reflux for 2 h. The mixture was allowed to cool to RT, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the product, 8-Methyl-3-((methyl(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)amino)methyl)-2-o-tolylisoquinolin-1(2H)-one (4003) (200 mg, 51% yield) as a slight yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:4].Br[CH2:12][CH2:13][CH:14]=[CH2:15]>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:10])[CH:7]([C:8]#[N:9])[CH2:15][CH2:14][CH:13]=[CH2:12])[CH3:4]
Reactant: C=CCCBr
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(C#N)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a flame dried flask charged with NaH (1.4 g, 35.46 mmol, 60% dispersion in mineral oil) and DMF (90 mL) equipped with a Firestone valve and under a stream of dry nitrogen was added, dropwise ethylcyanoacetate (3.14 mL, 29.56 mmol) over 20 min. The reaction mixture was then allowed to stir for 30 min, followed by addition of 4-bromobutene (3.0 mL, 29.56 mmol). The reaction mixture was allowed to stir overnight after which the solvent was removed by reduced pressure. The resulting crude mixture was dissolved in ethyl acetate, washed 3 times with 1N HCl solution and once with a saturated solution of brine. The organic and aqueous layers were separated and the organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using a mixture of 9:1 heptanes to ethyl acetate to yield a clear colorless oil.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC.O>[ClH:2].[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N:10]1[CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: COC(=O)c1ccc(OC)c(N2CCN(C)CC2)c1
Reaction time: 19 h
Yield: 16 %

Procedure:
A suspension of 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.92 g) and methyl 3-amino-4-methoxybenzoate (1.81 g) in n-butanol was refluxed with stirring for 19 h. Anhydrous sodium carbonate (0.54 g) was added and refluxing continued for 8.5 h. The solvent was then removed to give an oil which was taken up in water (50 ml) and 2N hydrochloric acid (50 ml) and extracted with ethyl acetate (2×50 ml). The acid solution was then basified with sodium bicarbonate and re-extracted with ethyl acetate (3×50 ml). The extracts were dried and concentrated to a semi-solid (2.47 g) which was absorbed from System A (200:8:1) (5 ml) onto Kieselgel G (100 g). Elution with the same solvent gave starting material and minor basic impurities. Further elution with System A (100:8:1) (450 ml) gave first minor impurities and later fractions afforded the free base of the desired product as a gum (0.48 g). This was taken up in methanol (5 ml), filtered and treated with ethereal hydrogen chloride and diluted to 25 ml with ethyl acetate. A cream coloured solid separated, was filtered and the solid (0.586 g) recrystallised from methanol:ethyl acetate to give the title compound m.p. 202°-204° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([Br:17])[CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1>[Br:17][C:12]1[CH:11]=[C:10]([C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:7]=2)=[O:9])[CH:15]=[C:14]([Br:16])[CH:13]=1
Reactant: C1COCCN1
Reactant: O=C(c1cc(Br)cc(Br)c1)c1ccnc(Cl)c1
Solvent: C1COCCO1
Product: O=C(c1cc(Br)cc(Br)c1)c1ccnc(N2CCOCC2)c1
Yield: 52.3 %

Procedure:
To (2-chloro-pyridin-4-yl)-(3,5-dibromo-phenyl)-methanone (0.200 g, 0.53 mmol) in 1.0 mL of 1,4-dioxane in a microwave tube was added 0.070 g (0.80 mmol) morpholine. The reaction was subjected to microwave irradiation at 120° C. for 60 minutes. The reaction mixture was cooled and concentrated. The crude product was chromatographed on silica gel using 1:1 hexane:ethyl acetate to give 0.118 g of the (3,5-dibromo-phenyl)-(2-morpholin-4-yl-pyridin-4-yl)-methanone. This compound was converted to [3-(1H-indol-4-yl)-5-(2-morpholin-4-yl-pyridine-4-carbonyl)-phenyl]-carbamic acid methyl ester as described for Example 90. 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J=5.3 Hz, 1H), 8.07 (t, J=1.8 Hz, 1H), 7.95 (s, 1H), 7.76 (t, J=1.6 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.29 (d, J=3.3 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.4 Hz, 1H), 7.08 (s, 1H), 6.95 (dd, J=5.1, 1.0 Hz, 1H), 6.62 (d, J=3.1 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.75 (s, 3H), 3.54 (t, J=4.9 Hz, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([N:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Example 28. LC (method 7): tR=1.12 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:11]1[C:12]([NH2:29])=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[N:16]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O.[Cu]I.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>[NH2:29][C:12]1[C:11]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=2)=[N:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:14][N:13]=1
Reactant: C#Cc1cccc(O)c1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3cccc(O)c3)n2)cc1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
3-Ethynylphenol (187.0 mg, 103.7 μL, 1.583 mmol) was added to a solution of 3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine (500 mg, 1.319 mmol), Et3N (1.335 g, 1.839 mL, 13.19 mmol), Copper(I) iodide (30.15 mg, 0.1583 mmol) and Pd(PPh3)4 (76.21 mg, 0.06595 mmol) in DMF (5 mL) and the resulting solution heated at 100° C. for 90 minutes in a sealed tube. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and 1MHCl/brine (1:1). The layers were separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organics extracts were washed with brine, dried over (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 100% EtOAc/Petroleum Ether) to give the title product as a yellow solid (352 mg, 68% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.44 (sept, 1H), 6.87-6.90 (m, 1H), 7.13-7.15 (m, 3H), 7.19-7.21 (m, 1H), 7.27 (t, 1H), 7.90 (d, J=8.6 Hz, 2H), 8.24 (d, J=8.6 Hz, 2H), 8.75 (s, 1H) and 9.77 (s, 1H) ppm; MS (ES+) 394.2.
Reaction SMILES: [NH2:1][C:2]1([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]3[CH:21]=[CH:22][N:23]=[C:11]23)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.CCOC(C)=O>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2([C:7](=[O:8])[NH:9][CH:10]3[CH2:16][CH2:15][C:14]4[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=4[N:12]4[CH:21]=[CH:22][N:23]=[C:11]34)[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:30])=[CH:27][CH:26]=1
Reactant: NC1(C(=O)NC2CCc3ccccc3-n3ccnc32)CCCC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)NC2CCc3ccccc3-n3ccnc32)CCCC1)c1ccc(Cl)cc1
Yield: 44.2 %

Procedure:
Combine 1-amino-N-(5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl)cyclopentanecarboxamide (158 mg, 509.02 μmoles), 4-chlorobenzoic acid (95.64 mg, 610.83 μmoles), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117.10 mg, 610.83 μmoles), and 1-hydroxybenzotriazole (82.54 mg, 610.83 μmoles;) in tetrahydrofuran (12 mL). Add diisopropylethylamine (106.53 μL, 610.83 μmoles) and stir the reaction at ambient temperature for approximately 16 hours. Dilute the reaction with EtOAc, wash with dilute sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (0-40% of a 5% solution of ammonia/methanol/dichloromethane (2N)/dichloromethane) to give the title compound (101.0 mg, 44%): MS (m/z): 449 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17]3[C:16]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[C:10](=[O:18])[C:9]=3[C:8](CS(C3C=CC(C)=CC=3)(=O)=O)=[N:7][C:6]=2[CH:30]=1.[NH2:31][CH2:32][CH2:33][N:34]([CH3:43])[CH2:35][CH2:36][CH2:37][N:38]([CH2:40][CH2:41][NH2:42])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17]3[C:16]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[C:10](=[O:18])[C:9]=3[C:8]([NH:42][CH2:41][CH2:40][N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH2:33][CH2:32][NH:31][C:8]3[C:9]4[C:10](=[O:18])[C:11]5[CH:12]=[N:13][CH:14]=[CH:15][C:16]=5[C:17]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][C:6]=4[N:7]=3)[CH3:43])[CH3:39])=[N:7][C:6]=2[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc3cc(Cl)ccc3c3c2C(=O)c2cnccc2-3)cc1
Reactant: CN(CCN)CCCN(C)CCN
Product: CN(CCCN(C)CCNc1nc2cc(Cl)ccc2c2c1C(=O)c1cnccc1-2)CCNc1nc2cc(Cl)ccc2c2c1C(=O)c1cnccc1-2

Procedure:
In a similar manner to Example 4, this compound was obtained starting from 3-chloro-6-(toluene-4-sulfonylmethyl)-5,9-diaza-benzo[c]fluoren-7-one (the compound of Reference Example 7c-2) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=2)=[CH:8][CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:31]([CH:33]([CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1)[C:34](OC)=O)=[O:32].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:46][O:45][C:42]1[N:41]=[CH:40][C:39]([CH2:38][C:33]2[C:31](=[O:32])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:34]=2)=[CH:44][N:43]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cccc(C(F)(F)F)n4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 6.14 %

Procedure:
To the solution of 4-((6-(trifluoromethyl)pyridin-2-yl)oxy)phenethyl carbamimidate, Trifluoroacetate (200 mg, 0.456 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (205 mg, 0.913 mmol) in NMP (3 mL) was added K2CO3 (252 mg, 1.825 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (14 mg, 6.14% yield). LCMS: rt=3.11 min, [M+H+]=500
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([C:29]3[C:30]([O:36][CH3:37])=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=3[O:27][CH3:26])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: COc1cc(OC)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1cc(OC)c(-c2nc(Nc3ccc(OC)c(Cl)c3)nc(NC3CCCCCC3)n2)c(OC)c1
Temperature: 80 °C

Procedure:
A mixture of compound 133 (0.5 grams), 1,3,5-trimethoxybenzene (0.2 grams) and AlCl3 (0.2 grams) in dichloroethane (10 mL) was stirred under nitrogen atmosphere. It was then heated at 80° C. for 3 hours. The reaction mixture was poured into ice-cold water (50 mL), extracted with chloroform and the organic layer was washed with water followed by concentration. The residue thus obtained was purified by column chromatography using petroleum ether-ethyl acetate to afford the N-(3-Chloro-4-methoxy-phenyl)-N′-cycloheptyl-6-(2,4,6-trimethoxy-phenyl)-[1,3,5]triazine-2,4-diamine.
Reaction SMILES: [C:1]([C:5]1[CH:49]=[CH:48][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][C:30](=[O:47])[C@H:31]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH:32]C(OC(C)(C)C)=O)[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>C(Cl)Cl>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][C:30](=[O:47])[C@H:31]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH2:32])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:48][CH:49]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2ccc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)c2ccc(NC(=O)[C@@H](N)Cc3ccccc3)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 1.5 h
Yield: 124.8 %

Procedure:
To a solution of 2-(4-tert-butylbenzoylamino)-4-[[N-(tert-butyloxycarbonyl)-L-phenylalanyl]amino]-N-(4-methoxyphenyl)benzamide (112 mg, 0.17 mmol) in methylene chloride (5 mL) was added trifluoroacetic acid (0.065 mL, 0.84 mmol). After 1.5 h, an additional portion of trifluoroacetic acid (0.50 mL, 6.5 mmol) was added and the resulting mixture stirred for 1 h. The mixture was concentrated in vacuo to give 144 mg (100%) of the title compound as a tan solid.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl[Si](C)(C)C.[CH:12]([Mg]Br)([CH3:14])[CH3:13]>C1COCC1>[CH:12]([CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([CH3:14])[CH3:13]
Reactant: O=C1C=CCC1
Reactant: CC(C)[Mg]Br
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)C1CCC(=O)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclopent-2-enone (1.5 mL, 18.27 mmol), CuBr—SMe2 (188 mg, 0.91 mmol), chlorotrimethylsilane (4.59 mL, 36.54 mmol) amd HMPA (6.55 g, 36.54 mmol) in THF (30 mL) was added isopropylmagnesium bromide (36.54 mL, 1 M in THF) at −70° C. After stirring for 1 h at −70° C., the reaction mixture was quenched with HCl (10%). The mixture was extracted with Et2O. The organic layer was washed with aqueous NaHCO3 and brine. After dried over Na2SO4, the organic layer was concentrated to give 3-isopropylcyclopentanone (4 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([I:14])[CH:5]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([I:14])[C:7]([NH2:13])=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(I)c(N)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(N)c(I)c1
Temperature: 70 °C

Procedure:
To a solution of 4-amino-3-iodo-5-nitro-benzoic acid methyl ester in ethyl acetate (50 mL) was added SnCl2 dihydrate. The mixture was heated to 70° C. for two hours, then cooled to room temperature and partitioned between ethyl acetate and satruated aqueous sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to provide 1.68 g (quantitative) of 3,4-diamino-5-iodo-benzoic acid methyl ester.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][CH2:18][CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N1CCC[C@H]1C(O)=O>>[SH:4][CH2:5][CH:6]([CH2:17][CH2:18][CH:19]([OH:23])[CH:20]([CH3:21])[CH3:22])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(CCC(O)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(C)C(O)CCC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[2-(acetylthiomethyl)-5-hydroxy-6-methylheptanoyl]-L-proline for the 1-3-acetylthio-2-(methylthiomethyl)propanoyl]-L-proline in the procedure of Example 17, 1-[2-mercaptomethyl-5-hydroxy-6-methylheptanoyl]-L-proline is obtained.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].O.Cl>CCO.ClCCl>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8]
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: OCc1cccc(O)c1
Reaction time: 0.12 h

Procedure:
NaBH4 (775 mg, 20.5 mmol) is gradually added to a solution of 3-hydroxybenzaldehyde (5 g, 40.9 mmol) in EtOH (25 mL) while cooling the reaction mixture with cold water. This mixture is stirred for 5-10 min at the same temperature. And then dichloromethane (DCM) (100 mL) is added followed by a 2M HCl aqueous solution (until pH ˜3). The organic phase is separated and the final product is extracted 4 times from the aqueous phase with a EtOH/DCM mixture in the proportion of 1:3. The collected organic phases are dried on Na2SO4. After evaporation of the solvents under reduced pressure, a viscous colorless oil is obtained (4.9 g, 97%), which gradually crystallizes.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.[CH3:21][CH:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].[Na].Cl>CO.[Cl-].[Na+].O.CCOCC>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][C:6](=[O:18])[CH2:5][CH2:4][C:22]2([CH3:21])[C:26](=[O:27])[CH2:25][CH2:24][C:23]2=[O:28])[CH:15]=[CH:14][CH:13]=1
Reactant: CC1C(=O)CCC1=O
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1
Temperature: 25 °C

Procedure:
Add the crude methiodide of 1-diethylamino-6-m-methoxyphenylhexan-3-one (2.5 g) in methanol (10 cc) ice-cold to a solution obtained by adding 2-methylcyclopentane-1,3-dione (0.5 g) to an ice-cold solution of sodium (0.21 g) in methanol (10 cc). Allow the reaction mixture to warm to room temperature and leave for 16 hours, after which add N hydrochloric acid (10 cc) and saturated brine (100 cc), ether-extracting the solution. Evaporate the washed and dried extracts to obtain crude 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione as a gum; dissolve in benzene (25 cc) containing toluene-p-sulfonic acid (0.4 g) and reflux the mixture for one hour. Cool, add ether (25 cc), and wash, dry, and evaporate the solution. Take up the resulting gum in benzene (5 cc) and adsorb on a column of Fuller's earth (100 g). Elute with a mixture of benzene and light petroleum to obtain a series of fractions, one of which crystallizes (0.04 g). Boil this fraction with methanol and decant the solution from insoluble oil which forms. Reduce the solution in bulk by evaporation, depositing crystals on cooling; recrystallize from methanol to obtain 13β-methyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one, m.p. 111°-113°C; ultraviolet absorption peak at 312 mμ (ε34,800).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3.[O:19]1[CH2:21][CH:20]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:21][CH:20]([OH:19])[CH2:22][NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3
Reactant: c1ccc(NCC2CO2)cc1
Reactant: COc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1cc(Br)ccc1n2CC(O)CNc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
NaH (0.0023 g of 60% suspension (in oil), 0.093 mmol) was added to a solution of 3-bromo-6-methoxy-9H-carbazole (0.014 g, 0.052 mmol) in anhydrous THF (0.1 mL) at 0° C. and stirred for 30 min. A solution of N-(oxiran-2-ylmethyl)aniline (0.0093 g, 0.062 mmol) in anhydrous THF (0.1 mL) was added dropwise to the reaction mixture. The reaction was warmed to room temperature and stirred for 48 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organics were concentrated and purified by chromatography (SiO2, 0-30% EtOAc/Hexane) to afford the title compound (0.007 g, 25%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>[N+](C)([O-])=O>[C:5]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][Cl:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCc2ccccc2CC1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)N1CCc2ccc(C(=O)CCCCl)cc2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Aluminum chloride (2.9 g, 21.7 mmol) was added little by little to a mixture of 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2 g, 10.5 mmol) and 4-chlorobutyryl chloride (1.56 g, 11 mmol) in nitromethane (5 ml) at room temperature and stirred for 2 hours at room temperature. The reaction solution was poured into ice water which was then extracted with ethyl acetate, washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, whereby 1-(3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-4-chloro-1-butanone (2.9 g) was obtained.