Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][C:6]=1[CH3:14].Cl[C:16](OC1C=CC=CC=1)=[O:17].C(N(CC)CC)C.[F:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[C:40]([S:42][CH3:43])[CH:39]=[C:38]([NH2:44])[N:37]=1>C(#N)C>[F:32][CH2:33][CH2:34][NH:35][C:36]1[N:37]=[C:38]([NH:44][C:16]([NH:13][S:10]([C:8]2[S:9][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:14])[CH:7]=2)(=[O:12])=[O:11])=[O:17])[CH:39]=[C:40]([S:42][CH3:43])[CH:41]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COCCc1sc(S(N)(=O)=O)cc1C
Reactant: CSc1cc(N)nc(NCCF)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCc1sc(S(=O)(=O)NC(=O)Nc2cc(SC)cc(NCCF)n2)cc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
5-(2-Methoxy-ethyl)-4-methyl-thiophene-2-sulfonic acid amide (0.063 g, 0.373 mmol) was dissolved in 2.2 mL of abs. acetonitrile and treated successively with phenyl chloroformate (0.058 g, 1.0 eq.) and triethylamine (0.129 mL, 2.5 eq.), and the mixture kept at ambient temperature for 1 h. The below prepared N-(2-fluoro-ethyl)-4-methylsulfanyl-pyridine-2,6-diamine (0.094 g, 1.0 eq.), dissolved in a tiny amount of acetonitrile, was then added, and the mixture heated to 60° C. for 18 h. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=4/6) and crystallization from AcOEt, yielded eventually 0.041 g of the title compound as off-white crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)[C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:47].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:72](NCC4C=CC=CN=4)=[O:73])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[NH2:102][CH2:103][C:104]1[CH:105]=[N:106][CH:107]=[CH:108][CH:109]=1>>[ClH:47].[OH:46][C:43]1[CH:44]=[CH:45][C:40]([CH:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:72]([NH:102][CH2:103][C:104]4[CH:105]=[N:106][CH:107]=[CH:108][CH:109]=4)=[O:73])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[CH:41][CH:42]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCc1cccnc1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)NCc6cccnc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 106) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethylpyridine with 3-aminomethylpyridine. MS (ES+) m/e 762.53 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[CH:10][C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])[CH2:6]2.[CH3:25][I:26]>>[I-:26].[OH:12][C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[C:5]1[CH2:4][CH:3]2[N+:2]([CH3:25])([CH3:1])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1
Reactant: CN1C2CCC1CC(=CC(O)(c1ccccc1)c1ccccc1)C2
Reactant: CI
Product: C[N+]1(C)C2CCC1CC(=CC(O)(c1ccccc1)c1ccccc1)C2
Product: [I-]

Procedure:
The title compound was prepared from 2-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-1,1-diphenyl-ethanol and methyliodide by following the experimental procedures in Example 4 (67% yield): LCMS (ES) m/z 334 (M+H)+; 1H-NMR(CDCl3) δ 1.50 (m, 1H), 1.98 (m, 1H), 2.11 (m, 1H), 2.35 (m, 2H), 2.87 (m, 1H), 2.96 (m, 1H), 3.23 (m, 1H), 3.27 (s, 3H), 3.56 (s, 3H), 4.00 (m, 1H), 4.28 (m, 1H), 6.49 (s, 1H), 7.35 (m, 8H), 7.49 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[N:4]=[C:5]([S:34][CH3:35])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:19]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([OH:15])[C:8]=1[F:16].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52]Cl>O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:36])[N:4]=[C:5]([S:34][CH3:35])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[C:20]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH:19]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([O:15][CH2:52][CH2:51][N:50]([CH3:54])[CH3:49])[C:8]=1[F:16]
Reactant: CN(C)CCCl
Reactant: CCc1cc(O)c(F)c(C(=Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(OCCN(C)C)c(F)c(C(=Nc2ccc(Br)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a mixture of {2-[4-bromo-3-(t-butoxycarbonylaminomethyl)phenylimino]-2-(5-ethyl-2-fluoro-3-hydroxyphenyl)-1-methylsulfanylethylidene}carbamic acid methyl ester (542 mg) and DMF (21.6 mL) there were added potassium carbonate (257 mg) and 2-dimethylaminoethyl chloride hydrochloride (268 mg) at 0° C. in that order, under a nitrogen atmosphere. The mixture was stirred for 4 hours at 0° C., and then potassium carbonate (257 mg) and 2-dimethylaminoethyl chloride hydrochloride (268 mg) were again added in that order, stirring was continued for 4 hours at 0° C., and potassium carbonate (257 mg) and 2-dimethylaminoethyl chloride hydrochloride (268 mg) were added. The mixture was stirred overnight at room temperature, and then ethyl acetate (200 mL) and water (100 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed twice with water (100 mL) and once with saturated aqueous sodium chloride (100 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate system) to obtain the target compound (242 mg) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[CH:3]1
Reactant: Cn1cc(CCNC(=O)OC(C)(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(CCN)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of tert-butyl (2-(1-methyl-1H-indol-3-yl)ethyl)carbamate (4 g, 14.6 mmol) in DCM (30 mL) was added TFA (15 mL) at ˜0° C. to 5° C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude title compound (2.5 g, crude) as yellow oil. MS (ESI) m/z 175.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]3)=[CH:7][C:6]=2[CH:5]=[C:4]([O:22][CH3:23])[CH:3]=1.[OH-].[K+]>C(O)CO.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:7][C:6]=2[CH:5]=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: CCOC(=O)N1CCC(c2cc3cc(OC)cc(Br)c3o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: Cc1ccccc1
Product: COc1cc(Br)c2oc(C3CCNCC3)cc2c1
Reaction time: 18 h

Procedure:
7.6 g of 4-(7-bromo-5-methoxy-benzofuran-2-yl)-1-ethoxycarbonyl-piperidine are dissolved in 80 ml of ethylene glycol. After the addition of 19.4 g of 86% potassium hydroxide, the resulting cloudy solution is heated at 160° with vigorous stirring for 18 hours. The reaction mixture is cooled to 100°, diluted with 80 ml of toluene, and cooled further to 20°. The reaction solution is extracted twice with 1000 ml of water each time and then four times with 200 ml of a 10% solution of methanesulfonic acid in water each time. The resulting solution in methanesulfonic acid is adjusted to pH 12 by the addition of 30% sodium hydroxide solution and extracted by shaking with 1000 ml of chloroform. The chloroform solution is dried over sodium sulfate, filtered and concentrated by evaporation. Crystallisation from ethyl acetate yields 4-(7-bromo-5-methoxybenzofuran-2-yl)-piperidine having a melting point of 149°-152°. There is obtained from the base by treatment with methanolic hydrochloric acid and recrystallisation from methanol/ether 4-(7-bromo-5-methoxy-benzofuran-2-yl)-piperidine-hydrochloride having a melting point of 242°-243°.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=C)[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I([O-])(=O)(=O)=[O:24].[Na+]>O.CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:24])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=Cc1cccc(C2(C)CCN(CCCCCC)CC2C)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCN1CCC(C)(c2cccc(C=O)c2)C(C)C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
1-Hexyl-3,4-dimethyl-4-(3-vinylphenyl)piperidine (Example 26, 200 mg, 0.67 mmol) was dissolved in a mixture of water (2 μL) and acetone (18 mL). Osmium tetroxide (200 μL, 2.5% w/w in tert-butanol) was added, followed by sodium periodate (572 mg, 2.68 mmol) which was added portionwise. The reaction mixture was stirred at room temperature for 26 hours, then it was filtered to remove precipitate and the solvent was removed by evaporation in vacuo. The residue was partitioned between dichloromethane (25 mL) and saturated sodium chloride solution (25 mL). The organic phase was separated, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (50 g) eluted with ethyl acetate:hexane:0.880 ammonia (74:25:1). The title compound was obtained as an oil (80 mg).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(OI1(OC(C)=O)(OC(C)=O)O[C:31](=O)[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=2)=O.C1C[O:45][CH2:44][CH2:43]1>ClCCl>[O:45]=[C:44]([CH2:31][C:30]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)/[CH:43]=[CH:2]/[CH:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCOC(=O)CCCCCCN1C(=O)OCC1CO
Reactant: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CCCCCCN1C(=O)OCC1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of alcohol 1-5 (273 mg) in dichloromethane (5 mL) was added Dess-Martin periodinane (451 mg) and the mixture was stirred at room temperature for 1 h and concentrated. The mixture was resuspended in ether, filtered and the filtrate was washed with saturated NaHCO3 and dried over Na2SO4. Filtration and concentration in vacuo afforded the crude aldehyde Ethyl 7-(4-formyl-2-oxo-1,3-oxazolidin-3-yl)heptanoate (1-7) which was used directly without further purification. To a suspension of NaH (47 mg) in THF (6 mL) was added dimethyl 2-oxo-3-phenylpropylphosphonate (282 mg) at 0° C. (formed a white slurry) and the mixture was stirred for an additional 1 h. To the mixture was then added aldehyde 1-7 (145 mg) in THF (4 mL) via cannula and the resultant mixture stirred at room temperature for 2 h and quenched with saturated NH4Cl. The mixture was then extracted with ethyl acetate (3×) and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography using ethyl acetate/hexanes (1:1) as the eluent to give the desired product 1-6. 1H NMR (400 mg, acetone-d6): δ 7.36–7.26 (m, 5H), 6.86 (dd, 1H), 6.43 (d, 1H), 4.57 (m, 1H), 4.50 (t, 1H), 4.12–3.96 (m, 5H), 3.28 (m, 1H), 2.96 (m, 1H), 2.28 (t, 2H), 1.65–1.45 (m, 4H), 1.35–1.25, m, 4H), 1.22 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27].[CH2:31]([OH:33])[CH3:32]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)[C:10]([C:25](=[O:29])[C:26]([O:33][CH2:31][CH3:32])=[O:27])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cccc3ccn(Cc4ccccc4)c23)cc1Cl
Reactant: CCO
Reactant: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(F)c(Cl)c3)cccc12
Yield: 61 %

Procedure:
Ethyl [1-benzyl-7-(3-chloro-4-fluorophenyl)-1H-indol-3-yl](oxo)acetate was prepared from 1-benzyl-7-(3-chloro-4-fluorophenyl)-1H-indole (0.182 g, 0.542 mmol), oxalyl chloride (0.28 mL, 3.3 mmol), and ethanol (0.75 mL) following the procedure described in Step 3 of Example 1. Purification by HPLC using 20% ethyl acetate in hexane as the mobile phase yielded the title compound as a hard yellow gum (0.143 g, 61%). 1H N MR (300 MHz, D MSO-d6): δ 8.7 (s, 1H), 8.35 (d, 1H, J=7.5 Hz), 7.3-7.4 (m, 2H), 7.0-7.25 (m, 6H), 6.35 (d, 2H, J=7.5 Hz), 5.35 (d, 1H, J=15.8 Hz), 5.15 (d, 1H, J=15.8 Hz), 4.35 (q, 2H, J=7.5 Hz), and 1.35 ppm (t, 3H, J=7.5 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][C:14](F)=[CH:15][C:8]=2[Si:7]([CH3:18])([CH3:17])[CH2:6]1.C[Si]1(C)C2C=CC=C([F:30])C=2C(=O)NC1.C([Li])CCC.ClCCCBr>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]2[C:12]([F:30])=[CH:13][CH:14]=[CH:15][C:8]=2[Si:7]([CH3:18])([CH3:17])[CH2:6]1
Reactant: C[Si]1(C)CNC(=O)c2c(F)cccc21
Reactant: C[Si]1(C)CN(CCCCl)C(=O)c2ccc(F)cc21
Agent: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si]1(C)CN(CCCCl)C(=O)c2c(F)cccc21

Procedure:
3-(3-Chloropropyl)-1,1-dimethyl-5-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline is obtained in a manner similar to that described in Example 11 for the preparation of 3-(3-chloropropyl)-1,1-dimethyl-7-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, but using 3.15 g of 1,1-dimethyl-5-fluoro-4-oxo-1,2,3,4-tetrahydro-3,1-benzazasiline, 11.3 cm3 of n-butyllithium, 5.7 g of 1-chloro-3-bromopropane and 65 cm3 of tetrahydrofuran. After purification by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99.5-0.5 by volume) as eluent, 1.15 g of 3-(3-chloropropyl)-1,1-dimethyl-5-fluoro-4-oxo 1,2,3,4-tetrahydro-3,1-benzazasiline are obtained.
Reaction SMILES: C(OC([N:8]1[C:12]([CH2:13][C@H:14]([N:35]([CH3:45])[C:36](C(OC(C)(C)C)=O)=[O:37])[C:15]([NH:17][C@@H:18]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C@@H:19]([OH:27])[CH2:20][C@@H:21]([CH:24]([CH3:26])[CH3:25])[CH:22]=[CH2:23])=[O:16])=[CH:11][N:10]=[CH:9]1)=O)(C)(C)C.CCOCC>Cl.O1CCOCC1>[CH3:45][N:35]([C@@H:14]([CH2:13][C:12]1[N:8]=[CH:9][NH:10][CH:11]=1)[C:15]([NH:17][C@@H:18]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C@@H:19]([OH:27])[CH2:20][C@@H:21]([CH:24]([CH3:25])[CH3:26])[CH:22]=[CH2:23])=[O:16])[CH:36]=[O:37]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cncn1C(=O)OC(C)(C)C)N(C)C(=O)C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)N(C)C=O)C(C)C
Reaction time: 5 h
Yield: 59.2 %

Procedure:
2.1 g of (S)-3-(t-butoxycarbonyl)-α-[1-(t-butoxycarbonyl)-N-methylformamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide were dissolved in 30 ml of 3N hydrogen chloride in dioxan and the mixture was left to stand at room temperature for 5 hours. 500 ml of ether were added and the precipitate formed was filtered off. The precipitate was washed with ether and dissolved in water. Solid sodium bicarbonate was added to the aqueous solution and the mixture was extracted several times with ethyl acetate, to obtain there was obtained 0.85 g of (S)-α-(N-methylformamido)-N-[(1S,2S,4S)-1-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl)imidazole-4-propion-amide which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C.O>[Cl:30][C:29]1[C:21]2[N:20]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:23](=[O:24])[C:22]=2[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1c(Cl)cccc1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.8 %

Procedure:
To a solution of 0.80 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride in 20 ml of acetonitrile, 0.44 g of 2-amino-3-chlorobenzoic acid was added. The mixture was stirred at room temperature for 10 minutes and then, 0.36 ml of triethylamine was added thereto. The mixture was stirred at room temperature for 20 minutes and then, 0.72 ml of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 0.22 ml of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 20 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 1.17 g of 8-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [C:1](=[O:53])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:42])[C@@H:12]([NH:20][C:21](=[O:41])[C@@H:22]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[C:37](=[O:38])[CH:36]=[CH:35][C:34]2=[O:39])[CH:23]([CH3:25])[CH3:24])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1.[N:54]1([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(OCC)C>CS(C)=O>[O:39]=[C:34]1[CH:35]=[CH:36][C:37](=[O:38])[N:33]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([NH:26][C@H:22]([C:21]([NH:20][C@H:12]([C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([N:57]2[CH2:56][CH2:55][N:54]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:59][CH2:58]2)=[O:53])=[CH:9][CH:8]=1)=[O:42])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:18])[NH2:19])=[O:41])[CH:23]([CH3:24])[CH3:25])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
Step 1 4-((S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl 4-nitrophenyl carbonate 58 (30 mg, 0.041 mmol) was reacted with tert-butyl piperazine-1-carboxylate (5.3 mg, 0.0287 mmol) in anhydrous DMSO under argon atmosphere at room temperature (FIG. 7d). The reaction mixture was stirred for 1 h, until disappearance of the starting material (HPLC-MS analysis). Diethyl ether (80 ml) was then added to the reaction mixture and the precipitate thus obtained was collected by filtration to give N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[({[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}oxy)methyl]phenyl}-N5-carbamoyl-L-omithinamide 59 as a yellow solid, 22.0 mg) was isolated and used without further purification in the next step. MS (ESI): 785 [M+H]+. Retention time=4.87 min (method 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].[CH3:10][C:11](OC(C)=O)=[O:12]>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:11](=[O:12])[CH3:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Product: CCc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethylaniline (2 g, 0.016 mol) was added slowly in portion into neat Ac2O (8 ml) at 0° C. After removed ice bath and the reaction was stirred at room temperature for 2 hour. The solvent was removed in vacuo and extracted with EtOAc, washed with water and brine, dried over Na2SO4. Concentrated to get crude N-(3-ethylphenyl)acetamide as light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:17]2[CH2:19][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Reaction time: 120 h
Yield: 71 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (1.87 g), [(1-ethoxycyclopropyl)oxy]trimethylsilane (8.05 mL), and acetic acid (5.72 mL) were dissolved in methanol (60 mL). To the resultant solution, sodium cyanoborohydride (1.89 g) was added at room temperature, followed by stirring for 5 days. Diethyl ether was added to the residue obtained by removal through evaporation of the reaction solvent under reduced pressure, and insoluble matter was filtered off. The filtrate was partitioned by addition of aqueous 1N sodium hydroxide thereto. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid (1.62 g, 71%).
Reaction SMILES: C1(C=[N:8][CH:9]2[C:17]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:26])[CH2:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)C=CC=CC=1.O.NN>C(O)C>[NH2:8][CH:9]1[C:17]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])[CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=C1Nc2ccccc2C12Cc1ccccc1C2N=Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC1c2ccccc2CC12C(=O)Nc1ccccc12
Temperature: 25 °C

Procedure:
To a slurry consisting of 1,3-dihydro-1-[(phenylmethylene)amino]spiro[2H-indene-2,3'-[3H]indole]-2'(1'H)one (13.8 g), and absolute ethanol (300 ml) was added hydrazine hydrate (13.9 ml). The resulting mixture was heated at reflux for 3 hours, cooled to room temperature and the resulting precipitate removed by filtration. The mother liquor was concentrated and the resulting oil solidified upon addition of ethyl acetate-hexane. The resulting solid was recovered by filtration. Additional product was obtained from the mother liquor as above. Recrystallization from ethyl acetate afforded 1-amino-1,3-dihydrospiro[2H-indene-2,3'-[3H]indol]-2'(1'H)one, m.p. 195°-197° C.