Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].Cl.[O:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C.[BH4-].[K+]>O>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)[CH2:2][N:26]1[CH2:27][CH2:28][CH:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc(C(O)CN3CCC(Oc4ccccc4)CC3)ccc2N1
Reaction time: 0.25 h

Procedure:
A mixture of 4.19 g (20 mmoles) 5-chloroacetyl-3H-indol-2-one 4 g dry sodium carbonate, 4.27 g (20 mmoles) 4-phenoxypiperidine hydrochloride and 100 ml ethanol is heated under reflux fo 1 h 15 min under an argon atmosphere. The mixture is left to cool, 10 ml water, then 8 g potassium borohydride are added and stirring is continued for 2 h 30 min at ambient temperature. A further 200 ml water are added, the mixture is stirred for 30 min and filtered, and the solid is washed with water and dried. 4.67 g of oohre orystals are obtained, which are purified by chromatography on a silica column, eluting with a 95/5 mixture of dichloromethane/ methanol.
Reaction SMILES: CN.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[S:16][C:17]([C:21]([O:23]CC)=O)=[C:18]([CH3:20])[N:19]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].COC1C=C(C=C(OC)C=1OC)[C:31]([NH2:33])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.ClC(C(C)=O)C(OCC)=O>C(O)CCC.C(O)C>[CH3:20][C:18]1[N:19]=[C:15]([C:7]2[CH:6]=[C:5]([O:4][CH3:3])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)[S:16][C:17]=1[C:21]([NH:33][CH3:31])=[O:23]
Reactant: CCOC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Reactant: COc1cc(C(N)=O)cc(OC)c1OC
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: CN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Solvent: CCCCO
Product: CNC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Reaction time: 240 h
Yield: 60 %

Procedure:
Into a mixture of 80 ml of 40% solution of methylamine and 420 ml of ethanol, 16.9 g of ethyl 2-(3,4,5-trimethoxyphenyl)-4-methylthiazole-5-carboxylate which had been prepared by heating a mixture of 3,4,5-trimethoxybenzamide, phosphorus pentasulfide, ethyl α-chloroacetoacetate and n-butylalcohol under a reflux condenser for 5 hours was dissolved and the solution was left for 10 days at room temperature. Then the solution was condensed to solid under a reduced pressure. The thus obtained residue was recrystallized from an aqueous ethanolic solution to obtain the object as colourless minute aciculate melting at 177.5° to 179.5° C. in an amount of 10.5 g corresponding to the yield of 60%.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([NH:33][S:34]([N:37]([CH2:39][CH:40](OC)[O:41]C)[CH3:38])(=[O:36])=[O:35])=[O:32])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([NH:33][S:34]([N:37]([CH3:38])[CH2:39][CH:40]=[O:41])(=[O:35])=[O:36])=[O:32])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([O:26][CH2:27][CH2:28][NH:29][CH3:30])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC(OC)OC)cc3n2C1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)CC=O)cc3n2C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A solution of (7S)-14-cyclohexyl-N-{[(2,2-dimethoxyethyl)(methyl)amino]sulfonyl}-7-[2-(methylamino)ethoxy]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide (0.06 M) in DCM was treated with an excess of TFA and H2O (>50 eq). The mixture was stirred at 40° C. for 30 min. All the volatiles were concentrated in vacuo to give the title compound, which was taken on without further purification. (ES+) m/z 583 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:5]=1)([OH:3])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:35][C:36](=[NH:38])[CH3:37].ClCCCl.C(O)C>CN(C=O)C>[CH3:37][C:36]1[N:38]=[C:1]([C:4]2[S:8][C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:6][CH:5]=2)[O:3][N:35]=1
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1noc(-c2cnc(N3CCN(C(=O)OC(C)(C)C)CC3)s2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
939 mg (3.0 mmol) of tert-butyl 4-(5-carboxythiazol-2-yl)piperazine-1-carboxylate [Precursor BBB61] were dissolved in DMF (15 ml) together with 534 mg (3.3 mmol) of CDI and the solution was stirred at RT 4 h. Subsequently, 243 mg (3.3 mmol) of N-hydroxyacetamidine were added and the mixture was stirred at 120° C. a further 4 h. The reaction solution was then poured onto water and the resulting precipitate was filtered off and washed with water. By means of CC (DCE/ethanol mixture) of the residue, 220 mg (0.63 mmol, 21%) of tert-butyl 4-[5-(3-methyl-[1,2,4]-oxadiazol-5-yl)-thiazol-2-yl]piperazine-1-carboxylate were obtained.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[CH3:13][OH:14]>>[CH3:13][O:14][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CO
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
0.46 gm (20 mMol) sodium were dissolved in 15 mL anhydrous methanol. To this solution were added 2.3 gm 6-chloro-3-nitro-2-picoline in portions. The resulting mixture was stirred for 18 hours at room temperature and then 1 hour at reflux. The reaction mixture was poured into 100 mL of ice water with vigorous stirring. The suspension was filtered and the solid dried at 30° C. under reduced pressure for 18 hours to provide 2.04 gm (91%) of the desired compound as a tan solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH3:50])[CH3:39])=[O:49])[CH2:48][CH2:47]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC(F)(F)F)c1
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CN(C)C(=O)CN1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OCC(F)(F)F)=N[C@@H](c3ccc(Cl)cc3)[C@H]2c2ccc(Cl)cc2)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride was prepared from (4S,5R)-2-[4-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12l) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 718.5 [(M+)+]
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][CH:20]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:21]([OH:38])[CH:22]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:34]([O:33][C:31]([NH:30][CH:22]([CH:21]([OH:38])[CH:20]([NH:19][C:6](=[O:8])[C@H:2]([CH:3]([CH3:4])[CH3:5])[NH:1][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 39 mg (0.16 mmol) of Cbz-Val-OH, 52 mg (0.14 mmol) of the resultant compound of Example 11, and 23 mg (0.17 mmol) of 1-hydroxybenzotriazole in 2 ml of dimethylformamide was treated with 0.019 ml (0.17 mmol) of 4-methylmorpholine, cooled to 0° C., and treated with 33 mg (0.17 mmol) of N-ethyl-N'-(dimethylaminopropyl)-carbodiimide hydrochloride. After being stirred at ambient temperature overnight, the solution was diluted with ethyl acetate, washed sequentially with 10% citric acid, water, and aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. Separation of the desired compounds by flash chromatography using methanol in chloroform gave 80 mg (95%) of the desired compound (Rf 0.40, 10% methanol in chloroform) as a white solid, m.p. 187°-187.5° C. Mass spectrum (M+H)+ =604.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16]O)=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:20]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][Br:20])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CO
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(C)c1CBr
Yield: 247.5 %

Procedure:
Cool a solution of (4-Benzyloxy-2,6-dimethyl-phenyl)-methanol (5.70 g, 24 mmol) in THF (100 mL) to 0° C. Treat the solution with Phosphorous tribromide (0.9 mL, 9.4 mmol) and stir the reaction for 2 hr at 0° C. Quench the reaction with water and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 7.1 g (99%) of product. 1H NMR (d6-CDCl3) δ 7.31-7.43 (m, 5H), 6.65 (s, 2H), 5.01 (s, 2H), 4.56 (s, 2H), 2.38 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[C:4](=[CH2:23])[CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[CH:24]1C=CC=CC=1.IC>>[CH3:24][O:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[C:4](=[CH2:23])[CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C(O)=C12
Reactant: c1ccccc1
Solvent: CI
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C(OC)=C12
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 4-hydroxy-6-methylenandrost-4-ene-3,17-dione (0.315 g, 1 mmole) in benzene (10 ml) potassium tert-butoxide (0.224 g, 2 mmole) is added and the mixture heated to reflux for 30 minutes. After cooling, iodomethane (0.710 g, 5 mmole) is added and the mixture boiled for a further 2 hours. Then the organic solution is washed with water, dried and evaporated in vacuum. Flash column chromatography of the residue on silica gel using n-hexane/ethyl acetate 60:40 affords 0.247 g (75% yield) of the title compound, m.p. 196°-198° C.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:20]([O:19][C:17]([C@@H:2]([NH:1][S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 220 mg of 4-chlorobenzenesulfonyl chloride and 270 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 84 mg. MS (ES+): m/e=498.1 (M+H)+; 442.1.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(O)=CC=1.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([O:18][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=2)(=[O:45])=[O:44])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Agent: O=C1c2ccncc2C(=O)c2c(Cl)ccc(O)c21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 1:1 mixture of 9-fluoro-6-hydroxybenzo[g]isoquinoline-5,10-dione and 9-chloro-6-hydroxybenzo[g]isoquinoline-5,10-dione, of Preparative Example 9a, (0.060 g) is dissolved in dry pyridine (2 mL) and p-toluenesulfonyl chloride (0.095 g) is added. After stirring at room temperature for one hour, triethylamine (0.25 mL) is added and stirring is continued for one additional hour. The reaction mixture is concentrated almost to dryness and partitioned between 1N HCl (4 mL)-20% ammonium sulfate (6 mL) and ethyl acetate (10 mL). The aqueous phase is separated, extracted with ethyl acetate (3×5 mL) and discarded. The combined organic solutions are dried over anhydrous sodium sulphate and concentrated to dryness to give an approximately 1:1 mixture (0.095 g) of 9-fluoro-6-(p-toluenesulfonyloxy) benzo[g] isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy) benzo[g]isoquinoline-5,10-dione which is used without further purification for the next step.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([CH:48]1[C:55]2([NH2:57])[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:58][C:49]1([C:59]([O:61][CH3:62])=[O:60])[CH2:50]3)[CH2:54]2)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36]>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([C:14]([NH:33][CH2:34][C:35]([NH:37][C@H:38]([C:46]([CH:48]1[C:55]2([NH2:57])[CH2:56][CH:51]3[CH2:52][CH:53]([CH2:58][C:49]1([C:59]([O:61][CH3:62])=[O:60])[CH2:50]3)[CH2:54]2)=[O:47])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])=[O:16])[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CN)C2
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixed anhydride is prepared by reacting 2.0 g of Boc-D-methionine with 0.90 ml of N-methylmorpholine and 1.06 ml isobutylchloroformate in 15 ml of tetrahydrofuran at -20° C. A solution of 2.84 g of methyl glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride in 15 ml tetrahydrofuran is neutralized with 0.78 ml N-methyl morpholine and added to the mixed anhydride reaction above. The reaction mixture is stirred for 2 hours at room temperature and allowed to stand overnight. The reaction mixture is diluted with 200 ml of ethyl acetate. The ethyl acetate layer is collected and washed with water, followed by washes with 0.2 M potassium bisulfate, water, and 1 M potassium bicarbonate and dried over magnesium sulfate. The solution is filtered and the solvent removed under reduced pressure. Purification of the residue by low pressure chromatography on silica gel affords methyl Boc-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate which is represented by the following formula ##STR17##
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17].N1C=CC=CC=1.O>C(#N)C>[C:16]([CH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:7]=2)[NH:11][CH:10]=1)#[N:17]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)Nc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 0.5 h

Procedure:
Acetyl chloride (0.21 ml) was added dropwise to a stirred solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) and pyridine (0.24 ml) in dry acetonitrile (10 ml) at 0°-2° under nitrogen. When the addition was complete the solution was stirred at 0° for 30 minutes, poured into water (50 ml) and extracted with ethyl acetate (3×25 ml). The combined extracts were dried (MgSO4), filtered and evaporated under reduced pressure to a brown solid (0.5 g) which was crystallised from an ethanol-cyclohexane mixture to give the title compound (0.43 g) as off-white needles, m.p. 171.5°-175°.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[C:28]([F:29])=[CH:27][N:26]=[C:25](Cl)[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:31][O:32][CH2:33][CH2:34][S:35]([CH2:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42])(=[O:37])=[O:36]>C(O)CCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[C:28]([F:29])=[CH:27][N:26]=[C:25]([NH:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:39]([CH2:38][S:35]([CH2:34][CH2:33][O:32][CH3:31])(=[O:37])=[O:36])[CH:40]=2)[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Reactant: COCCS(=O)(=O)Cc1cccc(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1
Temperature: 140 °C
Reaction time: 60 h
Yield: 8.9 %

Procedure:
4N solution of hydrogen chloride in dioxane (0.11 mL; 0.45 mmol) was added to a stirred solution of 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine (150 mg; 0.45 mmol) and 3-{[(2-methoxyethyl)sulfonyl]methyl}aniline (155 mg; 0.68 mmol; UkrOrgSynthesis Ltd.) in 1-butanol (1.0 mL). The batch was stirred at 140° C. for 60 hours. After cooling the batch was diluted with ethyl acetate and sodium bicarbonate solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (19 mg; 0.04 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1.Br[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C([O-])(O)=O.[Na+]>CCO>[N:32]1[CH:33]=[CH:34][CH:35]=[N:36][C:31]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]2[CH2:17][CH:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:19](=[O:22])[NH:20][CH2:21][C:15]=2[CH:14]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCN)cc2CNC1=O
Reactant: Brc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2CNC1=O
Reaction time: 24 h
Yield: 70.2 %

Procedure:
A mixture of methyl (±)-8-(3-amino-1-propyloxy)-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate trifluoroacetate salt (0.75 g, 2 mmol), 2-bromopyrimidine (0.5 g, 3 mmol), NaHCO3 (1.4 g, 17 mmol), and EtOH (10 mL) was heated to reflux. After 24 hr, the mixture was filtered and the insoluble material was washed with MeOH. The filtrate and washings were combined and concentrated, and the residue was purified by chromatography on silica gel (1%-6% MeOH/CH2Cl2) to give the title compound (0.54 g, 82%) as a white foam: MS (ES) m/e 385.5 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:37][C:38](=O)[NH:39][C:40]1[N:41]([C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=2)[N:42]=[C:43]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:44]=1>O1CCOCC1>[C:45]([C:43]1[CH:44]=[C:40]([NH:39][C:38](=[O:37])[NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@@H:5]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH:14]=3)[CH2:4][CH2:3]2)[N:41]([C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=2)[N:42]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: COCC(=O)Nc1cc(O[C@H]2CC[C@H](N)c3ccccc32)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCC(=O)Nc1cc(O[C@H]2CC[C@H](NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc32)ccn1
Temperature: 80 °C

Procedure:
To a solution of Intermediate 10d (204 mg, 0.62 mmol) and DIPEA (0.127 mL, 0.80 mmol) in 1,4-dioxane (6 mL), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 315 mg, 0.78 mmol) was added. The mixture was heated at 80° C. under argon for 17 h, and then evaporated to dryness. The residue was purified by FCC, eluting with 0-100% ethyl acetate in cyclohexane, to give the slightly impure product (0.262 g). Further purification by HPLC (Method 6) gave the title compound as a white solid (102 mg, 28%). LCMS (Method 5): Rt 4.51 min, m/z 583 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.69-1.81 (1H, m), 1.90-2.24 (3H, m), 2.36 (3H, s), 3.36 (3H, s), 4.05 (2H, s), 4.86-4.94 (1H, m), 5.62-5.67 (1H, m), 6.32 (1H, s), 6.91 (1H, dd, J 2.5, 5.9), 7.03 (1H, d, J 8.4), 7.26-7.37 (8H, m), 7.60 (1H, br d, J 2.0), 8.01 (1H, s), 8.16 (1H, d, J 5.7), 9.90 (1H, s).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([CH3:3])[CH3:2].[I-].[I:16]([O-])(=O)(=O)=O.[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[I:16][C:11]1[C:12]([CH3:14])=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)cc1C(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(C)cc1C(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask, was added a solution of methyl 2-isopropyl-4-methylbenzoate (compound 196.1, 6.50 g, 33.8 mmol, 1.00 equiv) in acetic acid (60 mL). Iodide (9.50 g, 37.4 mmol, 1.10 equiv), sodium periodate (3.60 g, 16.8 mmol, 0.50 equiv), and sulfuric acid (0.500 g, 0.15 equiv) were added to the reaction mixture. The resulting solution was stirred overnight at 100° C. After cooling to room temperature, the reaction was quenched with Na2S2O3 (aq., sat.). The mixture extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with 3×100 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 6.00 g (56%) of methyl 5-iodo-2-isopropyl-4-methylbenzoate as a yellow oil.