Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=O.[Br-].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7](/[CH:8]=[CH:34]/[C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][N:26]=2)[CH:10]=1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 112.6 %

Procedure:
A solution of 5-methoxy-4-[3-(morpholin-4-yl) propyloxy]-2-nitrobenzaldehyde (0.26 g, 0.79 mmol) obtained in Step 1 in methanol (8.0 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.73 g, 1.5 mmol) and potassium carbonate (0.34 g, 2.8 mmol), followed by stirring at room temperature for 3.5 hours. The reaction mixture was added with water and the precipitated solid was triturated in methanol to obtain (E)-3-{2-[5-methoxy-4-[3-(morpholin-4-yl)propyloxy]-2-nitrophenyl]vinyl}-1H-indazole (0.39 g, 100%).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[C:15](=[O:16])[NH:14][C:13](=O)N2)=[C:5]([F:18])[CH:4]=1>CO>[Cl:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[C:15](=[O:16])[N:11]3[CH:6]=[CH:5][CH:4]=[CH:3][CH2:13][N:14]3[C:15]2=[O:16])=[C:5]([F:18])[CH:4]=1
Reactant: COc1cc(-n2[nH]c(=O)[nH]c2=O)c(F)cc1Cl
Agent: [Na]
Solvent: CO
Product: COc1cc(-n2c(=O)n3n(c2=O)CC=CC=C3)c(F)cc1Cl
Reaction time: 4 h
Yield: 25.9 %

Procedure:
To a solution of metallic sodium (0.46 g) in methanol (20 ml), 2-(4-chloro-2-fluoro-5-methoxyphenyl)urazol (2.6 g) was added, and the resultant mixture was concentrated under reduced pressure. The residue was dissolved in dimethylformamide (20 ml), 1,5-dibromopentane (2.3 g) was added thereto, and the resulting mixture was stirred at 100° to 120° C. for 4 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from methanol to give 0.42 g of 2-(4-chloro-2-fluoro-5-methoxyphenyl)-1H,5H-[1,2,4]triazolo[1,2-a]-[1.2]diazepine-1,3(2H)-dione (Compound No. 3). M.P., 121.5°-123° C. IRνmax (cm -1): 1750, 1680. NMR δ (ppm): 1.8 (6H, m), 3.9 (3H, s).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][CH:26]([CH3:29])[CH:27]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][CH:26]([CH3:29])[CH3:27])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CC(C)C=O
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 64.9 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 2-methyl-propionaldehyde (0.20 g, 2.77 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with a mixture of 25% ethyl acetate in hexanes and filtered to give the title compound as a solid (0.073 g, 65%). MS (APCI+) m/z 417 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:27])[CH2:4][CH:5]([S:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C(O)C>C(Cl)Cl>[OH:1][NH:2][C:3](=[O:27])[CH2:4][CH:5]([S:16]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:36])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)NO)cc1OC
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(S(=O)C(CCCCc2ccccc2)CC(=O)NO)cc1OC
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To a solution of (±)-N-hydroxy-3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanamide (1.26 g, 3.24 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. is added m-CPBA (0.56 g, 3.24 mmol) in one portion. The mixture is stirred for 10 minutes after which TLC analysis indicated complete reaction. Ethanol (2 mL) is added and the mixture is partitioned between water (100 mL) and EtOAc (100 mL). Aqueous layer is extracted with EtOAc (2×50 mL) and combined organic phases are washed successively with 5% aqueous Na2S2O3 (50 mL), water (50 mL), 5% aqueous NaHCO3 (50 mL), water (50 mL) and brine (50 mL) then dried over MgSO4 and concentrated. The resulting yellow oil is chromatographed on silica gel (CH2Cl2 →2% MeOH/CH2Cl2 →5% MeOH/CH2Cl2) to afford 0.5 g of (±)-N-hydroxy-3-(3,4-dimethoxyphenyl)sulfinyl-7-phenylheptanamide (38%) as a mixture (2:1) of diastereomers in the form of a white foam. TLC analysis [CH2Cl2 /MeOH, 19:1, Rf (sulfide)=0.20, Rf (sulfoxide)=0.10]. 1H NMR (300 MHz, d6 -DMSO) δ 1.35-1.72 (m, 6H), 1.88-2.20 (m, 2H), 2.49 (m, 2H), 3.05 (m, 1H), 3.78 (br s, 6H), 7.0-7.18 (m, 6H), 7.22 (m, 2H), 8.80 (m, 1H), 10.49 (m,1H) ppm. Mass spectrum (FAB) m/z 406 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[CH2:22][CH2:21]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccccc4)CC3)n[nH]c12
Yield: 8.9 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.057 g, 0.17 mmol) was reacted with phenylsulfonyl chloride (0.022 mL, 0.17 mmol) in the presence of triethylamine (0.1 mL, 0.71 mmol) and DMAP (0.0021 g, 0.017 mmol) in DMF (3 mL) to give 0.007 g of pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4]1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl.CCN(C(C)C)C(C)C>ClCCl>[C:23]([NH:1][CH2:2][C@H:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CN)C1
Reactant: O=C(O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)[C@H](CNC(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Into a 50 mL round bottom flask was added 15S (820 mg, 2.68 mmol) and dichloromethane (15 mL). Benzoic acid (15T) (426 mg, 1.3 eq) and EDC (669 mg, 1.3 eq) was added and the flask was cooled to 0° C. DIEA (1.04 g, 3 equiv.) was slowly added and the reaction was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was purified by column chromatography with 5% methanol in dichloromethane to give 15U as a solid (865 mg, 79%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH2:19]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[CH2:19]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:24][CH:23]=1)[CH3:20]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: CCOc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (for preparation see German Auslegeschrift no. 1 061 788 [published 23.07.1959]), and 0.483 g (3.52 mmol) 4-ethoxyaniline is heated for 30 min at 90° C. The cooled reaction mixture is distributed with thorough stirring between a dichloromethane/methanol mixture (18:1) and saturated aqueous sodium carbonate solution. The organic phase washed with water and brine is dried over anhydrous sodium sulfate and evaporated under vacuum. Title compound is obtained after recrystallization of the residue from acetate/methanol and acetonitrile; m.p. 223-224° C.; ESI-MS: (M+H)+=357.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[O:17][C@H:18]([CH3:22])[C:19](Cl)=[O:20].[OH-].[Na+]>O.C1(C)C=CC=CC=1>[C:8]([C:7]([NH:6][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14])[CH3:22])([CH3:13])[CH:10]([CH3:12])[CH3:11])#[N:9]
Reactant: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)Cl
Reactant: CC(C)C(C)(N)C#N
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Cl)cc1Cl)C(=O)NC(C)(C#N)C(C)C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A stirred mixture of sodium bicarbonate (1.446 kg; 17.2 mol) in water at -3° to 3° C. is treated with a toluene solution of 2-amino-2,3-dimethylbutyronitrile (1.51 kg, 13.46 mol) over a 15 minute period, then treated sequentially with a toluene solution of (R)-2-(2,4-dichlorophenoxy)propionyl chloride (3.346 kg, 13.2 mol) over a 1.5 hour period at ice bath temperatures, stirred for 0.5 hours, treated with 50% NaOH (0.396 kg), heated to 55° C. and stirred for 0.5 hours. The resultant mixture is separated. The organic phase is washed with 5% NaOH and distilled at temperatures up to 80° C. at 10 mm Hg to remove the toluene. The pot residue is crystallized in isopropanol/water to afford the title product as a white solid, 4.131 kg (94.8% yield), characterized by HPLC analysis. The product is 99.7% pure. The isomer ratio is: 94.8% RR, RS and 5.2% SS, SR.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1>>[ClH:13].[ClH:13].[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:44]([C:41]2[CH:42]=[CH:43][C:38]([N:29]3[N:28]=[C:27]([C:19]4[C:20]5[CH2:21][C:22]([CH3:26])([CH3:25])[O:23][C:24]=5[C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[C@@H:36]4[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]4)[C:30]3=[O:37])=[CH:39][CH:40]=2)=[O:45])[CH2:10][CH2:11]1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: CN(C)CCCN1CCNCC1
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CCCN(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A2 and 1-(3-dimethylaminopropyl)-piperazine as described for compound 8. M.p. 262° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[C:21](=O)([O-])O.[Na+].C(OCC)(=O)C>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH2:12][C:13]([O:15][CH3:21])=[O:14]
Reactant: O=C(O)Cc1c(F)cc([N+](=O)[O-])cc1F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)Cc1c(F)cc([N+](=O)[O-])cc1F
Yield: 97 %

Procedure:
A solution of 2-(2,6-difluoro-4-nitrophenyl)acetic acid (27.90 g, 128.5 mmol) and conc. sulfuric acid (1.0 mL) in MeOH (260 mL) was heated under reflux for 18 hr. The reaction mixture was neutralized with aqueous sodium hydrogencarbonate solution, and ethyl acetate and water were added thereto. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→100% ethyl acetate/hexane) to give methyl 2-(2,6-difluoro-4-nitrophenyl)acetate (28.71 g, 128.5 mmol, 97.0%) as a yellow solid.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OS(O)(=O)=O>C(Cl)Cl>[CH3:14][O:13][C:11](=[O:12])[CH:2]([NH:1][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:4]([CH3:9])([CH3:5])[CH3:3])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 62 %

Procedure:
H-D-Tyr-O-me hydrochloride 2.1 (25 g, 107.7 mmol) is dissolved in methylene chloride (150 mL) and aqueous sodium bicarbonate (22 g in 150 mL water), and then cooled to 0° C. To this resulting solution benzyl chloroformate (20 g, 118 mmol) is slowly added. After complete addition, the resulting solution is warmed to room temperature, and is then stirred for 2 h. The organic phase is separated, dried over Na2SO4, and concentrated under reduced pressure, to give the crude carbamate 2.2 (35 g). The crude CBZ-Tyr-OMe product is dissolved in methylene chloride (300 mL) containing concentrated H2SO4. Isobutene is bubbled though the solution for 6 h. The reaction is then cooled to 0° C., and neutralized with saturated NaHCO3 aqueous solution. The organic phase is separated, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to afford the tert-butyl ether 2.3 (25.7 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]4[CH:31]=[CH:30][S:29][C:23]=4[NH:24][C:25](=O)[CH2:26][N:27]=3)=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:33]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]4[CH:31]=[CH:30][S:29][C:23]=4[NH:24][C:25](=[S:33])[CH2:26][N:27]=3)=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1cc(CCc2ccc(C3=NCC(=O)Nc4sccc43)cc2)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(CCc2ccc(C3=NCC(=S)Nc4sccc43)cc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 0.6 g (1.4 mmol) of the compound prepared in (e) above in 30 ml of dry pyridine was added 0.37 g (0.82 mmol) of phosphorus pentasulfide, and the resultant mixture was heated to 90° C. and maintained at this temperature for 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture to 25° C., the solvent was evaporated and the resultant residue was diluted with methylene chloride. The organic phase was then washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated to yield a red foam.
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].Br[C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1.[Mg].[NH4+].[Cl-].Cl>CCOCC.O>[NH2:10][C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1cccc(Br)c1
Reactant: CCOC(=O)CC#N
Agent: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C=C(N)c1cccc(C)c1
Temperature: 0 °C
Yield: 65.3 %

Procedure:
To 202 ml of 2.9 M phenylmagnesium bromide in ether (0.585 mol) was added 100 ml of ether. Then, 66.1 g (0.585 mol) of ethyl cyanoacetate was added over a few minutes with stirring at -40° to -15°. A heavy, thick precipitate formed that made stirring difficult. The mixture was allowed to warm slowly to 20°. Then, the Grignard reagent prepared from 100 g (0.585 mol) of 3-bromotoluene and 14.4 g (0.593 mol) of magnesium turnings in 300 ml of ether was added. The mixture was stirred at reflux for 4 hours, cooled, and poured slowly with stirring into 1 l. of ice-water mixture in which 62.6 g (1.17 mol) of NH4Cl was dissolved. Then, an ice-cold solution of 1.17 mol of HCl in 300 ml of water was added with stirring. The two layers were shaken together and separated. The aqueous layer was extracted with two 200-ml portions of ether. The ether layers were combined, dried (CaSO4), and concentrated under aspirator vacuum to 112.0 g of oil that contained 78.4 g (65% yield) of product (gas chromatography assay with internal standard). The oil was distilled to give 83.2 g of 89% pure product (62% yield of ester), boiling point 120°-130° (0.08 torr). Redistillation of the product through a fractionating column gave 57.2 g (48%) of 97% pure product, boiling point 118° (0.05 torr). A small sample was redistilled to give 100% pure material, boiling point 118° (0.1 torr).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH2:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[CH2:2][CH3:3].[Cl:27][C:28]1[CH:36]=[C:35]([O:37][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:39]([CH3:41])[CH3:40])[CH:34]=[C:33]([Cl:48])[C:29]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:4][C:5](=[O:26])[C@@H:6]([NH:25][C:30](=[O:31])[C:29]1[C:28]([Cl:27])=[CH:36][C:35]([O:37][Si:38]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:43])[CH3:44])[CH:39]([CH3:40])[CH3:41])=[CH:34][C:33]=1[Cl:48])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: CC(C)[Si](Oc1cc(Cl)c(C(=O)O)c(Cl)c1)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc1Cl

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 8, starting from (S)-2-amino-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (3.95 g, 11 mmol), 2,6-dichloro-4-triisopropylsilanyloxy-benzoic acid (3.63 g, 10 mmol), HBTU (5.42 g, 14.3 mmol), and DIPEA (4.26 g, 5.75 mL, 33.0 mmol), and after ISCO column chromatography purification, resulted in an amorphous white solid (1.7 g, 24%). ES(+)-HRMS m/e calcd. for C35H47Cl2N3O6Si (M+H)+ 704.2684, obsd. 704.2683.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH3:9].[N:10]1[CH2:11][CH2:12][CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16](=[O:23])[C:15]=12.[Cl-].[NH4+]>BrCCCCOCC.CCOCC.ClCCCl>[OH:23][C:16]1([CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH3:9])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[N:14]2[CH2:13][CH2:12][CH2:11][N:10]=[C:15]12
Reactant: CCOCCCCBr
Reactant: O=C1C2=NCCCN2c2ccccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCOCC
Product: CCOCCCCC1(O)C2=NCCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ether (10 ml) and a few drops 4-bromo-1-ethoxybutane were added to magnesium turnings (1.46 g). After the reaction started, the remainder of the 4-bromo-1-ethoxybutane (total 10.86 g) in ether (50 ml) was added dropwise over 20 minutes. The mixture was stirred under argon at room temperature for 30 minutes, cooled to 0° C. over 30 minutes and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° C. for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml), and the mixture stirred for a further 20 minutes. The mixture was concentrated in vacuo and the aqueous residue extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound as the free base (2.99 g), m.p. 123°-124° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 189°-190° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[C:24]1([CH2:30][SH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOC(C)=O>[CH2:30]([S:31][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH2:9])[CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(SCc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 55.9 %

Procedure:
To a mixture of 4,5-dichloro-2-nitro-phenylamine (3.00 g, 14.5 mmol) and DMF (72 mL) was added K2CO3 (5.31 g, 29.0 mmol) and phenyl-methanethiol (3.94 g, 31.7 mmol). The mixture was heated to 70° C. for 18 h and then cooled to 23° C. The reaction mixture was dissolved in EtOAc (200 mL), washed with saturated sodium bicarbonate solution (100 mL), washed with brine (3×100 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-45% EtOAc/hexanes) to yield the titled compound (2.39 g, 56%). MS (ESI/CI): mass calcd. for C13H11ClN2O2S, 294.0; m/z found, 295.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 7.96 (s, 1H), 7.56 (s, 2H), 7.50 (d, J=7.2 Hz, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.31 (t, J=7.4 Hz, 1H), 7.05 (s, 1H), 4.27 (s, 2H).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CC(C)=O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:24])[C:9]([CH3:25])=[C:8]3[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3C)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(3-benzyl-1,2-dimethyl-1H-indol-5-yl)-phenol (0.162 g, 0.495 mmol) was reacted with K2CO3 (0.089 g, 0.643 mmol) and methyl bromoacetate (0.098 g, 0.643 mmol) in acetone (5 ml) to give the product (0.161 g, 0.403 mmol, 81%) as an off-white solid, mp 113-117° C. 1H NMR (DMSO-d6) δ 2.40 (s, 3H), 3.67 (s, 3H), 3.70 (s, 3H), 4.06 (s, 2H), 4.80 (s, 2H), 6.96 (d, J=8.9 Hz, 2H), 7.08-7.11 (m, 1H), 7.19-7.24 (m, 4H), 7.29 (dd, J=1.7, 8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.9 Hz, 2H), 7.56 (d, J=1.5 Hz, 1H); [ESI(+)], m/z 400 (M+H)+.