Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](=O)[C:9](=[O:15])[NH:10]2.C([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: COc1cccc2c1C(=O)C(=O)N2
Agent: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1CC(=O)N2
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 79.2 %

Procedure:
Hydrazine monohydrate (265 mL, 5.46 mol) is added to a flask containing 4-methoxyisatin (484.26 g, 2.73 mol), sodium acetate (22.31 g, 0.27 mol) and dimethylformamide (2.4 L). The temperature rose from 19.2° C. to 31.9° C. within 5 minutes, and when the exotherm had ceased the solution is further heated to 110° C. over 40 minutes. Vigorous off-gassing is observed, and the temperature rose above the set point slowly. After 30 minutes the temperature stabilized at 110° C. and the gas evolution tapered off. The solution is kept at 110° C. for 40.5 hours at which point the heating mantle is removed and the solution is allowed to cool. At 40° C., the solution is seeded with 100 mg of 4-methoxyindole, and the contents are cooled to 17° C. with an ice bath. The resulting mixture is poured into water (6.2 L) which had been pre-cooled to 6° C. The flask is rinsed with water (600 mL), and the thick slurry is cooled to 4° C. before being filtered through polypropylene. The filter cake is rinsed with water (3×1.5 L) and the solid is dried in a 50° C. vacuum oven to provide 353 g of 4-methoxyindolin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+]([O-])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>O>[Cl:16][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Product: Fc1ccc(C(F)(F)F)cc1Cl

Procedure:
Nine parts of the 4-fluoro-3-nitrobenzotrifluoride of Example I, and six parts of phosphorous pentachloride were sealed tightly under a nitrogen atmosphere in a tubular reactor. The sealed reactor was heated in an oil bath for about two hours at 170°-180° C. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was dried and distilled at atmospheric pressure to yield 13.6 parts of 3-chloro-4-fluorobenzotrifluoride. The structure was confirmed by gas chromatography--mass spectrum, and by F19 and C13NMR analyses.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]([CH3:42])[S:11]([CH:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=[C:20]2[CH2:35][C@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH3:41])C#N)(=[O:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K]>>[CH2:1]([O:8][CH2:9][N:10]([CH3:42])[S:11]([CH2:14][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=[C:20]2[CH2:35][C@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH3:41])(=[O:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC[C@@H]1Cc1cn(COCc2ccccc2)c2ccc(C(C#N)S(=O)(=O)N(C)COCc3ccccc3)cc12
Agent: [K]
Product: CN1CCC[C@@H]1Cc1cn(COCc2ccccc2)c2ccc(CS(=O)(=O)N(C)COCc3ccccc3)cc12
Temperature: 25 °C
Yield: 33 %

Procedure:
To a stirred solution of N-benzyloxymethyl-1-[(R)-1-benzyloxymethyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-1-cyano-N-methylmethanesulfonamide (from step (e), 2.0 g, 3.4 mmol) in IMS (14 ml) at ambient temperature was added 2N potassium hydrodroxide solution (7 ml, 14 mmol). The dark brown solution was then brought to reflux and maintained at this temperature for 15 hr. The oily reaction mixture was then cooled to ambient temperature and extracted with ethyl acetate (3×20 ml). The organic extracts were combined and evaporated in vacuo to yield a dark brown oil. This was purified by flash column chromatography (ethyl acetate:triethylamine 95:5 as eluant) to yield the subtitle compound (631 mg, 33%) as a brown oil.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:35])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:11]([CH2:19][C:20]2[N:21]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=2)=[C:10]1[CH3:34])C.Cl>O1CCCC1.O>[C:28]1([S:25]([N:21]2[CH:22]=[CH:23][CH:24]=[C:20]2[CH2:19][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[N:9]([CH2:8][C:7]([OH:35])=[O:6])[C:10]=2[CH3:34])(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2cccn2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2cccn2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Lithium hydroxide monohydrate (138 mg, 3.3 mmol) was added in one portion to a stirred solution of [3-(1-benzenesulfonyl-1H-pyrrol-2-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid ethyl ester (507 mg, 1.1 mmol) in tetrahydrofuran:water (2:1; 10 ml) and the resulting mixture stirred at room temperature for 3 h. The solution was adjusted to pH 1 with 1M hydrochloric acid and then concentrated in vacuo to leave a yellow solid. The solid was partitioned between ethyl acetate (30 ml) and water (30 ml) and then the organic layer separated. The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were then dried and concentrated in vacuo to leave an off-white solid. Purification by flash column chromatography on silica gel eluting with 10% methanol:dichloromethane gave the carboxylic acid (130 mg, 28%) as a white solid, δH (250 MHz, d6-DMSO) 7.84 (2H, d J 7.1 Hz, Ar), 7.74 (1H, d J 7.1 Hz, Ar), 7.65-7.59 (2H, m, Ar), 7.44-7.41 (1H, m, Ar), 7.35-7.30 (1H, m, Ar), 6.82 (1H, td J 9.3, 2.4 Hz, Ar), 6.42 (1H, dd J 9.8, 2.4 Hz, Pyrrole-CH), 6.23-6.21 (1H, m, Pyrrole-CH), 5.56 (1H, br s, Pyrrole-CH), 4.94 (2H, s, CH2-Pyrrole), 4.02 (2H, s, CH2CO2H), 2.52 (3H, masked s, CCH3); Tr=1.63, m/z (ES+) (M+H)+ 427.19.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[C:35]=1[OH:36])[CH2:23][C@@H:24]([CH2:29][C:30]([O-])=[O:31])[C:25]([O:27][CH3:28])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[C:35]=1[OH:36])[CH2:23][C@@H:24]([CH2:29][C:30](=[O:31])[N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:5][CH2:6]1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.65 g (4.84 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to a mixture of 1.19 g (4.85 mmol) 1-methyl (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-succinate, 1.56 g (4.85 mmol) TBTU, 0.73 mL (5.00 mmol) triethylamine, in 30 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue was taken up in 200 mL EtOAc, the organic phase was washed with 10% citric acid and saturated Na2CO3 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the desired product was obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1.C(N(CC)CC)C.O>ClCCl>[C:1]1([S:7]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(O)cn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(OS(=O)(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Benzenesulfonyl chloride (12.9 mL, 101 mmol, 1.10 equiv) was added to a stirred solution of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol, 1 equiv) and triethylamine (15.3 mL, 110 mmol, 1.20 equiv) in dichloromethane (100 mL) at 0° C. After stirring for 2 h at 0° C., water (20 mL) was added and the resulting two-phase mixture was stirred vigorously for 1 h at 23° C. to quench any remaining sulfonyl chloride. Saturated aqueous potassium carbonate solution (100 mL) was added and the layers were separated. The aqueous layer was extracted with a second portion of dichloromethane (150 mL). The combined organic layers were dried over anhydrous potassium carbonate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with a gradient of 4:1 to 1:1 of hexane and ethyl acetate to provide 4 (21.8 g, 95%) as an oil. Chromatography may be avoided by using exactly one equivalent of benzenesulfonyl chloride to afford product of sufficient purity for direct submission to benzylic bromination conditions (see below). IR (neat) 3066, 1594, 1480, 1450, 1384, 1286, 1204, 1177, 1093, 1024, 865, 837, 804, 757, 741, 724, 692; 1H NMR (CDCl3) 8.01(d, 1H, J=2.7), 7.84 (d, 2H, J=7.9), 7.70 (t, 1H, J=7.2), 7.55 (t, 2H, J=7.8), 7.33 (dd, 1H, J=8.5, 2.7), 7.13 (d, 1H, J=8.5), 2.53 (s, 3H). Anal. Calcd. for C12H11NO3S: C, 57.82; H, 4.45; N, 5.62. Found C, 57.66; H, 4.33; N, 5.47.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[OH:9][C@@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: O[C@@H]1CCOC1
Reactant: Clc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc(O[C@@H]2CCOC2)nc1
Temperature: 90 °C
Yield: 46.4 %

Procedure:
To a solution of 5-bromo-2-chloropyridine (10 g, 52.1 mmol) in 100 mL of DMF was added commercially available (R)-(−)-3-hydroxytetrahydrofuran (6.87 g, 78.1 mmol) and Cs2CO3 (33.85 g, 0.104 mol), the resulting mixture was heated 90° C. for 36 hours. The solvent was concentrated and the residue was extracted with EtOAc (500 ml), washed with water (200 ml). The organic layer was dried over Na2SO4, concentrated and purified by chromatography on silica gel (eluting with Petrol ether: EtOAc=100:1) to afford 5-Bromo-2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridine (5.9 g, yield: 47%) as a solid. 1HNMR (CDCl3 400 MHz): δ8.15 (d, J=2.4 Hz, 1H), 7.61-7.64 (m, 1H), 6.64 (d, J=8.8 Hz, 1H), 5.47-5.50 (m, 1H), 3.85-4.02 (m, 4H), 2.07-2.28 (m, 2H), [α]D20=+18.5 (C=0.189, CHCl3).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[K+].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>CCO>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:7]3[NH:8][CH:9]=[N:10][C:6]=3[CH2:5][CH2:4][NH:3]2)[CH:19]=[CH:20][CH:21]=1
Reactant: NCCc1c[nH]cn1
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1cccc(C2NCCc3nc[nH]c32)c1
Temperature: 77 °C

Procedure:
Histamine dihydrochloride (3.68 g, 0.02 mol), KOH (3.36 g, 0.06 mol), and 3-bromobenzaldehyde were dissolved in H2 0 (250 mL) and EtOH(100 mL). The reaction mixture was heated for 24 h at 77° C. open to the atmosphere. The resulting white precipitate was filtered and dried under vacuum at 40° C. to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9](N2[C@@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(F)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of (4S)-3-[(2S)-2-(4-fluorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (2.40 g, 8.60 mmol) in 160 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (7.8 mL, 68.8 mmol) followed by LiOH (722 mg, 17.2 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (51 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.92 g (5.47 mmol, 64%) of (2S)-2-(4-fluorophenyl)propanoic acid; [α]D=+70° (C=1, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–11.4 (br, 1 H), 7.31–7.24 (m, 2 H), 7.04–6.97 (m, 2 H), 3.72 (q, 1 H, J=7.3 Hz), 1.49 (d, 3 H, J=7.3 Hz); ESMS m/e: 167.2 (M−H)+.
Reaction SMILES: [F:1][C:2]1([CH2:12][OH:13])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[H-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[N:21][C:22]=1Cl.[NH4+].[Cl-]>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[N:21][C:22]=1[O:13][CH2:12][C:2]1([F:1])[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: OCC1(F)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cnc(OCC2(F)CCC3(CC2)OCCO3)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 443B (500 mg) in N,N-dimethylformamide (5 mL) was added NaH (65% in mineral oil, 252 mg) at room temperature. The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (0.6 g) was added. The mixture was stirred at room temperature overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of solvent, the residue was loaded on a silica gel cartridge and eluted with 30% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]#[N:15])[CH:10]([NH:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:19]([F:30])[CH:18]=1)[CH2:9][CH2:8]2)(=O)[CH3:2].C([OH:33])C.OO.[OH-].[Na+]>O>[CH3:2][C:1]1[NH:15][C:14](=[O:33])[C:13]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][CH:10]([NH:16][C:17]4[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:19]([F:30])[CH:18]=4)[C:11]=3[CH:12]=2)[N:4]=1
Reactant: CC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of tert-butyl 4-[N-(5-acetamido-6-cyanoindan-1-yl)amino]-2-fluorobenzoate (0.182 g, 0.44 mmol), ethanol (2 ml), and water (0.4 ml) was cooled in an ice-bath, then 30% aqueous H2O2 solution (0.37 ml) was added followed by granulated sodium hydroxide pellets (0.030 g, 0.75 mmol). The reaction mixture was stirred at ˜0° C. for 10 min, then it was placed in an oil bath preheated to 55° C. and stirred at this temperature for 30 min The reaction mixture was allowed to cool to room temperature, then the solvents were removed in vacuo and the residue was suspended in water (˜15 ml). The pH of this mixture was adjusted to ˜4 with 1N hydrochloric acid. The white precipitate was collected by filtration, washed with water, and dried in vacuo over P2O5. The desired compound was obtained as a white solid 0.155 g (85%), m.p. 150-152° C.; 1H-N (250 MHz, DMSO-d6, TMS) 1.50 (s, 9H, C(C3)3), 2.32 (s, 3H, 2-CH3), 1.83, 2.53 (2×m, 2H, 7-H), 3.00 (m, 2H, 8-H), 5.15 (q, J=7.40 Hz, 1H, 6-H), 6.57 (m, 2H, 3′,5′-H), 7.16 (d, J=7.75 Hz, 1H, N10—H), 7.44, 7.87 (2×s, each 1H, 5-H, 9-H), 7.59 (t, J=8.73 Hz, 6′-H), 12.11 (s, 1H, N3-H), MS (ESI, m/z) 819 {(2M+H)+, 100%}, 432 {(M+Na)+, 10%}, 410 {M+H)+, 15%}; Found: C, 66.81; H, 5.89, N, 10.11; F, 4.58; C23H24FN3O30.25H2O requires C, 66.74; H, 5.96; N, 10.15%; F, 4.59%.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:3]1[N:4]2[C:5]3[CH:18]=[CH:17][CH:16]=[N:15][C:6]=3[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)Nc1ncccc1-n1ccnc1-2
Solvent: C1CCOC1
Product: Brc1cnc2n1-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a suspension of 9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (1.19 g, 5.1 mmol) in THF (60 mL) was slowly added N-bromosuccinimide (0.90 g, 4.3 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with sat.NaHCO3, extracted with ethyl acetate. The organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (hexane/ethyl acetate) to give a pale yellow solid (96%). 1H NMR (DMSO-d6) 400 MHz δ: 8.58 (s, 1H), 8.26 (dd, J=4.9, 1.4 Hz, 1H), 7.94 (dd, J=8.0, 1.7 Hz, 1H), 7.74 (dd, J=7.7, 1.4 Hz, 1H), 7.43 (s, 1H), 7.34 (td, J=7.7, 1.9 Hz, 1H), 7.25-7.21 (m, 2H), 7.08 (td, J=7.5, 1.2 Hz, 1H); LC/MS [M+H]: 314.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([O:43][CH2:44][C:45]([CH3:50])([CH3:49])[CH2:46][O:47][CH3:48])=[CH:38][C:37]=1[CH3:51]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:41]([CH3:42])=[CH:40][C:39]([O:43][CH2:44][C:45]([CH3:49])([CH3:50])[CH2:46][O:47][CH3:48])=[CH:38][C:37]=2[CH3:51])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: COCC(C)(C)COc1cc(C)c(Br)c(C)c1
Product: COCC(C)(C)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)c(C)c1

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-bromo-5-(3-methoxy-2,2-dimethylpropoxy)-1,3-dimethylbenzene following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=1.12 min; Mass spectrum (ESI+): m/z=563 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33])[CH2:16][Br:17])=[CH:11][C:10]=1[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OCc1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 5. Excess TBSCl and a higher reaction temperature were used.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)[CH2:14][CH2:15][CH2:16][CH3:17]>C(O)(=O)C>[CH2:13]([N:18]1[C:22]([C:3]2[C:4](=[O:11])[C:5]3[C:10]([C:1](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:21][CH:20]=[C:19]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CCCCCn1cccc1
Solvent: CC(=O)O
Product: CCCCCn1c(C2=CC(=O)c3ccccc3C2=O)ccc1C1=CC(=O)c2ccccc2C1=O
Yield: 87 %

Procedure:
The same procedure as in Example 7 was followed by stirring 10 millimol of 1,4-naphthoquinone with 2.5 millimol of N-pentylpyrrole in 40 ml of acetic acid at 50° C. for 5 hours. The 1-pentyl-2,5-bis(1,4-naphthoquinon-2-yl)pyrrole was thus obtained in a yield of 87% after chromatography on a column of silica.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:25])[C:9]([C:23]#[N:24])=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([NH:7][C:8](=[O:25])[C:9]([C:23]#[N:24])=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: N#CC(=Cc1c[nH]c2ccc([N+](=O)[O-])cc12)C(=O)Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N#CC(=Cc1c[nH]c2ccc(N)cc12)C(=O)Nc1ccccc1
Yield: 80 %

Procedure:
To a solution of N-phenyl β-(5-nitro-3-indolyl)-α-cyanoacrylamide (3.324 g, 0.010 mol) in anhydrous ethanol (200 ml) was added palladium on charcoal (0.200 g) and the mixture was hydrogenated at room temperature and atmospheric pressure until 3 equivalent of hydrogen has been taken up. The hydrogen uptake was graphed as function of time. The catalyst was filtered and the solution concentrated under vacuum until crystallization began. The mixture was cooled to 0°-5° C., filtered, the residue washed with ice-cooled ethanol and dried under vacuum. Thus almost pure title compound was obtained in about 80% yield (2.416 g). An analytical pure sample was obtained by crystallization from ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH2:8][CH:9]([OH:24])[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][CH:16]=1)([O-])=O.[H][H].[N+](C1C=C(C=CC=1)OCC1OC1)([O-])=O.C(C1C=CC(OCCN)=CC=1)(=O)N>[Pt]=O.CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH2:8][CH:9]([OH:24])[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: NC(=O)c1ccc(OCCNCC(O)COc2cccc([N+](=O)[O-])c2)cc1
Agent: O=[Pt]
Agent: NCCOc1ccc(C(N)=O)cc1
Agent: O=[N+]([O-])c1cccc(OCC2CO2)c1
Solvent: CO
Product: NC(=O)c1ccc(OCCNCC(O)COc2cccc(N)c2)cc1

Procedure:
A solution consisting of 12 g. of 1-(3-nitrophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol (m.p. 127°-129°C.) dissolved in 1000 ml. of methanol was subjected to catalytic hydrogenation over 0.3 g. of platinum oxide at room temperature (~25°C.) and 50 p.s.i. pressure of hydrogen [the 3-nitro starting material was prepared according to the procedure of Example VII from 1-(3-nitrophenoxy)-2,3-epoxypropane and 2-(4-carbamoylphenoxy)ethylamine]. Upon completion of this step, the resultant mixture was filtered and the clear filtrate thereafter evaporated to dryness while under reduced pressure to afford a white residual solid. Recrystallization of the latter material from methanol then gave pure 1-(3-aminophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol, m.p. 149°-157°C.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH2:17]Cl>>[CH3:25][O:24][C:20]1[CH:19]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:21]=1[O:22][CH3:23])[CH2:17][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: Sc1ncnc2ccccc12
Product: COc1cc(CSc2ncnc3ccccc23)cc(OC)c1OC
Yield: 42.2 %

Procedure:
The title compound(3.56 g) was prepared from 4-mercaptoquinazoline(4.0 g) and 3,4,5-trimethoxybenzyl chloride(7.3 g).