Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:7]1=[O:30])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:38][C:39]([NH2:41])=[O:40]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:1]([NH:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([O:27][CH2:38][C:39]([NH2:41])=[O:40])=[CH:26][C:20]=3[S:19](=[O:28])(=[O:29])[N:18]=2)[C:7]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)CBr
Reactant: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)c(O)c2ccccc21
Temperature: 165 °C
Yield: 94.9 %

Procedure:
The product of Example 322C (0.038 g, 0.089 mmol) was reacted with cesium carbonate (0.087 g, 0.27 mmol), 2-bromoacetamide (0.018 g, 0.13 mmol) and a catalytic amount of tetrabuylammonium iodide in N,N-dimethylformamide (3 mL) at 25° C. for 2 hours. The reaction was concentrated to half the volume under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.041 g, 95%). MS (ESI−) m/z 484 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.17 Hz, 3 H) 1.48 (m, 4 H) 2.76 (m, 2 H) 4.49 (s, 2 H) 5.90 (t, J=6.80 Hz, 1 H) 7.06 (t, J=6.99 Hz, 1 H) 7.21 (m, 2 H) 7.40 (m, 1 H) 7.54 (m, 2 H) 8.07 (dd, J=8.09, 1.10 Hz, 1 H) 16.24 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][N:6]([C:13](=[O:25])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([N+:22]([O-])=O)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][N:6]([C:13](=[O:25])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([NH2:22])[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1N

Procedure:
The nitro group of product 1a was reduced by hydrogenation at room temperature in ethanol with Pd (10% on charcoal) as catalyst.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:21]O>>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([O:16][CH3:21])=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CC1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CN(Cc2ccccc2)CC1C

Procedure:
1.3 g (4.9 mmol) (3RS,4RS)-1-benzyl-4-methyl-pyrrolidine-3-carboxylic acid (as hydrochloride salt) are dissolved in 10 ml of methanol and combined with 0.6 ml (8.5 mmol) thionyl chloride while cooling with an ice bath. The ice bath is removed and the mixture is refluxed for three hours. Then the mixture is evaporated down i. vac. and combined with 1N sodium hydroxide solution. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=[C:13]3[C:12]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[O:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[CH:18]=[C:13]2[C:12]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccccc2)c2cc(-c3ccccc3Oc3ccccc3)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(Oc2ccccc2-c2cnc3[nH]cc(-c4ccccc4)c3c2)cc1
Temperature: 105 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of azaindole 28 (1.16 g, 2.31 mmol) in EtOH (70 mL) was added a 10% sodium hydroxide solution (8.5 mL), and the mixture was heated at 105° C. After 1 h, the mixture was allowed to cool to r.t. and partitioned between chloroform and saturated brine. The aqueous layer was extracted with chloroform (3×), and the combined organic extracts dried (MgSO4), filtered and concentrated. The residue was purified by silicagel chromatography (gradient elution, hexanes to 5% EtOAc in dichloromethane) to afford a yellow solid which was washed with cold Et2O to furnish azaindole 29 (0.546 g, 65%) as a cream coloured solid. 1H NMR (400 MHz; CDCl3) δ6.95-6.98 (m, 2H), 7.04 (tt, J=7.4, 1.0 Hz, 1H), 7.11 (dd, J=8.1, 1.2 Hz, 1H), 7.25-7.31 (m, 4H), 7.35-7.41 (m, 3H), 7.54-7.57 (m, 4H), 8.41 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 10.78 (bs, 1H).
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)(Cl)Cl>C(O)C>[CH2:1]([N:7]([CH2:21][CH2:22][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Reactant: C1CCNCC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCN(CCN1CCCCC1)S(=O)(=O)c1cccc2cnccc12
Temperature: 80 °C
Yield: 80 %

Procedure:
In 30 ml of ethanol were dissolved 5.47 g of N-hexyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide and 2.85 g of piperidine, and the solution was heated in a pressure vessel at 80° C. for 3 hours. To the mixture obtained was added 100 ml of chloroform, and the resultant mixture was washed with 100 ml of water and dried with anhydrous magnesium sulfate. The chloroform was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: 3% methanol solution in chloroform) to obtain 3.6 g of N-hexyl-N-(2-piperidinoethyl)-5-isoquinolinesulfonamide [Compound (45)]. Compound (45) was analyzed to give the following data.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH3:11])[CH2:7][C:8](O)=[O:9])=[O:4].Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]([CH3:11])[CH2:7][C:8]([N:32]1[CH2:31][CH2:30][C:29]2[C:34](=[CH:35][C:26]([C:24]3[CH:25]=[C:20]([N:17]4[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]4)[N:21]=[C:22]([NH2:36])[N:23]=3)=[CH:27][CH:28]=2)[CH2:33]1)=[O:9]
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: COC(=O)NC(C)CC(=O)O
Agent: Cl
Product: COC(=O)NC(C)CC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from 3-[(methoxycarbonyl)amino]butanoic acid and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=468.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13].[CH:15]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13])[CH3:15]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1cc(OC)ccc1Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cc(OC)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-methoxy-benzeneacetic acid methyl ester (994 mg) was dissolved in THF and cooled to −78° C. Lithiumdiisopropylamide (2M in THF, 3.72 mL) was added drop wise and stirring was continued for 30 minutes. Iodomethane (879 mg, 0.39 mL) was added and stirring was continued for 30 minutes. The cooling bath was removed and the reaction was allowed to warm for 45 minutes. The mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate:heptane 1:3) to give the desired compound as a yellow oil (859 mg). 1H-NMR, (CDCl3): 7.27 (d, 1H), 6.85 (d, 1H), 6.74 (dd, 1H), 4.17 (q, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 1.48 (d, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30](=O)[CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Reaction time: 24 h
Yield: 83.5 %

Procedure:
To a solution of methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g, 2.53 mmol) and propionaldehyde (1 ml, 13.86 mmol) in 1,2-dichloroethane (30 ml) was added sodium triacetoxyborohydride (1.9 g, 8.96 mmol) at room temperature, and the mixture was stirred for 24 hours. To the reaction system was added 1N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in THF (50 ml) and methanol (50 ml), and to the solution was added 1N sodium hydroxide solution. After heating to reflux for 1 hour, the mixture was concentrated under reduced pressure. To the residue was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.895 g) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:34][N:35]([CH3:39])[C:36]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH:9]=2)=[CH:4][CH:3]=1)=[O:37]
Reactant: CN(C)C(=O)Cl
Reactant: CN(Cc1cccc(-c2ccc(N)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccc(-c2cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
tert-Butyl (2-{[(4′-aminobiphenyl-3-yl)methyl](methyl)amino}-2-oxoethyl)carbamate (200 mg) and pyridine (64 mg) were dissolved in methylene chloride (6 ml), followed by ice-cooling. Dimethylcarbamoylchloride (64 mg) was added thereto, followed by warming to room temperature and stirring for 1 hour. The reaction mixture was subjected to liquid separation with CHCl3 and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined and dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl {2-[({4′-[(dimethylcarbamoyl)amino]biphenyl-3-yl}methyl)(methyl)amino]-2-oxoethyl}carbamate (220 mg) as a colorless oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]1[CH2:20][C:21](OCC)=[O:22].S([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH:12]1[CH2:20][CH:21]=[O:22]
Reactant: CCOC(=O)CC1Cc2ccccc2C1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CCC1Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
Under cooling at -78° C., 1.5M diisobutyl aluminum hydride (DIBAH) dissolved in 65 ml of toluene was added to 19.34 g of ethyl 2-indanacetate dissolved in 200 ml of toluene. The mixture was stirred at the same temperature for 1.5 hours. A 15% sodium sulfite aqueous solution was added to the mixture. After the organic layer was collected by separation, washed and dried, the solvent was removed. The residue was purified by silica gel column chromatography (hexane-ethyl acetate (10:1)) to obtain 13.58 g of 2-indanacetaldehyde.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9](OCCC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:11][CH2:10][N:9]([CH2:32][CH2:31][O:30][C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(OCCc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylic acid ethyl ester (2.5 g, 5.76 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (56%); off white powder; mp 204° C.; MS: 462.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3C3C=C(Cl)C=CC=3OC3CCC4(OCCO4)CC3)[C:5]2=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>O1CCCC1.O>[Cl:22][C:18]1[CH:17]=[C:16]([CH:15]2[CH2:14][C:13](=[O:23])[NH:12][CH2:11][C:10]32[C:5]2[C:6](=[CH:7][CH:2]=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:42])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2OC2CCC3(CC2)OCCO3)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC(c2cccc(Cl)c2)C2(CN1)C(=O)Nc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.32 mmol) in tetrahydrofuran (15 mL) and water (1 mL) was added aqueous HCl (2 N, 1 mL). The reaction mixture was stirred at room temperature for 1 h, then neutralized to “pH” 7 by aqueous NaHCO3 solution. The mixture was then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:1) to give racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-cyclohexyloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.1 g, 54%)
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:19]C)=[CH:8][CH:9]=[C:10]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[O:4][C:3]=1C(OCC)=O>Cl>[CH3:1][C:2]1[C:6]2[C:7]([OH:19])=[CH:8][CH:9]=[C:10]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[O:4][CH:3]=1
Reactant: CCOC(=O)c1oc2c(C(=O)c3ccccc3)ccc(OC)c2c1C
Agent: Cl
Product: Cc1coc2c(C(=O)c3ccccc3)ccc(O)c12
Temperature: 195 °C

Procedure:
A mixture of ethyl 3-methyl-4-methoxy-7-benzoylbenzofuran-2-carboxylate (1.10 g, 3.25 mmol) and freshly fused pyridinium hydrochloride (2.14 g, 18.52 mmol) was heated to 195° C. for 45 minutes. After cooling, the reaction mixture was diluted with 2N HCl (25 mL) and extracted with ethyl acetate (3×25 mL). The combined extracts were washed with water (2×20 mL), dried (Na2SO4), and concentrated. Flash chromatography, using 20% ethyl acetate in hexane as eluant, afforded 3-methyl-4-hydroxy-7-benzoylbenzofuran 6. 1H NMR d 2.44 (3H, s), 6.06 (1H, br s), 6.65 (1H, d, J=8 Hz), 7.36 (1H, s), 7.54 (4H, m), 7.84 (2H, m).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[OH-].[NH4+:22]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:22]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: [NH4+]
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a one liter, stirred flask equipped with a reflux condenser was placed 89.7 gms. of ##STR8## 61.6 gms. of 2-chloroacetamido-5-chlorobenzophenone, 22.4 mls. of 26% ammonium hydroxide and 425 mls. of ethanol. Ammonia was bubbled into the reaction mixture while it was stirred and heated to reflux. Refluxing was continued for 5 hrs. thereafter with stirring. The reaction mixture was distilled to dryness in a Swissco evaporator. The residue was then heated at reflux for one hour in a mixture of 100 mls. of toluene and 100 mls. of water and cooled to room temperature yielding 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one. The product was filtered, washed with 20 mls. of water and 20 mls. of toluene and dried. It weighed 92.5 gms. or 85.4%. The crude product melted at 210°-213° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>CN(C)C=O.O>[CH3:11][O:10][C:8]1[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:1][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:9]=1
Reactant: COCCOCCBr
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOc1cc(OC)c(-c2cccs2)cc1C=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Ex-29C: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde from Ex-29B (0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Once at 80° C., 1-bromo-2-(2-methoxyethoxy)ethane (0.24 g, 1.3 mmol) was added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80° C. and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers was sequentially washed with a saturated ammonium chloride solution (1×15 mL), water (1×15 mL), and brine (1×15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 4:1) afforded 0.13 g (87%) of 4-methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-benzaldehyde as a pale yellow oil. 1H-NMR (300 MHz, CDCl3) δ 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H), 7.30 (dd, 1H), 7.07 (dd, 1H), 6.57 (s, 1H), 4.33 (t, 2H), 4.00 (s, 3H), 3.94 (t, 2H), 3.74 m, 2H), 3.59 (m, 2H), 3.40 (s, 3H). HRMS (EI) Calcd. for C17H20O5S: 336.1031. Found: 336.1027.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[Na+].[I-:11]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][I:11]
Reactant: Clc1ccccc1CBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccccc1CI
Yield: 95 %

Procedure:
A mixture of 2-chlorophenylmethylbromide (4 g, 19.47 mmol) and NaI (14 g, 97.33 mmol) in acetone (40 ml) was stirred under reflux for 1 hour. The reaction mixture was cooled, filtered and concentrated in vacuo. The residue was triturated with hexane and filtered. The solution was concentrated in vacuo, and the resulting oil purified by flash chromatography (silica, hexane) to afford the title compound (4.67 g, 63%) as an oil: 1H NMR (CDCl3) δ 7.34 (4H, m), 4.54 (2H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([N:12]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C@H:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13]1)=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>O1CCCC1.CCOCC.C(O)C>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C@H:15]1[CH2:16][CH2:17][N:12]([CH3:10])[CH2:13][C@H:14]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1CC[C@H](Oc2ccccc2F)[C@H](c2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CC[C@H](Oc2ccccc2F)[C@H](c2ccccc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.82 g of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran is added a solution of 5.51 g of cis-1-ethoxycarbonyl-4-(2-fluorophenoxy)-3-phenylpiperidine in 100 ml of tetrahydrofuran. The mixture is refluxed for 2 hours under nitrogen, cooled to 0° C. and diluted with ether (100 ml). Saturated sodium sulfate solution is cautiously added dropwise at 0°-10° C. until a flocculent white precipitate is obtained. The solid is filtered, washed with ether and the filtrate is concentrated in vacuo. The residue is taken up in ether (200 ml), the solution is washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo affords a nearly colorless oil. The oil is dissolved in 100 ml of ether and treated dropwise with a solution of 1.92 g of fumaric acid in a mixture of ether (150 ml) and absolute ethanol (25 ml). After stirring overnight the precipitated solid is filtered, washed with ether and dried to afford a colorless solid. Recrystallization from 25 ml of isopropanol gives product as colorless crystals, mp 148°-151° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.CS[C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32].C(N(CC)CC)C>CO>[CH3:32][N:31]1[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[S:28](=[C:6]2[C:5](=[O:7])[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:3][CH:2]2[CH3:1])[CH2:27]1
Reactant: CSc1sc2ccccc2[n+]1C
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1NN(c2ccccc2)C(=O)C1=S1CN(C)c2ccccc21
Reaction time: 1 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01 mol) was mixed with 3.68 g (0.01 mol) 2-methylthio-3-methylbenzothiazolium tosylate in 25 ml methanol. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for one hour, then filtered and washed with methanol. After drying the yield was 2.46 g (78%), mp 159°-162° C., λmax=375 (ε=25,000).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH3:17]>>[N+:9]([C:3]1[CH:4]=[C:5]([N:6]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:12])[CH:7]=[CH:8][C:2]=1[F:1])([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)CCC(C)=O
Product: Cc1ccc(C)n1-c1ccc(F)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
Prepared analogously from 4-fluoro- 3-nitroaniline and 2,5-hexanedione. Yield: 98%. Mp 99-101° C.