Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:3]([C:5]1[S:6][C:7]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=O)[CH2:20][CH2:19]3)=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[NH2:33][OH:34]>C(O)C>[CH3:1][N:2]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:3]([C:5]1[S:6][C:7]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[N:33][OH:34])[CH2:20][CH2:19]3)=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: CN1CCC(N(C)C(=O)c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=O)s2)CC1
Reactant: NO
Solvent: CCO
Product: CN1CCC(N(C)C(=O)c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)s2)CC1
Yield: 22 %

Procedure:
The product of step 4 (300 mg, 0.8 mmol) was heated at reflux in ethanol (10 ml) containing hydroxylamine (50% aqueous solution) (1 ml) for 1 hour. The solution was co-evaporated in ethanol (×3) to afford a crude solid. The product was purified twice by silica gel chromatography (1:9:40 0.880 ammonia:thanol:dichloromethane) to afford the title compound (80 mg, 22%); MS (AP+) m/e 461 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 8.80 g (50.9 mmol) of 3-bromophenol (distilled) and 1.28 g (5.1 mmol) of pyridinium p-toluenesulfonate in 50 ml of dichloromethane was added 6.42 g (7.0 ml, 76.3 mmol) of 3,4-dihydro-2H-pyran. The resulting clear solution was stirred at room temperature for 24 hours, partitioned between 200 ml of water and 400 ml of hexane, and the layers were separated. The organic phase was washed with 100 ml of water, 50 ml of 1N aqueous NaOH solution and 100 ml of brine solution, dried over K2CO3, filtered and concentrated in vacuo to a clear, slightly yellow oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded the title compound as a white solid. PMR (CDCl3):d 1.55-2.04 (6H, m), 3.55-3.65 (1H, m), 3.8-3.95 (1H, m), 5.40 (1H, t, J=2.9 Hz), 6.96-7.00 (1H, m), 7.09-7.17 (2H, m), 7.22-7.24 (1H, m).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:47])([CH2:45][CH3:46])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[NH2:31])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:47])([CH2:45][CH3:46])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[NH2:31])[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in dioxane) (2 mL, 0.5 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (20 mg, 0.03 mmol) in methanol (6 mL). After stirring at 60° C. for 1 h, volatiles were removed. The residue was purified by preparative HPLC eluting with 10-50% acetonitrile/water and lyophilized to afford the title compound. (M+H) found 367.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=O)=[C:4]2[CH2:3]1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH:23][NH2:24])=[O:19])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccccc2C1=O

Procedure:
50 g (187.3 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 400 ml of ethanol are heated to boiling under reflux for 2 hours together with 150 ml of hydrazine hydrate. The precipitated material is filtered off under suction and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide of melting point 312°-313°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[OH2:24]>O1CCN(CCCN)CC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:14][CH2:13][CH2:12][CH2:11][N:10]2[CH2:19][CH2:20][O:24][CH2:8][CH2:9]2)[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: O
Agent: NCCCN1CCOCC1
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCCN3CCOCC3)cc21
Temperature: 25 °C
Yield: 57 %

Procedure:
A suspension of Example A3 (0.200 g, 0.568 mmol) in 3-morpholinopropan-1-amine (1 mL) was subjected to microwave irradiation at 160° C. for 30 minutes. The mixture was cooled to RT, treated with water and the aqueous liquid decanted. The material was treated with MTBE and the resulting solid collected via filtration to afford 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-((3-morpholinopropyl)amino)-1,6-naphthyridin-2(1H)-one (150 mg, 57% yield). MS (ESI) m/z: 460.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13].[C:14](O)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:14]([O:10][CH2:9][C@H:7]1[O:8][CH:3]([O:2][CH3:1])[C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]1[OH:11])(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCC(=O)OC[C@H]1OC(OC)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
After 18 hours methyl-α-D-glucopyranoside (64 g, 0.33 mol, prepared according to example 6), dodecanoic acid (90 g, 0.45 mol) and 6 g lipase were added. After additional 22 hours the enzyme was removed by filtration and the product was worked up by short path distillation according to example 1, yielding a crude product containing 84% 6-O-dodecanoyl-D-glucopyranoside 9% methyl-D-glucoside and 7% diesters Part of the product was purified by chromatography and the identity of the title compound (being a ca 1:1 mixture of the anomers) was confirmed by NMR spectroscopy.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2)=[O:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:28]2)=[O:24]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(C(=O)OC)cc4C3)c(F)c21
Yield: 28.5 %

Procedure:
271 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 217 mg of 5-methoxycarbonylisoindoline hydrochloride, 457 mg of DBU, and 3ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 122 mg of the target compound.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[Br:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:6][C:7]1[CH:12]=[C:11]([O:13][CH2:2][CH:3]2[CH2:5][CH2:4]2)[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][CH2:2][CH:3]1[CH2:5][CH2:4]1)=[O:16]
Reactant: BrCC1CC1
Reactant: O=C(O)Cc1ccc(O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCC2CC2)cc1Br)OCC1CC1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of (bromomethyl)cyclopropane (10.52 g), (2-bromo-4-hydroxyphenyl)acetic acid (6.0 g) and potassium carbonate (7.18 g) in DMF (200 mL) was stirred at 80° C. for 8 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].Cl.[CH3:21][S:22]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:24])=[O:23].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][S:22]([CH3:21])(=[O:23])=[O:24])[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 68.5 %

Procedure:
5-fluoro-4-methyl-2-nitrophenyl methyl ether (Example 113, step B) (5.0 g, 27 mmol), K2CO3 (11.2 g, 81 mmol), and 1-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (8.0 g, 35 mmol) were weighed into a 150 mL sealed tube, taken up in 85 mL of DMSO and heated to 100° C. for 24 h. The mixture was poured into 500 mL of H2O, filtered, washed with H2O, air dried for 15 min, washed with hexanes (200 mL), washed with 20% Ether/Hexanes (200 mL), and air dried for 2 h to give the title compound of step C (6.6 g, 18.5 mmol, 68%). An additional (540 mg, 5.5%) of product was obtained by extraction of the H2O layer, followed by flash chromatography. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (s, 1H), 6.70 (s, 1H), 3.90 (s, 3H), 3.31-3.35 (m, 2H), 3.04 (s, 3H), 2.99-3.03 (m, 4H), 2.77 (t, J=6.60 Hz, 2H), 2.56-2.63 (m, 4H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[Br:31]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([Br:31])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1nc(Br)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (470 mg, 1.18 mmol) and N-bromosuccinimide (220 mg, 1.23 mmol) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was chromatographed (0-30% EtOAc/hexanes+2% AcOH) to give 451 mg of the title compound. MS: (+) m/z 479.06, 480.88 (M+1, 79/81Br)
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[N:25][C:26]=4[NH2:28])[N:21]([C@H:29]4[CH2:34][CH2:33][C@H:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)[CH2:31][CH2:30]4)[N:20]=3)=[CH:15][CH:14]=2)[N:11]=[CH:10][CH:9]=1)C>Br.C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([C@H:29]3[CH2:30][CH2:31][C@H:32]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:33][CH2:34]3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([N:12]4[C:8](=[O:7])[CH2:9][C:10]([CH3:1])=[N:11]4)=[CH:18][CH:17]=3)[C:27]=12
Reactant: CCOc1ccnn1-c1ccc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(-c3nn([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)C(=O)C1

Procedure:
A solution of trans-3-[4-(5-ethoxy-1H-1-pyrazolyl)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.100 g, 0.000194 mol) in 30% hydrobromic acid in acetic acid (2.5 mL) was heated at reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue neutralized with concentrated solution of ammonium hydroxide in water. The resulting suspension was concentrated under reduced pressure and the residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 5-45% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min) to yield trans-1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-3-methyl-4,5-dihydro-1H-5-pyrazolone diacetate (0.066 g, 0.00011 mol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[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]3[C:24](=C)[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[O:29]=[O+][O-]>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[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]3[C:24](=[O:29])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CCC(=O)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.72 mmol) prepared in example 80b in methanol and dichloromethane (1:1, 50 mL) at −78° C. was passed a stream of ozone until the color of the solution turned blue. The reaction mixture was degassed with nitrogen, then methyl disulfide (5 mL) was added. The reaction was slowly warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was purified by chromatography (EtOAc:CH2Cl2=1:1) to give the racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 160 mg, 50%)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+]>O1CCCC1.O>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 50 °C
Yield: 52 %

Procedure:
The compound (1.2 g) obtained in Example 201b was dissolved in tetrahydrofuran (32 mL) and water (8 mL), and lithium hydroxide (0.56 g) was added. The reaction mixture was heated at 40-60° C. for 48 hr, stirred and concentrated under reduced pressure. The residue was diluted with water and adjusted with 2.5N hydrochloric acid to pH 5-6. The resulting precipitate was collected by filtration and dried. The obtained solid was recrystallized from ethyl acetate to give the title compound (0.60 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:37][S:38]([CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:48][CH2:47]3)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ncc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC)n1
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1ncc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OCC)n1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 8) was reacted with 1-(2-methanesulfonylethyl)-piperazine dihydrochloride (example 3) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31H37N6O5SCl2 [(M+H)+] 675.1918, observed 675.1914.
Reaction SMILES: [C-:1]#[N:2].[K+].[O:4]=[C:5]1[CH2:11][O:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][CH2:6]1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:4][C:5]1([C:1]#[N:2])[CH2:6][O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[O:10][CH2:11]1
Reactant: [C-]#N
Reactant: O=C1COc2ccccc2OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CC1(O)COc2ccccc2OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 13.5 g. (208 millimoles) of potassium cyanide in 27 ml. of water is added dropwise to a mixture of 18.7 g. (114 millimoles) of 3-oxo-3,4-dihydro-2H-1,5-benzodioxepin and 21.2 g. (208 millimoles) of acetic anhydride with stirring and cooling. The mixture is stirred at ambient temperature overnight and then is made alkaline with 10% sodium carbonate solution. The product in the form of an oil is extracted with diethyl ether, treated with charcoal and dried over calcium sulfate. Evaporation of the solvent gives a solid that is recrystallized from carbon tetrachloride to give 3-hydroxy-3-cyano-3,4-dihydro-2H-1,5-benzodioxepin as plates, m.p. 108.5°-110° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[CH2:10]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[Cl-].[NH4+].[N-:28]=[N+]=[N-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[CH2:10][NH2:28])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC(COS(C)(=O)=O)C(C)O[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)NCC(CN)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 7 h
Yield: 202.8 %

Procedure:
To a solution of 7.00 g of 2-(N-allyloxycarbonylaminomethyl)-3-t-butyldimethylsilyloxy-1-methanesulfonyloxybutane and 1.42 g of ammonium chloride in 70 ml of N,N-dimethylformamide was added 1.73 g of sodium azide at 0° C. The mixture was stirred at 50° C. for 7 hours. After the starting material disappeared, 350 ml of ethyl acetate and 350 ml of water were added to the reaction mixture. The organic layer was washed in turn with water three times and brine. The half amount of solvent was evaporated and then 5.11 g of triphenylphosphine was added thereto portionwise. After stirring overnight, 2.15 g of 28% aqueous ammonia was added and the mixture was stirred for 8 hours, and then evaporated under reduced pressure to give 11.36 g of crude 2-(N-allyloxycarbonylaminomethyl)-3-(t-butyldimethylsilyloxy)butylamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH2:16])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2ccccc2)cn1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1ccc(OCc2ccccc2)cn1

Procedure:
2-(5-Benzyloxy-pyridin-2-ylmethyl)-isoindol-1,3-dione described in Preparation Example 184 (4.10 g, 11.9 mmol) was dissolved in ethanol (40 mL) and tetrahydrofuran (40 mL). Hydrazine monohydrate (5.77 mL, 119 mmol) was added to this solution at room temperature, and the solution was stirred under reflux for 50 minutes. The reaction solution was partitioned in water and ethyl acetate. This organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (2.8 g, quantitatively) was obtained as a pale yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([NH:21][NH2:22])=[O:20])([O-:15])=[O:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 81 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3-nitrobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 176 mg of the title compound (81%) as a orange solid in 98.4% purity by HPLC (Rt: 5.61, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.[Br-].[CH2:32]([CH:34]([CH2:37][CH3:38])[CH2:35][Zn+])[CH3:33]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[CH2:32]([CH:34]([CH2:37][CH3:38])[CH2:35][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:21]1)[CH3:33]
Reactant: CCC(CC)C[Zn+]
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: CCC(CC)Cc1ccc2oc(=O)cc(NC3CCN(CC=Cc4ccccc4)CC3)c2c1
Temperature: 160 °C
Yield: 23 %

Procedure:
Into a dry microwave vial under N2 was added 6-Bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(dppf)Cl2 (about 5 mol %), and CuI (about 6 mol %) in dry THF (0.5 mL) followed by 2-ethylbutyl zinc bromide (0.273 mL, 0.138 mmol (0.5M in THF)) dropwise. The solution was heated in the microwave for 10 minutes at 160° C., filtered, and was purified by Prep HPLC to give 4.7 mg (18%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 445 (M+H)+; 1H NMR (300 MHz, MeOH) δ ppm 0.90 (t, 6H), 1.29-1.38 (m, 4H), 1.60 m, 1H), 1.99 (m, 2H), 2.39 (br d, 2H), 2.60 (m, 2H), 3.24 (br t, 2H), 3.72 (br d, 2H), 3.97 (m, 3H), 5.42 (s, 1H), 6.31-6.40 (m, 1H), 6.95 (d, 1H), 7.24-7.54 (m. 8H), 7.84 (d, 1H).