Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11](OC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[C:3]([CH2:11][OH:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1c(F)cnc2[nH]ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(F)cnc2[nH]ccc12
Temperature: 0 °C
Yield: 97.9 %

Procedure:
To an oven-dried 200 mL round bottom flask equipped for stirring was added methyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (2.4 g, 12.36 mmol) under nitrogen. THF (100 mL) was added and the colorless solution was cooled to 0° C. Lithium aluminum hydride (27.2 mL, 27.2 mmol) was added and the solution was stirred at 0° C. for 3 h. The reaction was quenched with EtOAc (100 mL); brine (100 mL) was added, and the aqueous phase was extracted three times with EtOAc. The organics were dried over Na2SO4 and concentrated to afford the title compound as a yellow fine powder (2.01 g, 98%). 1H NMR (400 MHz, CD3OD) δ 4.96 (d, J=1.26 Hz, 2 H) 6.72 (d, J=3.54 Hz, 1 H) 7.44 (d, J=3.54 Hz, 1 H) 8.06 (d, J=2.78 Hz, 1 H). [M+H] calc'd for C8H7FN2O, 167; found, 167.5.
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH:33]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35]>CN(C=O)C>[CH3:37][O:36][C:34]([CH:33]([O:1][CH:2]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[O:8])=[CH:22][CH:23]=1)[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C(O)c3ccccc3)cc2)CC1
Reactant: COC(=O)C(Br)CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-{4-[hydroxy(phenyl)methyl]benzoyl}piperazine-1-carboxylate from step 3 (1.5 g, 3.8 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (0.16 g, 4.0 mmol) portionwise. The mixture was aged 15 minutes under a nitrogen atmosphere and methyl 2-bromo-4-methylpentanoate (0.65 mL, 4.0 mmol) was added dropwise. The reaction was allowed to warm to room temperature and was aged for 3 hours. The mixture was then partitioned between ethyl acetate and brine and the organic layer was dried and evaporated. The crude product was chromatographed on silica gel using 40% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:20]([C:19]3[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[N:4]2[N:3]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 54.3 %

Procedure:
6.0 g (4-chloro-phthalazin-1-yl)-hydrazine (compound C1) are suspended in a mixture of 160 ml toluene and 18 ml triethylamine at 60° C. and treated with a solution of 6.0 g 4-methoxy-benzoyl chloride in 48 ml toluene. The mixture is stirred at 110° C. for 6 h, cooled to ambient temperature, filtered with suction and rinsed with toluene. The solid is recrystallized from N,N-dimethylformamide, the precipitate is washed with water and dried to yield 5.2 g of the title compound (m.p.: 192-193° C.).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[CH3:23][C:24]1([CH3:32])[O:31][C:29](=[O:30])[CH2:28][C:26](=[O:27])[O:25]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:23][C:24]1([CH3:32])[O:31][C:29](=[O:30])[CH:28]([C:20](=[O:22])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[C:26](=[O:27])[O:25]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: -5 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
DMAP (106 g, 0.86 mol) was added to a solution of Boc-L-4-nitro-Phenylalanine (1800 g, 0.58 mol) and Meldrum's acid (92 g, 0.64 mol) in dichloromethane (1.5 L). The resulting solution was cooled at −5° C. under N2 atmosphere, followed by addition of DCC (240 g, 1.16 mol) in dichloromethane (1 L) over 1 h. The mixture was stirred overnight at 0˜5° C. Then the precipitated N, N′-dicyclohexylurea was removed by filtration and the filtrate was washed with 5% aqueous HCl (1 L×3), and brine (1 L×1), and was dried over MgSO4. After removal of MgSO4 by filtration, the organic phase was concentrated to dryness. The residue was triturated with EtOAc/hexane (1:1, 500 mL), and was dried to afford tert-butyl (S)-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-(4-nitrophenyl)-1-oxopropan-2-yl)carbamate (130.0 g, 51% yield) as a yellow solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20](=[O:45])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH:28]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:42][CH3:43])[CH:40]=3)[N:35]=[CH:34][C:33]=2O)[CH2:29][OH:30])[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:15]([O:19][C:20](=[O:45])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH:28]2[CH2:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([O:42][CH3:43])[CH:40]=4)[N:35]=[CH:34][C:33]=3[O:30][CH2:29]2)[CH2:24][CH2:23]1)([CH3:17])([CH3:18])[CH3:16]
Reactant: COc1ccc2ncc(O)c(CC(CO)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylazodicarboxylate (0.76 g, 3.80 mmol, 1.7 eq) is added at room temperature to a stirred solution of {trans-4-[2-hydroxy-1-(3-hydroxy-6-methoxy-quinolin-4-ylmethyl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.08 g, 2.26 mmol, 1.0 eq) and triphenylphosphine (1.90 g, 7.53 mmol, 3.33 eq) in tetrahydrofuran (120 mL). After 1 hour stirring at room temperature, solvent is evaporated to give a crude product that is purified by preparative HPLC to afford [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester as a white lyophilizated powder (670 mg, 71% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=O)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[OH:19][N:18]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)[C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1
Reactant: CSc1cccc(C(=O)c2nnnn2C)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CSc1cccc(C(=NO)c2nnnn2C)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
To a stirred solution of [3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methanone (5.62 g, 24 mmol) in dry pyridine (30 mL) was added hydroxylamine hydrochloride (4.17 g, 60 mmol). The reaction mixture was stirred at 70° C. for 5 h, then concentrated in vacuo and diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and dried over MgSO4. Evaporation of the solvent in vacuo afforded N-hydroxy-1-[3-(methylsulfanyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine as a yellow solid [6.91 g, yield 99.3%; HPLC/MS: m/z=250 (M+H); logP(HCOOH)=1.98].
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH:13]([N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])=[CH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH:13]([C:11]1[NH:10][N:9]=[N:8][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])[CH3:14]
Reactant: C=CN1CCCC1=O
Reactant: Cc1ccccc1-c1c[nH]nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1nn[nH]c1C(C)N1CCCC1=O
Temperature: 25 °C

Procedure:
A mixture of tolyltriazole (26.6 g; 0.2 moles), 1-vinyl-2-pyrrolidinone (22.2 g; 0.2 moles) and para toluene sulphonic acid (0.14 g) is heated in toluene (200 ml), under reflux, for 7 hours. The mixture is then cooled to ambient temperature and washed with 5% sodium bicarbonate solution (50 ml), water (2×50 ml) and finally, dried over anhydrous magnesium sulphate. The dried extract is filtered and then evaporated to yield a yellow oil. Short-path distillation of the crude product yields a pale yellow viscous oil (34.9 g; 71%), bp 175°/0.05 mbar.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.[CH3:17]O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:17])=[O:14]
Reactant: CO
Reactant: O=C(O)CCCCCCCCCCCO
Agent: Cl
Product: COC(=O)CCCCCCCCCCCO
Temperature: 22 °C
Reaction time: 3.5 h
Yield: 90 %

Procedure:
12-Hydroxydodecanoic acid (10.82 g, 50 mmol) was added to 3% HCl in CH3OH (210 ml). The reaction was stirred at 22° C. for 3.5 hours and concentrated on a rotary evaporator. The residue was taken up in ethyl acetate (200 ml) and washed with 1M K2CO3 (2×150 ml), and once with saturated aqueous NaCl (150 ml), dried over Na2SO4, concentrated and vacuum distilled to yield 10.3 g of methyl 12-hydroxydodecanoate in 90% yield; mp 33.5-35.0° C., 1H NMR (CDCl3) delta 3.66 (s, 3H), 3.62 (t, 2H), 2.88 (t, 2H), 1.28 (br s, 18H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]([CH3:26])[C:6]([C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]=[CH:10][C:9]=1[C:22](OC)=[O:23])=[O:7].[H-].[Na+].[NH4+].[Cl-].O>CN(C=O)C>[OH:23][C:22]1[C:9]2[CH:10]=[N:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:8]=2[C:6](=[O:7])[N:5]([CH3:26])[C:4]=1[C:3]([O:2][CH3:1])=[O:27]
Reactant: COC(=O)CN(C)C(=O)c1c(C(=O)OC)cnn1Cc1ccc(OC)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(O)c2cnn(Cc3ccc(OC)cc3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59.6 %

Procedure:
To a solution of methyl 5-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (1.1 g, 2.93 mmol) in DMF (20 mL) was added NaH (0.12 g, 2.85 mmol, 60% in mineral oil) and the mixture was stirred a ambient temperature under nitrogen atmosphere for 50 min. Saturated NH4Cl/water was slowly added and stirring at ambient temperature continued for 50 min. The solid was filtered, dissolved in dichloromethane and the filtrate dried over sodium sulfate and concentrated to provide the title compound (0.60 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.2 (s, 1H), 8.1 (s 1H), 7.22 (d, 2H), 6.9 (d, 2H), 5.8 (s, 2H), 3.9 (s, 3H), 3.7 (s, 3H), 3.42 (s, 3H); ES-LCMS: 344 (M+1).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CCC[CH2-].[B:19](OC)([O:22]C)[O:20]C.Cl>O1CCCC1>[O:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[B:19]([OH:22])[OH:20])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: OB(O)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diphenyl ether (0.85 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and the reaction mixture was cooled to 0° C. N-butyllithium (1.6M, 3.1 ml) was delivered by drops thereto and the reaction mixture was stirred for 30 minutes at the same temperature. Trimethyl borate (0.68 ml) was added thereto and the reaction mixture was stirred for two hours at room temperature. 1N hydrochloric acid was added to the reaction mixture and the water layer was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1.5:1 to 1:3) to obtain the title compound (304 mg) having the following physical data.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[F:7][C:8]([F:12])([F:11])[CH2:9]I.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:8]([F:12])([F:11])[F:7])[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(I)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-iodo-1H-pyrazole (960 mg, 5 mmol), 2,2,2-trifluoroethyl iodide (3.13 g, 15 mmol) and Cs2CO3(2.4 g, 7.7 mmol) in DMF (5 ml) is heated at 60° C. with stirring overnight. After cooling, the reaction mixture is partitioned between water (50 ml) and ether (20 ml). The organic layer is separated, dried (MgSO4) and concentrated to afford the title compound as an oil which solidified upon standing 1.0 g (72%). 1HNMR (CDCl3): δ (ppm) 4.70 (m, 2H), 7.56 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.C(O)(=O)C>C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:19])=[O:20])[C:15]([Br:17])=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCN(CC)S(=O)(=O)c1cc2c(cc1Br)CCc1nc(N)[nH]c(=O)c1-2
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Solvent: CC(=O)O
Product: CCN(CC)S(=O)(=O)c1cc2c(ccc3nc(N)[nH]c(=O)c32)cc1Br
Temperature: 25 °C
Yield: 33.2 %

Procedure:
3-Amino-8-bromo-N,N,-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one- 9-sulfonamide (0.165 g,0.39 mmole) was suspended in pivalic anhydride (5 ml) (Aldrich) and heated under nitrogen until dissolved. The solution was heated under reflux for 10 minutes, cooled, and the pivalic anhydride removed in vacuo. The dried solid was dissolved in benzene (20 ml), pyridine (0.05 ml) added, and the solution heated to boiling under nitrogen. N-8romosuccinimide (0.07 g, 0.47 mmole) was added, and the mixture refluxed for an additional 6 hours. The reaction mixture was cooled to room temperature, solvent removed in vacuo, and the solid residue crystallized from methanol. The pivalamide (0.105 g) was dissolved in methanol(2 ml), IN NaOH(4 ml) added, and the solution heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was neutralized with dilute acetic acid, the crystals collected by filtration and suspended in methanol. The collected crystals were dried in vacuo to give 3-amino-8-bromo-N,N- diethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-9-sulfonamide (0.055 g, 33%). MD >250° C. 1H NMR (DMSO-d 200 MHz) δ: 1.10 (t, J=7 Hz, 6'6H, ethyl CH,), 3.38 (q, J=7 Hz, 4H, ethyl CH2), 6.78 (br s, 2H, NH2), 7.47 (d, J=9Hz, 1H, Ar), 8.09 (d, J=9Hz, 1H, Ar), 8.40 (s, IH, Ar), 10.30 (s, 1H, Ar), 11.32 (br s 1H, NH). Anal Calculated for C16H17BrN4 03S: C,45.19; H,4.03; Br,18.79; N,13.17; S,7.54. Found: C,45.10; H,4.03; Br,18.74; N,13.07; S,7.56.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@@:8]2([CH2:13][CH2:12][CH2:11][N:10]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[CH:16][CH:15]=3)[CH2:9]2)[CH2:7][CH2:6][N:5]1[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O1CCC[CH2:32]1.CI>>[CH3:32][N:20]([C:17]1[CH:18]=[CH:19][C:14]([N:10]2[CH2:11][CH2:12][CH2:13][C@@:8]3([C:4](=[O:3])[N:5]([CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:6][CH2:7]3)[CH2:9]2)=[CH:15][CH:16]=1)[C:21](=[O:24])[O:22][CH3:23]
Reactant: COC(=O)Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)N(C)c1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (1.6 mg, 0.000041 mol) was added to a solution of methyl {4-[(5S)-1-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]dec-7-yl]phenyl}carbamate (8.0 mg, 0.000021 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) at rt. After stirring for 5 min., methyl iodide (2.6 μL, 0.000041 mol) was added and the reaction mixture was stirred for 1 h at rt. The crude product was purified by prep-HPLC. LC-MS: 402.3 (M+H)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1.C(O)C.O.O.[Sn](Cl)Cl>O.Cl>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:17]=[CH:16][C:14]([NH:15][NH2:1])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])=[CH:8][CH:7]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NNc1ccc(Oc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 0.52 g of sodium nitrite in 5 ml of water was added dropwise to a stirred mixture consisting of 1.9 g of 4-(4-chlorophenoxy)-3-nitroaniline, 25 ml of concentrated hydrochloric acid and 25 ml of ethanol cooled to 0° C., and the mixture was then stirred at 0° C. for 60 min and subsequently added dropwise to a suspension of 8.5 g of tin dichloride dihydrate in 8 ml of concentrated HCl. The precipitate was filtered off with suction, washed with water, suspended in 200 ml of water under nitrogen and decomposed with 100 ml of 30% strength sodium hydroxide solution at 10-15° C. The oil formed was extracted by shaking with ethyl acetate and washed with water, and the organic phase was dried with sodium sulfate. The product was then precipitated with isopropanolic HCl, filtered off with suction and dried in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Cl)=[CH:10][C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=1[CH3:17])=[O:5])[CH3:2].[CH3:18][NH2:19]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:19][CH3:18])=[CH:10][C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7]=1[CH3:17])=[O:5])[CH3:2]
Reactant: CN
Reactant: CCCn1c(C)c(C(=O)OCC)c(Cl)cc1=O
Solvent: CCO
Product: CCCn1c(C)c(C(=O)OCC)c(NC)cc1=O
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-2-methyl-6-oxo-1-propyl-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (166 mg, 0.644 mmol), 8 M methylamine in ethanol (0.7 mL) and ethanol (1.3 mL) was heated under microwave irradiation at 150° C. for 10 min and concentrated in vacuo. It was partitioned between ethyl acetate (15 mL) and sat. Na2CO3 (2×3 mL), washed with brine, dried (MgSO4) and evaporated. Yield 108 mg, 66%. LC-MS (m/z) 253.4 (MH+); tR=1.06 (method C). 1H NMR (500 MHz, CDCl3): 0.97 (t, J=7.4 Hz, 3H, Me of Pr), 1.37 (t, J=7.1 Hz, 3H, Me of Et), 1.68 (sextet, J=7.7 Hz, 2H), 2.51 (s, 3H, Me), 2.78 (d, J=4.9 Hz, 3H Me-NH), 3.98 (br. t, 2H, CH2N), 4.33 (q, J=7.2 Hz, 2H, CH2 of Et), 5.46 (s, 1H, C5-H), 6.43 (br., 1H, NH-Me).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]2[CH:7]=[N:8][S:9][C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>>[S:9]1[C:5]2[CH:4]=[C:3]([OH:2])[CH:11]=[CH:10][C:6]=2[CH:7]=[N:8]1
Reactant: COc1ccc2cnsc2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2cnsc2c1
Yield: 83.6 %

Procedure:
A method similar to the method described in WO 04/043904 was used. 6-Methoxybenzo[d]isothiazole (450 mg, 2.73 mmol) and pyridine hydrochloride (3.2 g, 27.27 mmol) were heated at 210° C. in a microwave oven for 20 min. The residue was partitioned between water (30 mL) and EtOAc (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel with EtOAc:heptane (1:1, v/v) as eluent to afford benzo[d]isothiazol-6-ol as a white solid (345 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.N[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2.Cl>>[CH2:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:1][C:2]3[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: Nc1cc(=O)[nH]c(=S)[nH]1
Reactant: Nc1ccc2c(c1)CCC2
Agent: Cl
Product: O=c1cc(Nc2ccc3c(c2)CCC3)[nH]c(=S)[nH]1
Yield: 6 %

Procedure:
6-Amino-2-thiouracil is heated for 4 hours at 160° C. with an equimolar mixture of 5-aminoindan and the hydrochloride of 5-aminoindan. The product is crystallized from ethanol/water and isolated in 6% yield, mp 269°-272° C.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[NH3:36]>O1CCCC1>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:36])=[O:19]
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)=C(C)C1=O
Reactant: N
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(CCCCCC(N)=O)c2ccccc2)=C(C)C1=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirred solution of p-nitrophenyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenyl-heptanate (0.71 g, 1.5 mmoles) in tetrahydrofuran (7 ml) was added concentrated ammonia (1.0 ml) at room temperature and kept stirring for 4 hours. After the reaction was completed, the solvent was evaporated in a reduced pressure. To the residue was added aqueous potassium carbonate and then extracted with ethylacetate. The organic layer was washed with water, dried over magnesium sulfate. Evaporation of the solvent gave 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanamide (0.46 g, 87%)
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:28][C:29](=[O:31])[CH3:30])([CH3:27])[CH3:26])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)O)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:28][C:29](=[O:31])[CH3:30])([CH3:26])[CH3:27])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN(CCCCCC(C)(C)OC(C)=O)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC/C=C/c1ccc(NS(C)(=O)=O)cc1)CCCCCC(C)(C)OC(C)=O

Procedure:
In the process as described in Example 2 the product from Example 13 is treated with trifluoroacetic acid to give the titled compound.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH2:21]>O1CCCC1>[I:20][C:18]1[CH:17]=[CH:16][C:15]2[NH:21][C:1](=[O:2])[NH:13][C:14]=2[CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(I)cc1N
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(I)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
1,1'- Carbonyldiimidazole (13.6 g) was added to a solution of 2-amino-4-iodophenylamine (13.2 g) [see Makromol. Chem. (1993), 194(3), 859-868] in tetrahydrofuran (100 ml). The reaction mixture was stirred for 18 hours at room temperature, after which time the solvent was removed under reduced pressure, and the residue partitioned between 1N aqueous sodium hydroxide and diethyl ether. The aqueous was acidified with concentrated aqueous hydrochloric acid, and the resulting white precipitate filtered off and washed with water to afford 5-iodo-1,3-dihydro-2H-1,3-benzimidazol-2-one (14.0 g) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)(=O)=O.[NH:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=2[CH:15]=[CH:14]1>>[N:8]1([CH2:7][CH2:6][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=3[CH:15]=[CH:14]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CS(=O)(=O)OCCN1CCCC1
Product: O=Cc1cccc2c1ccn2CCN1CCCC1
Yield: 32.3 %

Procedure:
The same procedures used in Example 154 were repeated except for using 5.32 g of N-(2-methanesulfonyloxyethyl)pyrrolidine and 2.00 g of indole-4-carbaldehyde as a starting material to give 1.08 g of 1-[2-(pyrrolidin-1-yl)ethyl]indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 33%.