Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH:19]([CH2:21][CH3:22])[CH2:18][CH:17]([CH2:23][CH3:24])[CH2:16]2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([N:15]2[CH2:16][CH:17]([CH2:23][CH3:24])[CH2:18][CH:19]([CH2:21][CH3:22])[CH2:20]2)[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CCC1CC(CC)CN(c2cc(Cl)ncn2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N2CC(CC)CC(CC)C2)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.6 %

Procedure:
0.16 g of sodium hydride (60% oil suspension) was suspended in 4 ml of tetrahydrofuran. 1 ml of tetrahydrofuran solution of 0.27 g of 2-butyn-1-ol was added dropwise therein, and the mixture was stirred for 10 minutes at room temperature. Into the mixture was added dropwise 1 ml of tetrahydrofuran solution of 0.64 g of 4-chloro-6-(3,5-diethylpiperidino)pyrimidine, wherein the ratio of cis/trans diastereomer on the piperidino ring was 1:1, and stirred for 5 hours at 60° C. Into the reaction mixture was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.41 g of 4-(2-butynyloxy)-6-(3,5-diethylpiperidino)pyrimidine (hereinafter, referred to as Compound (30)). Compound (30) had the cis/trans diastereomer originated two ethyls on the pyperidine ring. The ratio of the cis/trans diastereomer was about 1/1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]2[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:15]=12.[C:28]([N:47]1[CH:51]=[CH:50][N:49]=[C:48]1[CH:52]=[O:53])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C(O)=O>O1CCCC1.CCCCCC.O>[OH:53][CH:52]([C:48]1[N:47]([C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:51]=[CH:50][N:49]=1)[CH:24]1[C:23](=[O:27])[N:16]2[C:17]3[C:22]([C:14]([CH3:13])=[C:15]2[CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Cc1c2n(c3ccccc13)C(=O)CCC2
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
To a solution of diisopropylamine (557 mg) in tetrahydrofuran (15 ml) at -70° C. under a nitrogen atmosphere was added 1.64M butyllithium in hexane (3.35 ml). After being stirred at the same temperature for 20 minutes, the mixture was treated with a solution of 8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (995 mg) in tetrahydrofuran (10 ml) over 15 minutes. The mixture was stirred at -70° C. for 30 minutes, and a solution of 1-trityl-1H-imidazole-2-carbaldehyde (1.69 g) in tetrahydrofuran (20 ml) was added dropwise over 10 minutes. After the mixture was stirred at -70° C. for further 70 minutes, it was diluted with chilled water, neutralized with an aqueous solution of oxalic acid, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (20% ethyl acetate-chloroform) gave 8,9-dihydro-7-[(hydroxy)-(1-trityl-1H-imidazol-2-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.85 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:32]#[N:33])[CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]([C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:32]5[NH:36][N:35]=[N:34][N:33]=5)[CH:26]=4)[N:21]=3)[CH3:19])[CH2:16][CH2:17]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(C#N)cc4c(=O)n3C)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(-c5nnn[nH]5)cc4c(=O)n3C)CC2)cc1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To the 1 ml DMF solution of 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (10.0 mg, 0.02 mmol) was added sodium azide (16.7 mg, 0.24 mmol) and ammonium chloride (12.8 mg, 0.24 mmol). The reaction test tube was flushed with N2 and was irradiated at 200° C. for 40 minutes in the SmithSynthesizer Microwave Reactor with vigorous agitation by a magnetic stirrer. The mixture was cooled to room temperature, the solvent was removed by reduce pressure and extracted with water and ethyl acetate, dried over anhydrous MgSO4, and concentrated by rotary evaporation. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-6-(1H-tetrazol-5-yl)-3H-quinazolin-4-one (Yield 3.09 mg, 9.8%). 1H NMR (400 MHz, MeOD-d4): δ 1.79 (d, 3H, J=6.57 Hz), 3.39-3.12 (m, 8H), 3.70 (s, 3H), 3.92 (s, 3H), 4.70 (s, br, 1H), 7.17 (d, 2H, J=9.09 Hz), 7.76 (d, 2H, J=9.09 Hz), 7.87 (d, 1H, J=8.59 Hz), 8.47 (dd, 1H, J=8.59, 1.77 Hz), 8.89 (d, 1H, J=1.77 Hz). MS m/z calc. 510.18 found (ESI); 511.4 (M+1)+. Retention time 2.2 minutes.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:13]([Cl:35])=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:19][CH:18]=[CH:17][CH:16]=2>>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([Cl:35])[C:12]=2[N:11]=[CH:1]1)=[O:29])([CH3:32])([CH3:34])[CH3:33]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)c(Cl)nc2ccccc12
Product: CC(C)(C)OC(=O)NCCCCn1cnc2c(Cl)nc3ccccc3c21
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
0.32 ml (1.92 mmol)of Triethyl ortho-formate was added to 0.14 g (0.384 mmol) of 3-amino-4-[4-(tert-butoxycarbonylamino)butylamino]-2-chloroquinoline. The mixture was heated at 100° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=150:1 to 100:1 (v/v)) to obtain 0.12 g (0.321 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-4-chloro-1H-imidazo[4,5-c]quinoline as pale orange powder (mp: 148-150° C.). ##STR43## Its spectroscopic data are as follows: IR (KBr) cm-1 : 1695, 1510.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:5][C:6]=1[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28])#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:9]1[CH:8]=[C:7]([C:6]2[S:5][C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][C:2]=2[C:24]2[CH:25]=[CH:26][C:27]([F:28])=[C:22]([C:20]#[N:21])[CH:23]=2)[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CCOC(=O)c1cc(Br)c(-c2cc(F)cc(Cl)c2)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2ccc(F)c(C#N)c2)c(-c2cc(F)cc(Cl)c2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under argon, 220 mg (0.61 mmol) of the compound from Example 9A are provided in 6.2 ml of 1,2-dimethoxyethane, and 100 mg (0.61 mmol) of 3-cyano-4-fluorophenylboronic acid, 593 mg (1.82 mmol) of cesium carbonate, 20.0 mg (0.04 mmol) of dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane and 4.0 mg (0.02 mmol) of palladium(II) acetate are added. The mixture is stirred at 50° C. overnight. The same amount of catalyst and ligand is added once more, and the mixture is stirred at 50° C. overnight. The reaction mixture is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient with addition of 0.1% formic acid). 86.0 mg (35% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]([CH2:13][CH2:14][C:15](O)=[O:16])[CH2:8][CH2:9][C:10](O)=[O:11].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[S:7]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:8][CH2:9][CH2:10][OH:11]
Reactant: O=C(O)CCSCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCSCCCO
Yield: 19.8 %

Procedure:
2.55 g of lithium aluminum hydride are suspended in 100 ml of absolute tetrahydrofuran under argon gasification and treated with a warm solution of 12.0 g of 3,3'-thiodipropionic acid in 100 ml of absolute tetrahydrofuran. After completion of the addition, the resulting heterogenous mixture is heated to reflux for a further 22 hours. After cooling, the mixture is treated with 12.0 ml of saturated potassium carbonate solution, filtered and concentrated. Low-pressure chromatography (0.4 bar) of the resulting colorless oil on silica gel with ethyl acetate and subsequent bulb-tube distillation (150°-170° C./0.15-0.09 mm Hg) gives 2.0 g of 3,3'-thiodi-1-propanol as a colorless, viscous oil; nD23 =1.5088; relative fluorescence: 20 percent for UV excitation, 2 percent for violet excitation, 5 percent for blue excitation.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[Br:17]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:17][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[Cl:1]
Reactant: O=c1[nH]c2ccc(Cl)c([N+](=O)[O-])c2[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Br)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 28 °C
Reaction time: 120 h
Yield: 40.1 %

Procedure:
To a stirred solution of 6-chloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione (35 mg, 0.14 mmol) in DMF (0.35 mL), N-bromosuccinimide (39 mg, 0.22 mmol) was added and the solution was stirred at 28° C. for 5 days. The resulting solution was then diluted with water (3.5 mL) and the yellow solid was filtered, washed with water (2.0 mL) and dried to obtain 42 mg crude product as a yellow powder. It was purified by successive crystallization (three times) from DMSO-water (3:1) to furnish 18 mg (44%) of pure title compound as shining yellow flakes, m.p. >350° C.; 1H NMR (DMSO-d6): δ 7.483 (s, 1H), 12.222 (s, 1H), 12.323 (brs, 1H); IR (KBr, cm-1): 3418, 3118, 1700, 1550, 1400, 1350, 1006, 675, 562.
Reaction SMILES: [F:1][C:2]1([F:31])[CH2:3][CH2:4][N:5]([C:17]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:30])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([OH:12])=O.ON1C2C=CC=CC=2N=N1.[ClH:42].C(N=C=NCCCN(C)C)C.[N:54]1([CH2:60][CH2:61][OH:62])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[ClH:42].[F:31][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:17]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:30])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:57]1[CH2:58][CH2:59][N:54]([CH2:60][CH2:61][OH:62])[CH2:55][CH2:56]1)=[O:12]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)O)c2ccccc21
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCN(CCO)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.4 %

Procedure:
To a solution of 8.26 g of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetic acid in 150 ml of tetrahydrofuran were added 2.79 g of 1-hydroxybenzotriazole, 5.40 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 3.18 g of 2-(piperazin-1-yl)ethanol, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, the mixture was extracted with chloroform, and the solvent was evaporated from the extract. The residue was dissolved in 300 ml of 0.1N hydrochloric acid, washed with ethyl acetate, made alkaline with a 1N aqueous solution of sodium hydroxide, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate, and the solvent was evaporated off. The residue was crystallized from ethyl acetate, collected by filtration, and washed with ethyl acetate. The resulting crystals (9.0 g) were dissolved in 100 ml of chloroform, and 6 ml of a 4N HCl/ethyl acetate solution was added, followed by stirring at room temperature. The resulting crystals were collected by filtration and washed with chloroform. Those crude crystals (3.0 g of the above-obtained ones in 10.0 g) were recrystallized from a 90% aqueous ethanol solution to give 2.48 g of (Z)-2-(4-{[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}piperazin-1-yl)ethanol monohydrochloride as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]O[C:6]=2[CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:20]>CN(C)C=O>[O:1]=[C:2]1[CH2:3][CH2:4][CH2:5][C:6]2[NH:20][CH:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7]1=2
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc2c1C(=O)CCC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CCC2
Temperature: 100 °C

Procedure:
To a stirring suspension of 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (28.2 g. 157 mmol) in ethanol (500 mL) under Nitrogen at ambient temperature was added acetyl chloride (56 mL, 783 mmol) dropwise. After stirring 1 h, the solution was then heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was taken up into dichloromethane, washed with aqueous sodium bicarbonate, washed quickly with 1N sodium hyroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford Ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylate as an oil. A mixture of this ester (24.46 g, 117 mmol) and ammonium acetate (15.85 g, 206 mmol) in dimethylformamide (225 mL) was heated at 100° C. under Nitrogen for 1.25 h. The mixture was cooled, poured into ice water, and extracted two times with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue triturated with ether to give Ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11.31 g, 55 mmol) in 5N sodium hydroxide (200 mL) and ethanol (20 mL) was heated at reflux for 1 h. After cooling in an ice bath, the mixture was acididified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried in vacuo to afford 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:10]1[CH:55]=[CH:54][C:13]([CH2:14][C:15]2[C:24]3[C:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][C:20]([CH3:28])([CH3:27])[C:19]=3[CH:18]=[CH:17][C:16]=2[S:29][C:30]2[CH:39]=[CH:38][C:37]3[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:43])([CH3:42])[C:32]=3[C:31]=2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([OH:53])=[O:52])=[CH:47][CH:46]=2)=[CH:12][CH:11]=1)([OH:9])=[O:8].Cl>O.C(O)C.CN(C)C=O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C:15]2[C:24]3[C:23]([CH3:25])([CH3:26])[CH2:22][CH2:21][C:20]([CH3:27])([CH3:28])[C:19]=3[CH:18]=[CH:17][C:16]=2[S:29]([C:30]2[CH:39]=[CH:38][C:37]3[C:36]([CH3:41])([CH3:40])[CH2:35][CH2:34][C:33]([CH3:42])([CH3:43])[C:32]=3[C:31]=2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([OH:53])=[O:52])=[CH:47][CH:46]=2)=[O:2])=[CH:54][CH:55]=1)([OH:9])=[O:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1(C)CCC(C)(C)c2c1ccc(Sc1ccc3c(c1Cc1ccc(C(=O)O)cc1)C(C)(C)CCC3(C)C)c2Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2c1ccc(S(=O)c1ccc3c(c1Cc1ccc(C(=O)O)cc1)C(C)(C)CCC3(C)C)c2Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
A solution of 3.4 g (16 mmol) of sodium periodate in 30 ml of water was added dropwise to 5.3 g (15 mmol) of the thioether from Example 10 in a mixture of 150 ml of ethanol and 40 ml of dimethylformamide at 0° C., and the mixture was then stirred at the same temperature for 2 hours and at room temperature overnight. The reaction solution was then poured into water, the pH was adjusted to 5 with 2N hydrochloric acid, the mixture was extracted with dichloromethane, and the organic extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. Crystallization of the oily residue from ethanol yielded 2.2 g of title compound of melting point 198°-200° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH2:17][OH:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:7]([C:11]1[N:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:13]([CH2:17][OH:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
Potassium carbonate (0.48 g) was added to a solution of 2-butyl-4-chloro-5-hydroxymethylimidazole (prepared as described in U.S. Pat. No. 4,355,040) (0.56 g) and 5-(4'-bromomethylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (1.3 g) in DMF (15 ml) and the mixture was stirred under an atmosphere of argon at 60° C. for 5 hours. The mixture was cooled to ambient temperature, water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined extracts were washed with saturated sodium chloride solution, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole (180 mg) as a pale yellow solid, m.p. 182°-186° C.; NMR (CDCl3) 0.87(t,3H), 1.32(m,2H), 1.65(m,2H), 2.49(t,2H), 4.57(s,2H), 5.15(s,2H), 6.58(d,2H), 6.75(d,2H), 6.90(dd,2H), 7.36(dd,1H), 7.65(m,2H), 7.85(dd,1H), 8.00(dd,2H); mass spectrum (+ve FAB, DMSO/CH3OH/m-nitrobenzyl alcohol): 544 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13].[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:30]=[C:31]2\[CH2:32][CH2:33][C@H:34]3[CH2:39][NH:38][CH2:37][C@@H:36]([C:40]4[CH:45]=[C:44]([F:46])[C:43]([F:47])=[C:42]([F:48])[CH:41]=4)[N:35]3[C:49]\2=[O:50])[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:10][N:11]([CH3:15])[C:12]([N:38]1[CH2:37][C@@H:36]([C:40]2[CH:45]=[C:44]([F:46])[C:43]([F:47])=[C:42]([F:48])[CH:41]=2)[N:35]2[C:49](=[O:50])/[C:31](=[CH:30]/[C:20]3[CH:21]=[CH:22][C:23]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:18]([O:17][CH3:16])[CH:19]=3)/[CH2:32][CH2:33][C@H:34]2[CH2:39]1)=[O:13]
Reactant: COc1cc(/C=C2\CC[C@H]3CNC[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CC[C@H]3CN(C(=O)N(C)C)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
IPEA (0.02 mL) and dimethylcarbamyl chloride (0.006 mL) were sequentially added to a solution of (4R*,9aS*)-7-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}-4-(3,4,5-trifluorophenyl)octahydropyrido[1,2-a]pyrazin-6-one (20 mg) in methylene chloride (3 mL), and the reaction solution was stirred at 0° C. for one hour and at room temperature for five hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate 1:1->ethyl acetate->ethyl acetate:methanol 4:1) to obtain 17 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:17]=1)[C:11](OC)=[O:12].O.[OH-].[Na+]>O1CCCC1>[OH:12][CH2:11][C:10]1[CH:9]=[C:8]([OH:7])[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=1
Reactant: COCOc1cc(O)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cc(O)cc(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
With ice cooling, to a solution of aluminum lithium hydride (1.80 g, 47.5 mmol) in tetrahydrofuran (50 mL) was added dropwise a solution of methyl 3-hydroxy-5-(methoxymethoxy)benzoate (7.74 g, 36.5 mmol) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for 4 hours. To the reaction solution were successively added water (2 mL), a 15% aqueous sodium hydroxide solution (2 mL) and water (7 mL), and the mixture was further stirred for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=5:5) to give the title compound (4.46 g, yield 66%) as an oily matter.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)cnc1Cl
Reaction time: 3 h

Procedure:
Iron (Fe) powder (9.75 g, 0.174 mol, Sigma-Aldrich) was added in portions over a period of 2 h to a stirred solution of 2-chloro-3-methyl-5-nitropyridine (10 g, 0.058 mol, Combi-blocks) in acetic acid/water (29 mL: 88 mL). After 3 h, the reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with aqueous sodium bicarbonate, brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 6-chloro-5-methylpyridine-3-amine as a brown solid (8.0 g; 97%). MS m/z=142.03 [M+H]+.