Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:7][C@@H:6]2[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][O:11][C@@H:5]2[CH2:4][O:3]1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[OH:3][CH2:4][C@@H:5]1[C@H:6]([OH:7])[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH2:10][O:11]1
Reactant: CC1(C)OC[C@H]2OC[C@H](O)[C@H](O)[C@H]2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@H]1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C

Procedure:
To a solution of (−)-(4aR,7S,8S,8aR)-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxine-7,8-diol (22 mg, 0.10 mmol) in MeOH (2 mL) was added a solution of methanolic HCl (0.5 mL, prepared from 0.5 mL conc. HCl in 30 mL of MeOH). The solution was stirred for 1H at ambient temperature. Aqueous saturated NaHCO3 (5 mL) was added and the mixture was diluted with EtOAc (50 mL). The mixture was washed with saturated NaHCO3 (30 mL). The aqueous layer was washed with EtOAc (30 mL×2). The combined organic layers were dried over Na2SO4, and concentrated in vacuo
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[F:17][C:18]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:19]=1[CH:20]=[C:21](Cl)[C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:17][C:18]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:19]=1[CH:20]=[CH:21][C:22]([NH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:5]=1)[CH3:3])=[O:23]
Reactant: O=C(O)C(Cl)=Cc1cc(F)ccc1F
Reactant: C[C@H](N)c1cccc(Nc2ccncc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1cc(F)ccc1F)c1cccc(Nc2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A mixture of (S)-[3-(1-amino-ethyl)-phenyl]-pyridin-4-yl-amine (0.1 mmol), 2.5-difluoro-chlorocinnamic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.1 mmol), triethylamine (0.3 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography with 5% methnol in ethyl acetate to provide the title compound (31 mg) as a solid.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH-].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11]>CO>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:4]2[C:5](=[O:6])[CH2:7][NH:1][C:2]2=[O:3])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C1CNC(=O)N1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CNC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 57.9 %

Procedure:
A solution of hydantoin (5.0 g, Aldrich) in 2N aqu. NaOH (25 ml) was stirred at room temperature for 1 hour, then a solution of p-nitrobenzyl bromide (10.8 g, Aldrich) in methanol (50 ml) was added and the mixture refluxed for 16 hours. The mixture was cooled and the pale yellow precipitate filtered off, dried in vacuo, and recrystalised from ethanol to give the desired product as pale yellow crystals (6.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: COc1ccc(CS(C)=O)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CS(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(methylsulfinylmethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]=1B(O)O.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1.Cl.CCOCC>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[ClH:22].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]=1[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)C1=Cc2ccccc2CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: Cc1nccn1Cc1cc(C2=Cc3ccccc3CC2)cnn1
Reaction time: 12 h
Yield: 60.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.02 g, 0.017 mmol), biphenyl-2-yl-dicyclohexyl-phosphane (0.005 g, 0.014 mmol), K3PO4 (0.21 g, 1 mmol) and 3,4-dihydro-naphthalene-2-boronic acid (0.13 g, 0.7 mmol) were mixed in degassed toluene (2 ml). 5-Chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine (0.1 g, 0.48 mmol) was added and the mixture was refluxed for 24 hours. After further addition of tetrakis(triphenylphosphine)palladium (0.02 g, 0.017 mmol), biphenyl-2-yl-dicyclohexyl-phosphane (0.005 g, 0.014 mmol) and 3,4-dihydro-naphthalene-2-boronic acid (0.13 g, 0.7 mmol) reflux was continued for another 12 hours. After removal of the solvent in vacuo the residue was dissolved in AcOEt, washed with H2O, dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed over silica gel [gradient CH2Cl2 to 40% (CH2Cl2—MeOH—NH4OH 90:10:1)] to provide a white foam which was dissolved in MeOH (2 ml). HCl-Et2O was added to provide the title compound (0.098 g, 40%) as a light yellow solid, MS: m/e=303.3 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[N:34]=[N:35][NH:36][N:27]=4)[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Yield: 44.9 %

Procedure:
Heat a mixture of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-3-cyano-benzenesulfonamide (1.00 g, 2.15 mmol), sodium azide (1.40 g, 21.5 mmol), and ammonium chloride (1.15 g, 21.5 mmol) in dimethylformamide (10 mL) at 110° C. overnight. Cool the reaction to room temperature and dilute with water (120 mL). Filter the resulting mixture, wash the filtered material several times with water and dry. Dissolve the residue in hot acetone (20 mL) and purify via chromatography, eluting with 1:1 hexanes:acetone with 1% acetic acid to afford the title compound as a tan solid (490 mg, 45%): 1H NMR (DMSO-d6) δ 0.80 (t, 3H), 1.42 (sextet, 2H), 2.49 (s, 3H), 2.50 (t, 2H), 5.16 (s, 2H), 6.59 (d, 1H), 7.10 (d, 1H), 7.12 (d, 1H), 7.24 (s, 1H), 7.25 (t, 1H), 7.70 (d, 1H), 7.73 (t, 1H), 7.87 (d, 1H), 8.22 (d, 1H), 8.49 (s, 1H), 10.56 (s, 1H), 12.82 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 506 (100).
Reaction SMILES: [P:1]([O-:16])([O-:15])([O:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:14])[C:11]=2[Cl:13])[NH:6][CH:5]=1)=[O:2]>CN(C)C=O>[CH:8]1[C:7]2[NH:6][CH:5]=[C:4]([O:3][P:1]([OH:15])([OH:16])=[O:2])[C:12]=2[C:11]([Cl:13])=[C:10]([Br:14])[CH:9]=1
Reactant: O=P([O-])([O-])Oc1c[nH]c2ccc(Br)c(Cl)c12
Solvent: CN(C)C=O
Product: O=P(O)(O)Oc1c[nH]c2ccc(Br)c(Cl)c12

Procedure:
50 mg/ml 5-bromo-4-chloro-3-indolyl phosphate in dimethyl formamide
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:6]([C:7]([NH:9]O)=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][N:9]=[C:7]([OH:8])[C:6]=2[CH:11]=1
Reactant: O=C(NO)c1cc(F)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Oc1noc2ccc(F)cc12
Reaction time: 1 h

Procedure:
To a suspension of 2.44 g of 5-fluorosalicylhydroxamic acid in 22 ml of tetrahydrofuran is added 1.83 g of thionyl chloride at 10° C., and they are subjected to reaction at 20°-25° C. for one hour. Subsequently, at 10°-15° C., 4.67 g of triethylamine is dropped over 30 minutes, and thereafter, reaction is effected at 20°-25° C. for one hour. To the reaction mixture is added 200 ml of water, and the pH is adjusted to 3 with 2N hydrochloric acid. The crystals precipitated are collected by filtration to obtain 1.32 g of colorless, crystalline 5-fluoro-3-hydroxy-1,2-benzoisoxazole having a melting point of 201°-203° C.
Reaction SMILES: [CH:1]([NH:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:3])[CH3:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)CCl.[OH-].[Na+]>[C:16]([N:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)N(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1

Procedure:
A mixture of 3,4-dichlorobenzoic acid, 2-isopropylhydrazide (0.98 g, 0.004 mole) and benzoyl chloride (0.56 g, 0.004 mole) is stirred overnight in 1.2 mL of ethylene dichloride and 6.5 mL of 10% sodium hydroxide. The organic phase is removed and the aqueous mixture is extracted with 25 mL of ethylene dichloride. The organic extracts are combined and concentrated to a yellow oil which is taken up in hot isopropyl alcohol. Cooling the alcohol solution causes precipitation of the title compound as a white crystalline product, which is collected by filtration and has a mp of 157° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[N:30]([CH2:31][C:32]([OH:34])=[O:33])[N:29]=[N:28][N:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8](=[O:9])[NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[N:30]([CH2:31][C:32]([OH:34])=[O:33])[N:29]=[N:28][N:27]=3)=[CH:3][N:4]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: O=C(O)Cn1nnnc1S
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nnnn3CC(=O)O)s2)c(C(=O)C2CCCC2)c1
Yield: 27.9 %

Procedure:
(5-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-tetrazol-1-yl)-acetic acid (136 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and (5-mercapto-tetrazol-1-yl)-acetic acid (320 mg, 2 mmol) following the general procedure Y.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:18][CH2:17][O:16][CH2:15][CH:14]1[CH2:19][OH:20].[OH-].[Li+]>>[O:13]1[CH2:18][CH2:17][O:16][CH2:15][CH:14]1[CH2:19][O:20][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC1COCCO1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC2COCCO2)nc1
Yield: 58 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 58% yield starting from ethyl 6-chloronicotinate and 1,4-dioxan-2-ylmethanol. The reduction was performed using 3 equiv of lithium hydroxide. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, 1 H), 8.14 (dd, 1 H), 6.93 (d, 1 H), 4.28-4.32 (m, 2 H), 3.84-3.92 (m, 1 H), 3.72-3.83 (m, 2 H), 3.56-3.69 (m, 2 H), 3.44-3.55 (m, 1 H), 3.35-3.42 (m, 1 H); S (ESI) m/z 240[M+H+], m/z 238[M−H+];
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[S:27]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:34])[CH3:33])=[CH:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:34][CH:32]([C:29]1[CH:30]=[CH:31][S:27][CH:28]=1)[CH3:33]
Reactant: CC(N)c1ccsc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccsc1
Yield: 52.8 %

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with (±)-1-thiophen-3-yl-ethylamine (prepared as described in J. Heterocycl. Chem. 1988, 25, 1571-1581) (90 mg, 0.70 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to give (±)-7-chloro-6-(1-thiophen-3-yl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 53%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[S:11]1[C:15]2[C:16]([CH2:20][OH:21])=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.C(N(CC)CC)C.[Cl-].[NH4+]>C(Cl)Cl>[S:11]1[C:15]2[C:16]([CH:20]=[O:21])=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: OCc1cccc2nnsc12
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cccc2nnsc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (7.03 mL, 83.0 mmol) in methylene chloride (50 mL) was added dimethyl sulfoxide (8.84 mL, 125 mmol) and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added 1,2,3-benzothiadiazol-7-ylmethanol (6.90 g, 41.5 mmol) at −78° C. and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (35.0 mL, 249 mmol) at −78° C. and the mixture was stirred for 30 min. The reaction mixture was warmed to room temperature, and stirred at room temperature for 4 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (methylene chloride/hexane) to give the title compound (6.20 g, yield 91%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])=[CH:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Xe](F)[F:29]>C(#N)C.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])=[C:21]([F:29])[N:22]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: F[Xe]F
Reactant: CC(C)C(=O)c1cnc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)C(=O)c1[nH]c(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)nc1F
Yield: 13.2 %

Procedure:
To a solution (13 mL) of 1-(2-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-1H-imidazol-5-yl)-2-methylpropan-1-one (0.507 g) in acetonitrile was added xenon difluoride (0.440 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60, volume ratio) and recrystallized from diethyl ether-hexane to give the title compound (0.07 g, yield 13%) as colorless crystals. melting point 161-162° C.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:12]=2)[CH:7]=[C:6]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:5]=1)([CH3:3])=[CH2:2]>[Pt]>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:12]=2)[CH:7]=[C:6]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1nc(Nc2cc(C)[nH]n2)cc2cc(OC)c(OCCOC)cc12
Agent: [Pt]
Product: COCCOc1cc2c(C(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [1-Isopropenyl-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (120 mg) and 10% Pt/C (12 mg) was sealed in high-pressure bottle under 40 psi of H2 and stirred overnight at room temperature. Then the mixture was filtered and the organic layer was concentrated to give [1-Isopropyl-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: 371 (MH+).
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.Br[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[C:29]2=[O:36]>>[O:35]=[C:30]1[C:29](=[O:36])[C:28]2[C:32](=[CH:33][CH:34]=[C:26]([C:12]#[C:11][C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:27]=2)[NH:31]1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc3c(c2)C(=O)C(=O)N3)c1)c1ccccc1
Yield: 22.2 %

Procedure:
In a manner similar to that described in Example 443, (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 5-bromoisatin (116 mg, 0.46 mmol) were reacted to give the title compound as a reddish oil (40 mg).
Reaction SMILES: [CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=3)=[CH:4][C:3]=2[O:2]1.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]1[O:18][C:17]2[CH:16]=[CH:15][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([CH:11]=[N:20][NH:21][C:22]([NH2:24])=[O:23])=[CH:9][CH:8]=3)=[CH:4][C:3]=2[O:2]1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=Cc1ccc(Oc2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a solution of 4-(3,4-methylenedioxyphenoxy)benzaldehyde (1.7 g, 7.0 mmol) in ethanol (40 mL) was added a solution of semicarbazide hydrochloride (0.82 g, 7.1 mmol) and sodium acetate (0.55 g, 6.7 mmol) in water (10 mL). The mixture was stirred at room temperature for 30 min. The resulting white solid was collected by filtration, washed with water and dried in vacuo to yield the title compound (1.2 g, 4.0 mmol, 57%), mp: 225-226° C. 1H NMR (DMSO-d6): δ 10.17 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=8.7, 2H), 6.93 (d, J=8.3, 1H), 6.92 (d, J=8.7, 2H), 6.77 (d, J=2.4, 1H), 6.53 (dd, J=2.4, 8.3, 1H), 6.44 (s, 2H), 6.06 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N(C)C(=O)C2C=C(C=O)C=CC=2OCC2C=CC=CC=2)C=CC=CC=1>>[CH2:28]([N:27]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:16]([CH:18]=[O:19])=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(C(=O)O)c(OCc2ccccc2)c1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CN(C(=O)c1cc(C=O)ccc1OCc1ccccc1)c1ccccc1
Product: O=Cc1ccc(C(=O)N(Cc2ccccc2)Cc2ccccc2)c(OCc2ccccc2)c1

Procedure:
N,N-dibenzyl-2-benzyloxy-4-formylbenzamide was prepared from 2-benzyloxy-4-formylbenzoic acid (146 mg, 1 eq) and dibenzylamine (0.22 mL, 2 eq) using the same procedure as for N-phenyl-N-methyl-2-benzyloxy-5-formylbenzamide. The product was obtained as a brown oil (236 g, 95%). 1H NMR (CDCl3) δ9.96 (s, 1H, O═C—H), 5.24 (m, 3H, OCH2Ph and NCH2Ph), 4.33 (d, 1H, NCH2Ph), 4.11 (m, 2H, NCH2Ph).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([CH2:14][O:15]C(=O)C)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](I)[CH2:26][CH:27]([CH3:29])[CH3:28].C(Cl)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([CH2:14][OH:15])[N:10]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)CCI
Reactant: COC(=O)c1cccc2[nH]c(COC(C)=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1nc(CO)n2CCC(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-acetoxymethyl-1H-benzoimidazole-4-carboxylic acid methyl ester (2.09 g, 8.42 mmol) and cesium carbonate (4.1 g, 12.6 mmol) in DMF (15 mL) at ambient temperature was added isoamyl iodide (1.34 mL, 10.1 mmol). The mixture was stirred overnight and DMF was removed in vacuo. The residue was suspended in water and extracted with ethyl acetate (twice), the combined organic phases were washed with brine, dried (MgSO4) and concentrated. The residue (2-acetoxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-4-carboxylic acid methyl ester) was dissolved in methanol (20 mL) and cooled to 0° C., followed by the addition of acetyl chloride (6.0 mL, 84 mmol) and slowly allowed to reach room temperature. After stirring for 3 hrs the volatiles were removed in vacuo and the residue triturated in ethyl acetate to afford 2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-4-carboxylic acid methyl ester after filtration (1.98 g, 85% over 2 steps) as a white solid. 1H NMR Analysis of the crude acetate indicated that the desired N-1 regioisomer was contaminated with the N-3 isomer (ca. 15%), which was efficiently eliminated by the ethyl acetate wash (<2%). The 1H NMR spectral data of the regioisomeric impurity 2-acetoxymethyl-3-(3-methyl-butyl)-3H-benzoimidazole-4-carboxylic acid methyl ester matched those of an authentic sample prepared via an independent route.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][N:12]=[CH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:9][C:8](=[O:24])[NH:7][C:6]1=[O:25])[CH:2]([CH3:4])[CH3:3].[CH:26](=O)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.N1CCCCC1.C(O)(=O)C>CN(C)C=O.C(O)(C)C>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[C:9]2[C:8](=[O:24])[NH:7][C:6]1=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: O=Cc1ccncc1
Reactant: CC(C)Cn1c(NN=Cc2cccc3ccccc23)cc(=O)[nH]c1=O
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
1-naphthaldehyde (3-isobutyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (3.4 g) was dissolved in a solution of dimethylformamide (99 ml) and isopropanol (24 ml). isonicotinaldehyde (1.3 g) was added followed by piperidine (0.99 ml) and acetic acid (0.12 ml) The mixture was stirred at room temperature for 18 hours. Solvents were removed under reduced pressure. Crude residue was crystallized in methanol/water to give the title compound (3.28 g). Mass: 425.95 (M+H).