Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:11][CH2:10][CH2:9]O1.[I:20](O)(=O)=O>>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[CH:11][CH2:10][CH2:9][I:20]
Reactant: [O-][I+2]([O-])O
Reactant: Cc1ccccc1C1(c2ccccc2C)CCCO1
Product: Cc1ccccc1C(=CCCI)c1ccccc1C

Procedure:
A solution of 2,2-di-(2-tolyl)-tetrahydrofuran 33a (40 g) in 57% aqueous iodic acid (250 mL) was boiled under reflux for 30 min. The cooled solution was extracted wiyh diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo. The residue was subjected to CC (n-heptane/ethyl acetate 15:1) to give the title compound 36a as an oil (44 g). 1H NMR (CDCl3) δ2.10 (s,3H), 2.30 (s,3H), 2.65 (q,2H), 3.19 (t,2H), 5.73 (t,1H), 7.05-7.22 (m,8H)
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[C:21]([CH3:31])([CH3:30])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-:32].[Na+]>CCO.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:28]([NH2:29])=[O:32])[CH:26]=4)[C:21]([CH3:31])([CH3:30])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(C#N)cc21
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(C(N)=O)cc21

Procedure:
1-(7-Fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (80 mg, 0.195 mmol) in EtOH (3 mL) was treated with sodium hydroxide (156 mg, 3.91 mmol) in water (1.0 mL). The reaction was heated at reflux for 3 h. After this time the reaction was evaporated in vacuo. Reverse phase HPLC (10% to 60% acetonitrile in water) gave 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (1H, ddd, J=4.8, 1.8, 1.1 Hz), 8.34 (1H, d, J=1.8 Hz), 7.99-8.06 (1H, m), 7.80-7.96 (4H, m), 7.48-7.61 (2H, m), 7.31 (1H, br. s.), 6.61 (1H, d, J=1.8 Hz), 3.90-3.99 (1H, m), 3.85 (1H, d, J=9.4 Hz), 2.27 (3H, s), 1.53 (3H, s), 1.45 (3H, s). Mass Spectrum (ESI) m/e=428 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]([C:23]1[O:27][C:26]([CH3:28])=[C:25]([C:29](Cl)=[O:30])[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[O:27][C:26]([CH3:28])=[C:25]([C:29]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:30])[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)Cl
Product: Cc1oc(C(C)(C)C)cc1C(=O)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 29 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 5-tert-butyl-2-methylfuran-3-carbonyl chloride to afford the title compound (25 mg, 29%). 1H-NMR (δ, ppm, DMSO-d6): 1.25 (s, 9H, t-Bu), 3.29 (s, 3H, Me), 6.47 (d, 1H, HPy,5, J=6.0 Hz), 6.64 (s, 1H, Hfur), 6.86 (d, 1H, Harom, J=8.0 Hz), 7.38 (t, 1H, Harom, J=8.0 Hz), 7.57 (t, 1H, Harom, J=2.2 Hz), 7.61 (d, 1H, Harom, J=8.0 Hz), 7.79 (d, 1H, HPy,6, J=6.0 Hz), 9.68 (s, 1H, NHamide), 11.18 (s, 1H, NHPy3), 11.37 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C22H23N4O4: 407.1719; found: 407.1721.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[Cl:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][Cl:10])=[CH:4][C:3]=1[F:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cnc(Cl)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: Fc1cc(CCl)cnc1Cl
Yield: 52.6 %

Procedure:
1.00 g (6.87 mmol) of 6-chloro-5-fluoro-3-methylpyridine (F. L. Setliff, Organic Preparations and Procedures International 1971, 3, 217-222), 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2′-azobis(2-methylpropanenitrile) in 100 ml of chlorobenzene are boiled under reflux for 2 days. After about 16 and 32 hours, in each case a further 1.01 g (7.56 mmol) of N-chlorosuccinimide and 0.11 g (0.69 mmol) of 2,2′-azobis(2-methylpropanenitrile) are added. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:20) gives 0.65 g (53% of theory) of 6-chloro-3-chloromethyl-5-fluoropyridine.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:43][C:44]1[CH:45]=[C:46]([C@@H:51]([O:55][C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[N:61]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[N:60]=[CH:59]3)[C@@H:52]([NH2:54])[CH3:53])[CH:47]=[CH:48][C:49]=1[CH3:50]>CN1C(=O)CCC1>[CH3:43][C:44]1[CH:45]=[C:46]([C@@H:51]([O:55][C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[N:61]([C:65]2[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=2)[N:60]=[CH:59]3)[C@@H:52]([NH:54][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:9])[CH3:53])[CH:47]=[CH:48][C:49]=1[CH3:50]
Reactant: Cc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1C
Reactant: Cc1cnc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cnc(C(=O)N[C@@H](C)[C@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)c2ccc(C)c(C)c2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-methyl-1,3-thiazole-2-carboxylic acid (29 mg, 0.2 mmol) was dissolved in NMP (1 mL) together with HATU (76 mg, 0.2 mmol) and DIEA (133 uL, 0.8 mmol). The mixture was stirred in r.t. for 5 min before (1R,2S)-1-(3,4-dimethylphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (58 mg, 0.15 mmol, prepared analogously to Example 6a with corresponding starting material) was added. The reaction mixture was stirred in r.t. overnight before it was evaporated under reduced pressure and purified by semi-prep. HPLC.
Reaction SMILES: [OH-].[K+:2].[NH2:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5][C:6]([OH:8])=[O:7].C(O)C>O>[NH2:3][CH:4]([C:9]([O-:11])=[O:10])[CH2:5][C:6]([O-:8])=[O:7].[K+:2].[K+:2]
Reactant: NC(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(CC(=O)[O-])C(=O)[O-]

Procedure:
Potassium hydroxide 11.3 g was added to a suspension of 13.3 g DL-aspartic acid in a mixed solvent of 60 ml ethyl alcohol and 60 ml water to form a solution of dipotassium DL-aspartate. To the ice-cooled resultant solution a solution of lauric acid-sulfuric acid mixed acid anhydride and 10 ml of 10 N potassium hydroxide was added dropwise simultaneously with stirring. While the pH was controlled to 12 stirring at room temperature was then continued for 1 hour. The reaction mixture was treated in the similar manner as in Example 3 to obtain 14.3 g crude crystals of N-lauroyl-DL-aspartic acid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:10]([CH2:14][CH3:15])([OH:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:5]1[N:6]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:10]([CH2:14][CH3:15])([OH:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(O)(CC)CC)c(C(=O)OCC)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(C(O)(CC)CC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 52.1 %

Procedure:
Following a procedure similar to that described in Example 18(a), but using 0.75 g of ethyl 2-butyl-4-(1-ethyl-1-hydroxypropyl)imidazole-5-carboxylate (prepared as described in Preparation 13), 0.12 g of sodium hydride (as a 55% w/w dispersion in mineral oil) and 1.51 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, there were obtained 1.05 g of the title compound as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl[C:20]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][N+:21]=1[O-].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(N)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2 g, 8 mmol), 2-chloro-4-nitro-pyridine oxide (2.2 g, 12 mmol) and Cs2CO3 (5.7 g, 18 mmol) were mixed in DMF (50 mL) and stirred at room temperature for 1 h. Water was added and the reaction mixture was adjusted to pH 3. The reaction mixture was extracted with ethyl acetate. The organic layers were concentrated to give a residue. The residue was purified by flash column chromatography (dichloromethane:methanol=15:1) to give the title compound (0.77 g, 29%) as a brown solid. MS found (electrospray): (M+H)+=389.1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1ncnc(Cl)c1-c1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2ncnc(Cl)c2-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 63.2 %

Procedure:
To a mixture of 4,6-dichloro-5-phenylpyrimidine (675 mg, 3.0 mmol), 4-chlorophenylboronic acid (704 mg, 4.5 mmol) and tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) in toluene (10 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 3 mL, 6 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 5 h, after which time analysis by HPLC/MS indicated that the the reaction was complete. After cooling the reaction mixture to room temperature, water (15 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain 571 mg of the title compound as a white solid. HPLC/MS: retention time=3.85 min, [M+H]30 =301.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Br)=[O:5].[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH3:12].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: Cc1ccccc1C(=O)Br
Reactant: CCOc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1ccccc1NC(=O)c1ccccc1C
Temperature: 40 °C
Yield: 94.5 %

Procedure:
A 19.9 g (0.1 mol) portion of o-methylbenzoyl bromide was added dropwise with cooling to a mixture of 13.7 g (0.1 mol) of o-ethoxyaniline and 8.4 g (0.1 mol) of sodium bicarbonate in 200 ml of acetone with stirring. After addition of the o-methylbenzoyl bromide, the reaction mixture was warmed to 40°C and the mixture was refluxed and stirred for another 40 hours. After filtering, the ether was distilled from the reaction mixture and the residual material was re-dissolved in ether and washed with water. The ether layer was dried over anhydrous sodium sulfate, the ether was removed and the product was distilled to obtain 24.1 g (94.5%) of a clear pink liquid having a boiling point of 148°C/0.04 mm Hg and nD20 of 1.5929. IR cm-1 (film) νNH 3295(S), νCO 1655,1615(S).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](C(OC(C)(C)C)=O)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[N:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:30])[C:11]=2[CH2:31][O:32]C(=O)C)[CH:9]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:26]([C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:30])[N:16]([C:12]1[C:11]([CH2:31][OH:32])=[C:10]([C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][CH:7]=3)[CH:15]=[CH:14][CH:13]=1)[N:25]=[CH:24]2)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2COC(C)=O)cn1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4c[nH]c(C(=O)O)c4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
To a solution of 4-[2-acetoxymethyl-3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-phenyl]-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (136 mg, 0.24 mmol) in 5 mL of dioxane and 5 mL of water was added NaOH (40 mg) and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure. The residue was dissolved in 8 mL of water, and acidified with 1 N HCl to pH 3-4. The mixture was extracted with ethyl acetate (5 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 4-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrole-2-carboxylic acid (99 mg, yield 100%). LC-MS calcd for C24H23N3O4 (m/e) 417.17, obsd 418 [M+1]+.
Reaction SMILES: [SH:1][CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])=[O:4].[OH-:18].[Na+].II>O.C(O)C>[O:18]=[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])[CH2:2][S:1][S:1][CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])=[O:4]
Reactant: [OH-]
Reactant: O=C(O)C1CCc2ccccc2N1C(=O)CS
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2ccccc2N1C(=O)CSSCC(=O)N1c2ccccc2CCC1C(=O)O

Procedure:
(±)-1,2,3,4-Tetrahydro-1-(2-mercapto-1-oxoethyl)-2-quinolinecarboxylic acid (3 g) was suspended in water (40 ml) and the pH was adjusted to 6.5 with 2 N sodium hydroxide. A saturated solution of iodine in ethanol was then added dropwise while maintaining the pH at 6.5 by the slow addition of 2 N sodium hydroxide. When a yellow color remained for at least five minutes, addition of the iodine solution was terminated and the yellow color was discharged with saturated aqueous sodium thiosulfate. The mixture was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with 10% hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The (±) 1,1'-[dithiobis(1-oxo-2,1-ethanediyl)]-bis-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid was recrystallized from ethyl acetate; yield 0.7 g, m.p. 172°-174°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([S:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[C:16]([NH:15][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:21]=2)=[CH:25][CH:26]=1
Reactant: Nc1cc(OCc2ccc(Cl)cc2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(OCc4ccc(Cl)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (85 mg, 0.41 mmol) was reacted with the product from Example 143a (146 mg, 0.41 mmol) for 26 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (89 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H) 1.83 (sext, J=7.35 Hz, 2H) 3.00 (dd, J=7.35 Hz, 2H) 5.13 (s, 2H) 6.27 (d, J=6.99 Hz, 1H) 6.64 (d, J=8.82 Hz, 2H) 7.05-7.25 (m, J=8.45 Hz, 4H) 7.48 (m, 4H) 7.83 (d, J=8.45 Hz, 1H) 8.40 (d, J=6.99 Hz, 1H) 9.00 (d, J=8.46 Hz, 1H) 9.78 (s, 1H) 11.03 (br s, 1H) 14.40 (br s, 1H); MS (ESI+) m/z, 528, 530 (M+H−TFA)+; (ESI−) m/z, 526, 528 (M−H−TFA)−.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:51]([C:53]1[CH:60]=[CH:59][C:56]([CH:57]=O)=[CH:55][CH:54]=1)#[N:52]>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH2:57][C:56]1[CH:59]=[CH:60][C:53]([C:51]#[N:52])=[CH:54][CH:55]=1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccc(C#N)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 42.3 %

Procedure:
The title compound was prepared by a similar method to example 5 from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (400 mg, 0.82 mmol), sodium triacetoxyborohydride (260 mg, 1.22 mmol) and 4-cyanobenzaldehyde (120 mg, 0.9 mmol) The product was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (92:7:1) gradually increasing polarity to dichloromethane:methanol:ammonia (90:10:1), which gave the title compound (210 mg) as a foam. MS: 606 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[S:11][C:9]3=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>>[CH3:1][C:2]1[C:7]2[N:8]3[CH2:13][CH:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[S:11](=[O:25])[C:9]3=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc2nc3n(c12)CC(c1ccccn1)S3
Product: Cc1cccc2nc3n(c12)CC(c1ccccn1)S3=O
Yield: 70 %

Procedure:
In a similar manner to Example 4 2,3-dihydro-5-methyl-2-(2-pyridyl)thiazolo[3,2-a]-benzimidazole (1.07 g) was reacted with m-chloroperoxybenzoic acid to give the title compound (0.74 g, 70%) mp 148.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[C:20]2[CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:19]3[C:23]([CH3:24])=[N:22][N:21]=[C:20]3[CH2:25][N:26]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:8]=2[CH:18]=1)([O-:3])=[O:2]
Reactant: Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 4, 5-nitro-2'-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone was heated in ethanol with hydrazine hydrate to give 8-nitro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH3:20][NH:21][C:22](=S)[NH:23][NH2:24]>C(O)C>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:22]([NH:21][CH3:20])=[N:23][N:24]=3)[N:14]=2)[CH:8]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CNC(=S)NN
Solvent: CCO
Product: CCN(C(C)=O)c1cccc(-c2ccc3nnc(NC)n3n2)c1
Yield: 26.7 %

Procedure:
A solution of 7.0 g N-ethyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 5.3 g 4-methyl thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours. The mixture was worked up and the product chromatographed as described in Example 70. Recrystalization of the product fractions from dichloromethone-hexane afforded 2.1 g of yellow crystals, mp 193°-195° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[C:13]1([C:5]2[CH2:4][C:3]3[C:7]([CH:6]=2)=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=3[CH3:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c2c1C=C(c1ccccc1)C2
Temperature: -20 °C

Procedure:
20 ml of triethylamine, 2.88 g (20 mmole) of 4,7-dimethyl-indene, 4.08 g (20 mmole) of iodobenzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 12 h. After it all the triethylamine was removed under reduced pressure. The residue was treated with the mixture 50 ml of water and 50 ml of diethyl ether. Etherial layer was separated, washed twice with water, filtered and dried over Na2SO4. Ether was removed and some 20 ml of pentane were added to the reaction mixture. It was cooled down to −20° C. and product was crystallized as white crystals, which were filtered, washed with small portion of cold pentane and dried in vacuum. The yield of product was 38%.