Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25]([O:27]C)=[O:26])[CH2:6]1)[CH:2]=[CH2:3].O.[OH-].[Li+]>C1COCC1.CO.O>[OH2:18].[CH2:1]([S:4][C@:5]1([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:13])([CH3:14])[CH3:15])[C@H:7]([C:25]([OH:27])=[O:26])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Reaction time: 24 h
Yield: 173.1 %

Procedure:
To a solution of (2S,4R)-methyl 4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylate (362 mg, 0.639 mmol) in THF (5 mL) and MeOH (5.00 mL) was added pre-made solution of lithium hydroxide hydrate (80 mg, 1.916 mmol) in Water (5 mL). The resulting cloudy solution was stirred at room for 24 h. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (312 mg, 0.553 mmol, 87% yield) as a white solid. LC-MS (retention time: 2.96 min, method B), MS m/z 553 (M+H).
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:27](=[O:28])[C:26]([C:29]([NH2:31])=[O:30])=[C:25]([OH:32])[C@:24]2([OH:33])[C@H:5]1[CH2:6][C@H:7]1[C:21]([C:22]2=[O:23])=[C:20]([OH:34])[C:10]2[C:11]([OH:19])=[C:12]([NH2:18])[CH:13]=[C:14]([N:15]([CH3:17])[CH3:16])[C:9]=2[CH2:8]1)[CH3:3].[C:35]1([C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:42][CH:43]=O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(#N)C>CN(C=O)C.CCOCC>[CH3:17][N:15]([CH3:16])[C:14]1[C:9]2[CH2:8][C@@H:7]3[C:21](=[C:22]([OH:23])[C@@:24]4([OH:33])[C@@H:5]([CH2:6]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]([OH:28])=[C:26]([C:29]([NH2:31])=[O:30])[C:25]4=[O:32])[C:20](=[O:34])[C:10]=2[C:11]2[O:19][C:43]([CH:42]=[C:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:18][C:12]=2[CH:13]=1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CN(C)c1cc(N)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCOCC
Product: CN(C)c1cc2nc(C=C(c3ccccc3)c3ccccc3)oc2c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
9-aminominocycline sulfate salt (0.500 g, 0.748 mmol) is dissolved in anhydrous DMF and treated with β-phenylcinnamaldehyde (0.779 g, 3.74 mmol, 5 equivalents) The solution is then treated with DDQ (0.085 g, 0.374 mmol, 0.5 equivalents) and stirred at room temperature for 5 min. ES+ mass spectrometry showed a 1:1 ratio of product and starting material. A second portion of DDQ (0.068 g, 0.300 mmol, 0.4 equivalents) is added. After approximately 5 minutes, acetonitrile (7.5 mL) is added, and the entire reaction mixture is poured slowly into ether (750 mL.) The pink solid is removed by filtration and washed with fresh ether to yield 0.480 g of the crude product. This material is dissolved in water (75 mL) to give a solution at pH 2.2, which is extracted with dichloromethane (2×100 mL.) The pH of the aqueous layer is raised to 3.0 with aqueous ammonia, and the solution is again extracted with dichloromethane (2×100 mL.) The four organic extracts are dried (Na2SO4), filtered and concentrated to a volume of about 2 mL. A small portion of methanol (1 mL) is added, and the concentrated solution is treated dropwise with 1M HCl in ether. The solid precipitate is filtered, washed with fresh ether and dried under vacuum the product as its HCl salt.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][N:13]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]1[NH:23][C:18]2=[CH:19][N:20]=[CH:21][CH:22]=[C:17]2[CH:16]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:38]>>[ClH:38].[ClH:38].[CH3:1][NH:2][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]1[NH:23][C:18]2=[CH:19][N:20]=[CH:21][CH:22]=[C:17]2[CH:16]=1
Reactant: CN(CCON=C(c1ccccc1)c1cc2ccncc2[nH]1)C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCON=C(c1ccccc1)c1cc2ccncc2[nH]1
Product: Cl
Reaction time: 5 h
Yield: 51 %

Procedure:
tert-Butyl methyl[2-[[[phenyl (1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethyl]carbamate (Example 128) (100 mg, 0.25 mmol) in trifluoroacetic acid/CH2Cl2 (2:1, 5 mL) was stirred at ambient temperature. After 5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (35 mL) and washed with saturated NaHCO3 (20 mL) and saturated NaCl (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 89:10:1 CH2Cl2/MeOH/NH4OH). The obtained product was dissolved in EtOAc, an excess of 1 N HCl in Et2O was added and the mixture was concentrated under reduced pressure. The resulting solid was triturated with EtOAc and collected by vacuum filtration to give phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-[2-(methylamino)ethyl]oxime dihydrochloride (46.8 mg, 51%) as an off-white solid (geometry of the oxime double bond undefined): 1H NMR (500 MHz, DMSO-d6) δ 2.63 (3H, s), 3.39 (2H, br s), 4.59 (2H, t, J=4.5 Hz), 6.96 (1H, s), 7.50-7.61 (5H, m), 8.14 (1H, d, J=6.3 Hz), 8.34 (1H, d, J=6.3 Hz), 9.31-9.35 (3H, m), 13.56 (1H, s), 15.28 (1H, br s); ESI MS m/z 295 [C17H18N4O+H]+; HPLC (Method A) 96.6% (AUC), tR=13.5 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.C([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[C:29](Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21]1=[O:37])(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7]/[C:29](=[C:22]2\[C:21](=[O:37])[NH:20][C:28]3[C:23]\2=[CH:24][CH:25]=[CH:26][CH:27]=3)/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.18 g (1.5 mmol) of 4-methoxyaniline and 0.2 g (0.28 mmol) of triethylamine are dissolved in 5 ml of dichloromethane and at 5° C. combined with a solution of 0.45 g (1.5 mmol) of 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone in 10 ml of dichloromethane and then stirred for 3 hours at ambient temperature. After removal of the solvent in vacuo the residue is taken up in ethyl acetate/water. The organic phase is washed with water, dried and the solvent is eliminated in vacuo. Then the mixture is dissolved in 15 ml of methanol, combined with 3 ml of 1N sodium hydroxide solution, stirred for 3 hours at ambient temperature and diluted with water and ethyl acetate. The organic phase is dried and concentrated by evaporation. The residue is heated in ethyl acetate, cooled, then suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]12(O)[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2.CS(O)(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[C:10]12([C:6]3[CH:7]=[C:2]([Br:1])[C:3]([CH3:9])=[CH:4][C:5]=3[OH:8])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cc(O)ccc1Br
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Temperature: 54 °C
Yield: 84.3 %

Procedure:
A mixture of 4-bromo-3-methylphenol (4.68 g, 25 mmol), 1-adamantanol (3.81 g, 25 mmol), and MeSO3H (1.2 mL) in CH2Cl2 (18 mL) was stirred and heated at 54° C. (oil-bath) for 28.8 h. The resulting solution was diluted with CHCl3 (150 mL), washed with H2O, 5% NaHCO3, and brine and dried. The residue obtained on concentration was washed with hot hexane to give 6.77 g (85%) of 2-(1-adamantyl)-4-bromo-5-methylphenol as a white solid, mp 155-156° C. IR 3541, 2905, 2845, 1147 cm−1; 1H NMR δ (CDCl3) 1.77 (bs, 6H, AdCH2), 2.07 (bs, 9H, AdCH and AdCH2), 2.28 (s, 3H, CH3), 4.67 (s, 1H, OH), 6.54 (s, 1H, 6-ArH), 7.30 (s, 1H, 3-ArH).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)C>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:19][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][O:4]1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCO
Product: Clc1ccc(C2(CBr)OCC(c3ccccc3)O2)cc1

Procedure:
A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 8.4 parts of α-hydroxymethyl)benzylalcohol, 0.1 parts of p-toluene sulfonic acid, 210 parts of benzene and 40 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is triturated in methanol. The product is filtered off and crystallized from methanol, yielding 2-(bromomethyl)-2-(p-chlorophenyl)-4-phenyl-1,3-dioxolane; mp. 60°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+]>CO.O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[OH:23])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccccc1
Yield: 83.6 %

Procedure:
A solution of 100 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanone and 23 mg of sodium borohydride in 5 ml of methanol was stirred at rt for 17 h. The mixture was diluted with 4 ml of water and extracted four times with diethyl ether. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum spirit 40°–60° C. for the elution to give 84 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-phenyl-methanol as a colourless gum. Mass spectrum (EI) m/z 440 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC)=O)=[CH:20][CH:19]=3)[CH:9]=2)=[CH:4][CH:3]=1.[NH3:30]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:30])=[O:27])=[CH:20][CH:19]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ccc(Cl)cc3)nc3c2CCC3)cc1
Solvent: CO
Product: Cl
Product: NC(=O)Cc1ccc(Nc2cc(-c3ccc(Cl)cc3)nc3c2CCC3)cc1
Yield: 22 %

Procedure:
Following General Procedure C, ethyl 2-(4-((2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate (0.075 g, 0.18 mmol) was reacted with ammonia in methanol (7 M, 4 mL), followed by the formation of the hydrochloride salt to form the title compound (0.017 g, 22%) as an off-white solid. MW=414.33. 1H NMR (DMSO-d6, 300 MHz) δ 14.03 (s, 1H), 9.80 (s, 1H), 7.83-7.75 (m, 2H), 7.70-7.63 (m, 2H), 7.54 (s, 1H), 7.42-7.30 (m, 4H), 6.98 (s, 1H), 6.94 (s, 1H), 3.42 (s, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.31-2.18 (m, 2H); APCI MS m/z 378 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC)=O)[CH2:19][CH2:18]3)=[N:13][NH:14]2)=[CH:10][CH:9]=1.O>O1CCCC1>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 68.1 %

Procedure:
To a stirred suspension, under nitrogen, of 4.7 g of lithium aluminum hydride (50-55% oil dispersion) in 90 ml of tetrahydrofuran was added, dropwise, 8.9 g of 6-fluoro-3-(1-methoxycarbonyl-4-piperidinyl)-1H-indazole, dissolved in 50 ml of tetrahydrofuran. After the addition was complete, the reaction was heated under reflux for 2 hr. The reaction was cooled in an ice-salt bath and water was carefully added. The mixture was filtered and the filter cake was washed with tetrahydrofuran and twice with not methanol. The filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate to yield 5.1 g (68%) of product, mp 217°-220°. Recrystallization from ethanol (twice) provided the analytical sample, mp 218°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:7][C:6](=[O:8])[CH:5]([CH:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10](O)=[O:11])[O:4]1.[C:23]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:7][C:6](=[O:8])[CH:5]([CH:9]([C:10]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:34])=[O:11])[CH2:13][CH2:14][CH2:15][CH3:16])[O:4]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CCCCC(C(=O)O)C1OC(OC)(c2ccccc2)OC1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C1OC(OC)(c2ccccc2)OC1=O
Reaction time: 8 h
Yield: 50 %

Procedure:
To 2-(2-methoxy-2-phenyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid I-1 (10 mmol; prepared as described in Method I, above) in DMF (50 mL) was added proline O-t-butyl ester (10 mmol), DIEA (25 mmol) and PyBOP (10 mmol) and the solution stirred for 8 h. The reaction was diluted with ethyl acetate and washed with water, sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford 1-(2-methoxy-2-phenyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)pentane 1-2 (5 mmol, 50%).
Reaction SMILES: N1C=CC=CC=1C.Cl[S:9]([OH:12])(=[O:11])=[O:10].[C:13]1([C:19]2[N:20]=[CH:21][C:22]([N:31]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]([NH2:43])=[O:42])[CH:32]([CH3:34])[CH3:33])=[N:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.ClCCl>[C:13]1([C:19]2[N:20]=[CH:21][C:22]([N:31]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]([NH:43][S:9](=[O:11])(=[O:10])[OH:12])=[O:42])[CH:32]([CH3:34])[CH3:33])=[N:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)N(CCCCOCC(N)=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: Cc1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)N(CCCCOCC(=O)NS(=O)(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, a solution of 1.443 g of 2-picoline in 1.7 ml of 1,2-dichloroethane was cooled to −10° C. A solution of chlorosulfonic acid in 3.5 ml of 1,2-dichloroethane was added dropwise at 0° C. or lower and, after stirring for 15 minutes, 712 mg of 2-[4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy]acetamide was added. The reaction solution was heated to 75° C. and air-cooled to room temperature after stirring for 2 hours. The reaction solution was diluted with dichloromethane and then washed in turn with an aqueous 0.6M sodium hydrogen sulfate and water. The reaction solution was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 798 mg of N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic acid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH2:30]>C(O)=O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:30])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=3)(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)O)c2)cc1
Reactant: O
Solvent: O=CO
Product: Cc1cccnc1NS(=O)(=O)c1ccc(CC(=O)c2ccc(O)c(C(=O)O)c2)cc1
Yield: 71 %

Procedure:
A solution of 2-hydroxy-5-[[4-[(3-methyl-2-pyridinylamino)sulfonyl]phenyl]ethynyl]benzoic acid (4.1 g, 0.01 mol) in formic acid (100 ml) was refluxed for 30 h. Water (200 ml) was added and the product crystallized to yield 3.0 g (71%) product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 79 %

Procedure:
As described for example 2b, 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.5 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (143 mg, 79%) which was obtained as a white solid. MS: m/e=364.2 [M+H]+.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:13]#[CH:14].[C:15]1(C)C=CC=C[CH:16]=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Re].[Re]>[C:1]([O:12][CH:13]=[CH2:14])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:15]=[CH2:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C#C
Reactant: Cc1ccccc1
Agent: [Re]
Agent: [C-]#[O+]
Product: C=COC(=O)c1ccc(C(=O)OC=C)cc1

Procedure:
A mixture of 8.0 g of terephthalic acid (48 mmol), 0.10 g of Re2(CO)10 (0.15 mmol) and 17.3 g of toluene was subjected to vinylation at 140° C., a nitrogen pressure of 2 bar and an acetylene pressure of 18 bar for 6 h. Divinyl terephthalate was obtained, which was detectable by means of GC-MS analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:24]([CH3:23])(=[O:26])=[O:25])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccnc(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1ccnc(Cl)c1
Reaction time: 0.17 h
Yield: 107.2 %

Procedure:
To a 0° C. solution of (2-chloro-pyridin-4-yl)-methanol (2.00 g, 13 mmol) (prepared from the corresponding carboxylic acid according to the procedure in U.S. Pat. No. 6,218,537), ethyl acetate (30 mL) and triethylamine (2.9 mL, 21 mmol) was added drop wise methansulfonyl chloride (1.4 mL, 18 mmol). The solution was stirred for 10 minutes and then water (5 mL) was added. The reaction mixture was extracted with three 30 mL portions of ethyl acetate, the organics combined and washed with water (30 mL) and brine (30 mL), dried on sodium sulfate, and concentrated to a crude oil. Pentane was added to the residue and stirred at 0° C. The precipitate was collected and dried in vacuo to give methanesulfonic acid 2-chloro-pyridin-4-ylmethyl ester (3.09 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 10 g of 2-nitro-5-chlorobenzoic acid and 30 mL of N-methylpiperazine is stirred at 120° C. for 6 hours. To the reaction mixture 150 mL of ethyl acetate is added. The precipitated yellow crystalline material is filtered off, dissolved in 15 mL of water. The pH of the mixture is adjusted to 6 with acetic acid. The precipitated material is filtered off, washed with water and dried, to obtain 11.2 g of the title compound. m.p.: 212° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[O:13]([CH2:20][CH:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH:28]([OH:30])=[O:29]>>[C:11]([OH:12])(=[O:13])[C:28]([OH:30])=[O:29].[O:13]([CH2:20][CH:21]1[O:26][CH2:25][CH2:24][N:23]([CH2:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:22]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(OCC2CNCCO2)cc1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: O=CO
Agent: Cl
Product: O=C(O)C(=O)O
Product: c1ccc(OCC2CN(Cc3cnc4ccccc4c3)CCO2)cc1
Reaction time: 6 h

Procedure:
Quinoline-3-carboxaldehyde (447 mg, 2.8 mmol), 2(RS)-(phenoxymethyl)morpholine (500 mg, 2.59 mmol) and anhydrous formic acid (0.1 ml) were heated at 120° C. (oil bath temperature), with stirring, for 6 hours. The reaction mixture was cooled, 2M hydrochloric acid (20 ml) added and the solution washed with ethyl acetate (20 ml). The aqueous was basified to pH=11 with 2M aqueous sodium hydroxide, then extracted with ethyl acetate (2×30 ml). The combined organics were dried (sodium sulphate) then evaporated to give a gum which was purified by column chromatography on silica (200 g) using ethyl acetate to ethyl acetate/methanol (25:1) to afford the title compound free base as a pale yellow gum (340 mg, 36%). The hydrogen oxalate salt had mp 164°-166° C. (ethanol/water). MS CI+, m/z=335 for (M+H)+. 1H NMR (360 MHz, DMSO-d6) δ2.23 (1H, dd, J1 =J2 ==11 Hz), 2.35 (1H, ddd, J1 =3, J2 =J3 =11 Hz), 2.80 (1H, d, J=11 Hz), 2.97 (1H, d, J=11 Hz), 3.61 (1H, ddd, J1 =2, J2 =J3 =11 Hz), 3.80-3.92 (4H, m), 3.96 (2H, d, J=5 Hz), 6.89-6.94 (3H, m), 7.23-7.28 (2H, m), 7.59-7.64 (1H, m), 7.73-7.78 (1H, m), 7.97-8.04 (2H, m), 8.29 (1H, d, J=2 Hz), 8.90 (1H, d, J=2 Hz). Found: C, 63.38; H, 5.84; N, 6.48. C21H22N2O2.C2H2O4.0.5H2O requires C, 63.73; H, 5.81; N, 6.46%.