Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH2:20]([N:27]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCC.CCOCC>[CH2:20]([N:27]1[CH2:31][CH2:30][C:29]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:8])=[O:7])([OH:32])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1C1(O)CCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of N-(tert-butyl)benzenesulfonamide (536 mg, 0.00251 mol) in ether (10 mL, 0.1 mol) was added 1.7 M of tert-butyllithium in pentane (4.4 mL) under nitrogen at −78° C. The mixture was stirred at −78 Celsius for 15 min, then at 0 Celsius for 1 hour, and then cooled down to −78 Celsius again. A solution of 1-benzylpyrrolidin-3-one (400.0 mg, 0.002283 mol) in ether (3 mL) was added to the above solution. The reaction solution was stirred at ±78 Celsius for 2 hours, then quenched with saturated NH4Cl aqueous solution, and then extracted with EtOAc. The organic phase was washed with brine, then dried over MgSO4. The residue was purified by flash chromatography on silica gel column with 30% AcOEt in hexanes to give the desired compound (350 mg, 39% yield). MS (ESI): 389.1 (M+
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])[CH:4]=[CH2:5].[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])/[CH:4]=[CH:5]/[C:28]1[CH:27]=[N:26][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:30][CH:29]=1
Reactant: Brc1ccc(Nc2ccccc2)nc1
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(Nc2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (from Example 76 (a)) was taken up in propionitrile (50 mL). To this solution was added with stirring 2-phenylamino-5-bromopyridine (1.3 g, 5.2 mmole), DIEA (1.8 mL, 10 mmole), Pd(OAc)2 (112 mg, 0.5 mmole) and P(o-tol)3 (304 mg, 1.0 mmole). The reaction was purged with argon then stirred at reflux for 16 h. After cooling to room temperature the reaction was concentrated to dryness under vacuum. Flash chromatography on silica gel (5% methanol/CHCl3) followed by a second flash column on silica gel (50-70% EtOAc/CHCl3) left a residue that was triturated with EtOAc/petroleum ether. Filtration and drying under vacuum gave the title compound (1.42 g, 69%) as an off-white powder: MS (ES) m/e 396.20 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][C:15]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[CH3:24][S:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([CH:12]2[CH2:17][CH2:16][C:15]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][CH2:13]2)[C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([S:25][CH3:24])[CH:27]=2)=[O:34])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CNC2CCC3(CCCCC3)CC2)cc1
Reactant: CSc1cccc(N=C=O)c1
Solvent: CC#N
Product: COC(=O)c1ccc(CN(C(=O)Nc2cccc(SC)c2)C2CCC3(CCCCC3)CC2)cc1
Reaction time: 48 h
Yield: 44.2 %

Procedure:
The above 4-(spiro[5.5]undec-3-ylaminomethyl)benzoic acid methyl ester (1.02 g, 3.2 mmol) was added acetonitrile (50 mL) and 3-(methylthio)phenylisocyanate (668 mg, 4 mmol). Upon stirring for 2 days, the reaction appeared incomplete as shown by HPLC, so another portion of 3-(methylthio)phenylisocyanate (240 mg) was added. After stirring for 2 hours the solvent was evaporated. The residue was taken up in dichloromethane (2 mL) and purified by chromatography on silica using dichloromethane as eluent affording 4-[3-(3-methylsulfanylphenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]benzoic acid methyl ester (680 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[S:16][CH:15]=[C:14]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:13]=2)=[O:11])=[CH:8][CH:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+].CO>C(OCC)(=O)C>[OH:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[S:16][CH:15]=[C:14]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:13]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1ccc(C(=O)c2cc(S(N)(=O)=O)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NS(=O)(=O)c1csc(C(=O)c2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 0.1 %

Procedure:
14 mg (41.3 mmol) of 5-(4-acetoxymethylbenzoyl)-3-thiophene sulfonamide and 9 mg (61.8 mmol) of K2CO3 were added to 3 mL of methanol. After stirring at rt for 11 h the solution was diluted with ethyl acetate and washed with 1N HCl followed with water (2×) and brine. The solvent was removed under vacuum to afford 12.5 mg of 5-(4-hydroxymethylbenzoyl)-3-thiophene sulfonamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:13](O)[CH3:14]>>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH3:14]
Reactant: CCO
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1cc(Br)ccc1N

Procedure:
As in scheme 1 step 1, from 2-amino-5-bromobenzoic acid, ethanol and HCl gas and heating under reflux for 16 h to afford an off-white solid, mp 83° C.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C(N(CC)CC)C.[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](Cl)=O)[CH2:19][CH2:18]1)=[O:16]>O1CCCC1>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: CC(N)=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](c2nc(C)no2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of acetamide oxime (0.19 g, 2.6 mmol) and triethylamine (0.36 ml, 2.6 mmol) in tetrahydrofuran (24 ml) was added trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (0.50 g, 2.4 mmol) at 0-5° C. After completed addition the cooling bath was removed, and the mixture was stirred for 30 minutes. The precipitated ammonium salts were removed by filtration and washed with tetrahydrofuran. The filtrate was concentrated to dryness. The residue was redissolved in 1,4-dioxane (24 ml). The mixture was treated with a catalytic amount of toluene-4-sulfonic acid monohydrate and heated at reflux over night (16 h). The solvent was evaporated. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.48 g, 88%) as light brown oil. MS m/e: 225 ([M+H]+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][CH:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16]>ClCCl>[CH3:14][CH:15]([S:17]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:19])=[O:18])[CH3:16]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of piperazine (1 g) and triethylamine (1.78 mL) in dichloromethane (20 mL) at 0° C. was added dropwise 2-propanesulfonyl chloride (1.30 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into dichloromethane (2×40 mL). The combined organic layers were washed with saturated aqueous brine solution (2×40 mL), dried (MgSO4) and concentrated to afford 1-(propane-2-sulfonyl)-piperazine as a white solid (1.87 g, 84%).
Reaction SMILES: Cl.Cl.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([C@@:24]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[CH3:25])=[CH:23][C:16]=3[N:15]=2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].C(N(CC)CC)C.[CH3:47][C:48]1[CH:65]=[CH:64][C:51]([C:52](OC2C=CC([N+]([O-])=O)=CC=2)=[O:53])=[CH:50][CH:49]=1>C(Cl)Cl>[CH3:47][C:48]1[CH:65]=[CH:64][C:51]([C:52]([NH:5][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][C:22]([C@@:24]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:26]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:27])[CH3:25])=[CH:23][C:16]=4[N:15]=3)=[CH:8][CH:7]=2)=[NH:4])=[O:53])=[CH:50][CH:49]=1
Reactant: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Reactant: Cc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccc(C)cc3)cc1)n2C
Temperature: 50 °C

Procedure:
A suspension of 0.7 g (1.2 mmol) of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride in 25 ml of methylene chloride is combined with 4.0 ml (28 mmol) of triethylamine and 0.8 g (3.0 mmol) of 4-nitrophenyl 4-methyl-benzoate and heated to 50° C. for 3.5 hours, whereupon a clear solution is formed. After cooling, it is washed with sodium bicarbonate solution, saline solution and water, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified on silica gel, eluting with ethyl acetate/ethanol (50:1 and 9:1). The uniform fractions are combined, concentrated by evaporation, triturated with ether, suction filtered and dried.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O>[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3([CH3:16])[CH2:7][C:6]4[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=4[O:4]3)[CH2:28][CH2:27]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(COC(c3ccccc3)c3ccccc3)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
In an autoclave, a mixture of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.5 g), 4-[(diphenylmethoxy)methyl]piperidine (3.0 g), and triethylamine (7.4 mL) was stirred under argon gas at 180° C. for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1) to provide 2.4 g of 2-[[4-[(diphenylmethoxy)methyl]-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine. Yield 95%. This product was treated with 0.45 g of oxalic acid and, then, recrystallized from ethanol to provide 1.8 g of the title compound. Yield 58%.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCc1ccc2c(c1)CCC2
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc2c(c1)CCC2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3 g-see Preparation 3), 5-(2-bromoethyl)indane (0.24 g-see Preparation 6), anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.23 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](C(N)=O)C1
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: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of cis-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (131 mg, 0.367 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (146 mg, 0.441 mmol), Na2CO3 (97.2 mg, 0.917 mmol), Pd(PPh3)4 (25.5 mg, 0.0221 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 18 h. To the cooled reaction solution was added water (15 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (2×15 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz): δ=2.60-2.70 (m, 4H), 2.84-2.90 (m, 1H), 5.14-5.23 (quintet, 1H, J=8.7 Hz), 6.31 (brs, 2H), 6.92 (s, 1H), 7.40 (s, 1H), 7.50-7.62 (m, 3H), 7.78-7.82 (m, 2H), 8.08-8.10 (d, 1H, J=8.4 Hz), 8.15-8.23 (m, 3H), 8.30-8.37 (m, 2H), 8.49-8.51 (d, 1H, J=8.4 Hz). MS (ES+): 435.0 [MH+]. HPLC: tR=2.4 min (polar—5 min).
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].[OH:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH2:12]S[C:10]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:9]1=2>O.CO>[OH:7][CH:8]1[C:13]([CH3:12])([CH3:14])[CH2:15][S:3](=[O:5])(=[O:4])[C:10]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:9]1=2
Reactant: O=S([O-])OO
Reactant: CC1(C)CSc2sc(S(N)(=O)=O)cc2C1O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)CS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91 %

Procedure:
A solution of OXONE® (2.71 g, 0.0044 m) in water (15 ml) was added to a solution of 5,6-dihydro-4-hydroxy-5,5-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide (0.90 g, 0.0032 m) in methanol (15 ml) over 10 minutes and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was filtered, the solid was washed with methanol, and the combined filtrate and washings were concentrated in vacuo below 65° C. to remove methanol. The aqueous suspension was extracted with ethyl acetate (3×50 ml), the combined extracts were washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 0.91 g (91%) of crude product which was purified by chromatography on silica gel, eluting with 10% methanol-chloroform.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH3:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16].ClC([O-])=O>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:16][CH2:15][C:14]([CH3:19])([CH3:13])[CH2:17][OH:18])=[O:3]
Reactant: CC(C)(CO)CO
Reactant: COc1ccccc1OC(=O)Cl
Agent: O=C([O-])Cl
Product: COc1ccccc1OC(=O)OCC(C)(C)CO

Procedure:
The reaction of 2-methoxyphenol chloroformate with 2,2-dimethyl-1,3-propanediol is conducted on a 0.01 mole scale employing the same conditions as described in Example III, except that the addition of the chloroformate solution is accomplished at room temperature. A 1.4 g yield of the pure product is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]([O-:4])=[O:3].[CH:5]1([CH3:15])[CH2:10][CH2:9][CH:8]([CH:11]([CH3:13])[CH3:12])[CH:7](O)[CH2:6]1.C1(C)CCC(C(C)C)C(Cl)C1.C(=O)(OC1C(C(C)C)CCC(C)C1)OC1C(C(C)C)CCC(C)C1>>[Cl:1][C:2]([O:4][CH:7]1[CH:8]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:10][CH:5]([CH3:15])[CH2:6]1)=[O:3]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C([O-])Cl
Agent: CC1CCC(C(C)C)C(Cl)C1
Agent: CC1CCC(C(C)C)C(OC(=O)OC2CC(C)CCC2C(C)C)C1
Product: CC1CCC(C(C)C)C(OC(=O)Cl)C1

Procedure:
The product obtained is analysed by gas chromatography. The purity of the chloroformate is 99%, and less than 0.5% by weight of menthol and 250 ppm of menthyl chloride are found. Bismenthyl carbonate is not detected.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH2:2][OH:1])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(N)cc(CO)c1

Procedure:
A mixture of the product from step (ii) (23.4 g), ammonium chloride (23 g) and iron powder (23 g) in methanol (200 ml) and water (200 ml) was heated at reflux for 1 hour. The mixture was filtered and concentrated under reduced pressure and the residue treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated. Yield 19.38 g.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[O:28][C:18]([C:19]4[CH:27]=[CH:26][C:22]([C:23]5[O:24][C:13]([C:9]6[N:8]=[C:7]([C:1]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)[CH:12]=[CH:11][CH:10]=6)=[N:14][N:15]=5)=[CH:21][CH:20]=4)=[N:15][N:14]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: c1ccc(-c2cccc(-c3nnc(-c4ccc(-c5nnc(-c6cccc(-c7ccccc7)n6)o5)cc4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 2.30 g of terephthaloyl dichloride was added. Temperature was elevated to 100° C., and stirring was conducted for 5 hours. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated yellow solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with dispersion washing by a chloroform-methanol mixed solution to obtain 3.40 g (yield 58%) of PhpyOXDp. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 8.45 ppm (4H), 8.29 ppm (2H), 8.16 ppm (4H), 7.93-8.02 ppm (4H), 7.50-7.59 ppm (6H).
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]1([NH:32][C:33]2[N:34]=[CH:35][C:36]([C:44]([OH:46])=O)=[N:37][C:38]=2[O:39][CH2:40][CH2:41][O:42][CH3:43])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH3:47][O:48][C:49](=[O:56])[C:50]([NH2:55])([CH2:53][CH3:54])[CH2:51][CH3:52]>>[CH3:47][O:48][C:49](=[O:56])[C:50]([NH:55][C:44]([C:36]1[CH:35]=[N:34][C:33]([NH:32][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=1)=[O:46])([CH2:53][CH3:54])[CH2:51][CH3:52]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: COCCOc1nc(C(=O)O)cnc1NC1CCCCC1
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(NC2CCCCC2)c(OCCOC)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-cyclohexylamino-6-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 423.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC(C)C)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-4-(4-isobutylpiperazin-1-yl)-3-nitropyridin-2-amine (0.032 g, 0.10 mmol), and ethanol (3.0 ml) was added 4-methoxybenzaldehyde (0.023 g, 0.17 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 4.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 40% ethyl acetate in dichloromethane, and then 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a white solid (0.013 g, 32%); 1H-NMR (500 MHz, DMSO-d6) 0.90 (d, J=6.55 Hz, 6H, CH(CH3)2), 1.83 (m, 1H, CH(CH3)2), 2.12 (d, J=7.39 Hz, 2H, N—CH2), 2.55 (br s, 4H, piperazine N(CH2)2), 3.68 (br s, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.83 Hz, 2H) and 8.13 (d, J=8.78 Hz, 2H) (3,5-C6H4OMe2 and 2,6-C6H4—OMe), 8.07 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.30 (s, 1H, imidazo[4,5-b]pyridine N—H);