Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:27]2[CH:31]=[C:30]([C:32]3[C:33]4[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=4[N:35]=[CH:36][N:37]=3)[CH:29]=[N:28]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:16]([F:26])=[C:17]([C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:18]#[N:19])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:27]2[CH:31]=[C:30]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH:29]=[N:28]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:16]([F:26])=[C:17]([C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:18]#[N:19])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2]
Reactant: CN(C)c1ccc(CN2CCC(N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)c(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(CN2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)c(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a reaction vial were added 3-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile (56 mg, 0.1 mmol), trifluoroacetic acid (1.5 mL) and methylene chloride (1.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated in vacuum. The residue was dissolved in 5 mL of a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the mixture was purified by HPLC (method B) to give the title compound. LC-MS: 539.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 8.79 (s, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.42 (t, J=8.8 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 3.68 (d, J=8.4 Hz, 2H), 3.51 (m, 4H), 3.38 (s, 2H), 3.01 (s, 6H), 2.67 (m, 2H), 2.17 (m, 1H), 1.97 (m, 2H), 1.63 (m, 2H), 1.15 (m, 2H).
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[N:12]=[C:13]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]=3[N:23]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C1COCC1>[N:6]1([C:11]2[N:12]=[C:13]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:15]=3[N:23]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1ccc2c(c1)[nH]c1nc(N3CCCC3)nc(N3CCCC3)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Reaction time: 1 h

Procedure:
n-Butyllithium (4.26 mL; 1.6 M in hexane) is added to a mixture of 2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (III, EXAMPLE 2, 2.0 g) in THF (50 mL) at -15°. After 1 hr, t-butyl bromoacetate (1.27 g) in THF (20 mL) is added, and the mixture is stirred for 2 hr at 20-25°. The mixture is partitioned between aqueous sodium bicarbonate and methylene chloride, and the organic layer is dried and concentrated. Chromatography of the crude product (silica gel; hexane/methylene chloride/ethyl acetate (70/25/5) gives the title compound, mp=131-133°; NMR (CDCl3) 7.87, 7.15, 4.92, 3.92, 3.61, 1.96 and 1.43 δ; MS (m/z=421 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[F:17])=[O:7])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:20][C:4]1[CH:3]=[C:2]([Br:1])[CH:19]=[CH:18][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[F:17])=[O:7]
Reactant: O=C(NCc1ccc(Br)cc1F)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc(Br)ccc1C(=O)NCc1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 4-bromo-N-(4-bromo-2-fluorobenzyl)-2-nitrobenzamide (3.4 g) and iron (1.45 g) in acetic acid (66 ml) was stirred at 100° C. for 30 minutes. After cooling, iron was filtered off. The filtrate was evaporated to give a residue, which was made alkaline with aqueous 1N sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent gave 2-amino-4-bromo-N-(4-bromo-2-fluorobenzyl)benzamide (3.10 g).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]=[C:19]([NH2:24])[C:18]3[N:25]=[C:26]([CH2:31][O:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH3:30])[C:17]=3[C:16]=2[CH:15]=1.[OH-].[Na+]>ClCCl>[NH2:24][C:19]1[C:18]2[N:25]=[C:26]([CH2:31][O:32][CH2:33][CH3:34])[N:27]([CH2:28][CH2:29][CH3:30])[C:17]=2[C:16]2[CH:15]=[C:14]([O:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCN)cc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNS(C)(=O)=O)cc3c21
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
Methanesulfonic anhydride (0.265 g, 1.52 mmol) was added in one portion to a solution of 8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.46 mmol) in dichloromethane (10 mL), and the reaction was stirred for 30 minutes. A precipitate formed. Aqueous sodium hydroxide (25 mL of 10%) was added, and the mixture was stirred for 20 minutes. The aqueous layer was separated and extracted with dichloromethane. The combined organic fractions were washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was purified by column chromatography on silica gel (eluting with a dichloromethane:methanol ranging in ratios from 97:3 to 94:6) and then recrystallized from acetonitrile to yield 0.302 g of N-[2-(4-amino-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]methanesulfonamide as white, granular crystals, mp 178-179.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8](Cl)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1)#[N:2].C(N(CC)CC)C.[H][H]>O1CCOCC1.[C].[Pd]>[C:1]([C:3]1[CH:19]=[CH:18][C:6]2[NH:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2nc(Cl)c3ccccc3c(=O)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1CN2
Yield: 46.2 %

Procedure:
The resulting 2-cyano-6-chloro-11-oxodibenz[b,e]azepine (17.4 g) and triethylamine (9 g) were dissolved in dioxane (840 ml), and the solution was catalytically hydrogenated for 17 hours at room temperature at a hydrogen pressure of 4 kg/cm2 with 10% palladium-carbon powder (2 g) as a catalyst. After the hydrogenation, the catalyst was filtered off, and the filtrate was concentrated at reduced pressure. The concentrate was purified by silica gel chromatography, and recrystallized from acetone to obtain 5,6-dihydro-2-cyano-11-oxodibenz[b,e]azepine (7.06 g).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[CH:26][S:27][C:28]1[N:33]([CH3:34])[C:32](=[O:35])[C:31](=[O:36])[N:30]([CH2:37][CH:38](OCC)[O:39]CC)[N:29]=1)[CH:20]([NH:45][C:46](=[O:76])[C:47](=[N:73][O:74][CH3:75])[C:48]1[N:49]=[C:50]([NH:53]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:51][CH:52]=1)[C:19]2=[O:77])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O.O>[NH2:53][C:50]1[S:51][CH:52]=[C:48]([C:47](=[N:73][O:74][CH3:75])[C:46]([NH:45][CH:20]2[C:19](=[O:77])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH:25]=[CH:26][S:27][C:28]2[N:33]([CH3:34])[C:32](=[O:35])[C:31](=[O:36])[N:30]([CH2:37][CH:38]=[O:39])[N:29]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:76])[N:49]=1
Reactant: CCOC(Cn1nc(SC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C3SC2)n(C)c(=O)c1=O)OCC
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CSc3nn(CC=O)c(=O)c(=O)n3C)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
A solution of product (9c) (1.9 g) in formic acid (20 cc) is stirred for 30 minutes at 50° C. and then diluted with water (2 cc) and stirred for 10 minutes at 50° C. After cooling to 20° C., the reaction mixture is filtered and the filtrate is concentrated under reduced pressure (0.1 mm Hg; 0.013 kPa) at 35° C. The residue is triturated with ethanol (20 cc), which is evaporated off under reduced pressure (30 mm Hg; 4 kPa) at 40°. This operation is repeated 3 times and the residue is then taken up in ethanol (30 cc). The solid is isolated on a vacuum filter, washed with ethanol (3×10 cc) and with ethyl ether (3×10 cc) and dried. This yields the E form of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-3-[2-(5,6 -dioxo-1-formylmethyl-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)thiovinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (product 9) (0.96 g) in the form of a cream-coloured solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:21]([OH:22])=[CH:20][C:10]2[CH2:11][C:12]3([O:19][C:9]=2[CH:8]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:6])([CH3:5])[CH3:4].[CH2:23](Br)[CH:24]=[CH:25][CH3:26]>CN(C)C=O>[CH2:23]([O:22][C:21]1[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:8][C:9]2[O:19][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11][C:10]=2[CH:20]=1)[CH:24]=[CH:25][CH3:26]
Reactant: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Reactant: CC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCOc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2
Yield: 93 %

Procedure:
0.13 g of oily sodium hydride and 0.74 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 7 were treated with 0.33 ml of crotyl bromide in dimethylformamide in the same manner as in Example 8-1) to give 0.82 g of a mixture of geometrical isomers of 5-(2-butenyloxy)-6-t-butyl-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (yield 93%).
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH:18](Br)[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.C(OCC)(=O)C>[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[N:2]=[C:1]([SH:3])[S:4][C:18]=2[CH2:17]1)=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1Br
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCc2nc(S)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a solution of ammonium dithiocarbamate (0.19 g, 1.7 mmol) in 2 mL of ethanol was added 1-benzyloxycarbonyl-3-bromo-4-piperidone (0.53 g, 1.7 mol). The reaction was stirred at rt overnight. The next morning the reaction was heated at 75° C. for 2 h. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water (2X) and then brine. The solvent was removed under reduced pressure and the product subjected to flash chromatography (2:1 hexane/ethyl acetate). Crystallization from ethyl acetate/hexane afforded 0.14 g of 5-benzyloxycarbonyl-2-mercapto-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[NH:24][CH:25]=[CH:26]4)=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccc2[nH]ccc2c1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and indole-5-carboxylic acid were combined to provide N5-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-5-indolecarboxamide as an off white solid. 1H NMR (300 MHz, DMSO-d6) δ11.31 (s, 1H), 8.34 (t, J=5.5 Hz, 1H), 8.06 (m, 2H), 7.63-7.58 (m, 2H), 7.42-7.38 (m, 3H), 7.22 (t, J=7.1 Hz, 1H), 6.67 (broad s, 2H), 6.50 (s, 1H), 4.58 (m, 2H), 3.81 (t, J=6.6 Hz, 2H), 3.34 (m, 2H), 3.25 (s, 3H), 3.21 (t, J=6.6 Hz, 2H), 1.89 (m, 2H), 1.72 (m,2H); MS (EI) m/e 456.2264 (456.2274 calcd for C26H28N6O2).
Reaction SMILES: [CH2:1](Br)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].CS(C)=O.[CH3:29][O:30][C:31]1[CH:38]=[C:37]([O:39][CH3:40])[C:34]([CH:35]=O)=[C:33]([OH:41])[CH:32]=1>>[CH3:40][O:39][C:37]1[C:34]([CH2:35][CH2:1][CH3:2])=[C:33]([OH:41])[CH:32]=[C:31]([O:30][CH3:29])[CH:38]=1
Reactant: CCBr
Reactant: COc1cc(O)c(C=O)c(OC)c1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CCCc1c(O)cc(OC)cc1OC
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Triphenylphosphine ethylbromide (4.1 g) was added to a 2N sodium hydride/dimethyl sulfoxide solution (11 ml), prior to agitation at 50° C. for 30 minutes. To the mixture was added 4,6-dimethoxy-2-hydroxybenzaldehyde (1 g), for agitation at 50° C. overnight. After the termination of the reaction, the resulting solution was partitioned with ethyl acetate and dilute hydrochloric acid, and the resulting ethyl acetate phase was washed in water and subsequently in a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=3:1), followed by addition of a catalytic amount of platinum dioxide for hydrogenation, to recover 3,5-dimethoxy-2-propylphenol (0.5 g; yield of 46%). By 1H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])O[C:3]1([O:17]C)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:19][C:2]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:17]
Reactant: C1COCCN1
Reactant: COC1(c2ccc(N3CCCCC3)cc2)OC1(C)C
Product: CC(C)(C(=O)c1ccc(N2CCCCC2)cc1)N1CCOCC1
Temperature: 130 °C

Procedure:
12.1 g (46.3 mmol) of 3,3-dimethyl-2-methoxy-2-(4-piperidinophenyl)-oxirane and 26.1 g (0.30 mol) of morpholine are added together, and the mixture is heated to the refluxing temperature (about 130° C.). After 6 hours the mixture is cooled down and the morpholine is distilled off under reduced pressure. The residue is taken up in toluene and is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and is extracted with toluene. The toluene solution is dried with K2CO3 and concentrated. The residue is recrystallised from methanol. Melting point 159°-162° C.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH2:30]([N:27]1[CH2:28][CH2:29][C:22]2([S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)[CH2:25][CH2:26]1)[CH3:31]
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCC2(CC1)CN=C(c1cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg) and acetaldehyde (90%) (100 μL) in tetrahydrofuran (3 ml) was added sodium triacetoxyborohydride (125 mg), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (83 mg, yield 80%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 215° C.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[C:16](OC(=O)C)(=[O:18])[CH3:17].S(=O)(=O)(O)O>>[C:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:18])[CH3:17]
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Temperature: 25 °C

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-Imidazo(4,5-b)pyridine (5 grams), 25 milliliters of acetic anhydride and 0.1 milliliter of sulfuric acid were mixed with stirring at 25° C. for fifteen minutes. The reaction mixture was then heated to reflux and refluxed for one-half hour, poured into ice with stirring, stirred for ten minutes and filtered. Filtration yielded the desired 1-acetoxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product as a solid. It was taken up in ether, dried over magnesium sulfate, and the ether evaporated. The product then melted at 103°-04° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:13]1([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]1>>[CH:13]1([C:16]([NH:18][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[O:17])[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Reactant: NC(=O)C1CC1
Product: COC(=O)c1cc(C)nc(NC(=O)C2CC2)c1
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (1.3 g, a pale yellow solid) from methyl 2-chloro-6-methylisonicotinate (1.5 g, 8.1 mmol) and cyclopropanecarboxamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:4])=[O:3].CC1C=CC(S(O[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:28][CH:27]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:30][CH:31]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 4-hydroxyphenyl methanesulfonate (7.04 g @ 82% strength, 30.6 mmol, (prepared by methanesulfonylation of quinol)) dissolved in acetonitrile (72 mL) was added to a mixture of 2-[4-(tert-Butoxycarbonylamino)phenyl]ethyl 4-methylbenzenesulfonate (prepared as described in WO 99/62871) (12.0 g, 30.6 mmol) and potassium carbonate (6.42 g of −325 mesh, 46.0 mmol) under nitrogen and the resulting mixture gently stirred. Acetonitrile (36 mL) and water (12 mL) were added, the stirring rate increased and the reaction mixture was boiled under reflux (80° C.) for 11 to 24 hours. After cooling back to 60° C., the solvent volume was reduced by 6 volumes (˜72 mL) by distillation at reduced pressure. Toluene (108 mL) and water (24 mL) were added and the mixture stirred for 5 minutes at 60° C. The solution was filtered through Celite™ (and/or 5% w/w charcoal) and returned to the reaction vessel at 60° C. The phases were allowed to separate and the lower aqueous phase run off and discarded. Dilute aqueous sodium hydroxide solution (10.2 mL of 2.5%, 0.625 M) was added and the mixture stirred at 60° C. for 5 minutes. The phases were allowed to separate and the lower aqueous phase was run off and discarded. Water (24 mL) was added and stirred at 60° C. for 5 minutes, before the phases were allowed to separate and the lower aqueous phase was run off and discarded. The solvent volume was reduced by distillation at atmospheric pressure until a still-head temperature of ˜110° C. was achieved. Fresh toluene was added to make the total volume up to 8 volumes (96 mL). The solution was cooled to 60° C., filtered and then cooled to 45° C. Iso-hexane (143 mL) was added dropwise over 1 hour, maintaining the temperature at 45° C., and then the solution cooled to 20° C. at 1° C./minute. The resulting solid was isolated by filtration, washed by displacement with iso-hexane (29 mL) and dried in a vacuum oven at 50° C. to yield the title compound as a buff solid (9.9 g, 79%). HPLC (Rt 10.9 mins); m.p. 117-118° C.; 1H NMR (400 MHz, d6-DMSO) δ 9.22 (˜1H, s), 7.36 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.4 Hz), 6.98 (2H, d, J=9.2 Hz), 4.13 (2H, t, J=6.6 Hz), 3.29 (3H, s), 2.93 (2H, t, J=6.6 Hz), 1.44 (9H, s); 13C NMR (100.6 MHz, d6-DMSO) δ 157.18, 152.77, 142.44, 137.80, 131.62, 129.04, 124.01, 123.28, 118.15, 115.45, 78.83, 68.69, 36.89, 34.14 and 28.10; MS (ES+) 425 (M+NH4+, 5%), 308 (10%), 120 (100%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[N:12][C:11]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C(OC(C)(C)C)=O)=[CH:10][N:9]=1)(=O)=O.[CH3:29][S-:30].[Na+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:29][S:30][CH2:6][CH2:7][C:8]1[N:9]=[CH:10][C:11]([NH:14][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:12][CH:13]=1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(CCOS(C)(=O)=O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCCc1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To 2-(5-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)ethyl methanesulfonate (540 mg, 1.293 mmol) in DMF (7 mL) was added sodium thiomethoxide (408 mg, 5.82 mmol) and was stirred at 85° C. for 3 h, followed by LCMS. The reaction was let cool, 200 mL of ethyl acetate and saturated sodium bicarbonate was added. The organic layer was extracted and washed water (3×), saturated salt solution, dried sodium sulfate, filtered through 2 cm silica gel plug and flushed with ethyl acetate. The solvent was concentrated off to constant mass to give 294 mg of the desired product as free base used as is, (84% yield). LCMS (m/z): 270.4 (MH+), 0.84 min. 1H NMR (400 MHz, CDCl3) δ ppm 9.19 (s, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.20 (br. s., 1H), 2.99-3.08 (m, 2H), 2.79-2.94 (m, 2H), 2.12 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:9][CH:10]=[CH2:11])(=[O:8])[CH3:7].CO>[O-]S(C(F)(F)F)(=O)=O.[Ag+].O>[C:6]([O:9][CH:10]=[CH:11][CH2:4][CH:3]([CH3:5])[CH:2]=[CH2:1])(=[O:8])[CH3:7]
Reactant: C=COC(C)=O
Reactant: C=CC(=C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: O
Product: C=CC(C)CC=COC(C)=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 6 %

Procedure:
4 mg (0.016 mmol) of (η6-benzene) ruthenium (II) dichloride, 15 mg (0.058 mmol) of silver triflate and 11.2 mg (0.052 mmol) of N-2-aminoethyl-p-toluenesulfonamide were placed in a sealed tube, which was then charged with 2 ml (20 mmol) of isoprene, 2 ml (22 mmol) of vinyl acetate and 2 ml of methanol. The mixture was heated with stirring at 100° C. for 6 hours in an argon atmosphere. The reaction mixture was poured into water and the organic layer was concentrated to obtain 0.17 g (yield: 6% based on isoprene) of a co-dimer (4-methylhexa-1,5-dien-1-yl acetate) (Purity: 75%, regioisomer: 17%, cyclic dimer of dienes: 8%).