Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[ClH:11]>P(Cl)(Cl)(Cl)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: Cl
Agent: O=c1[nH]c2ccccc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2[nH]1

Procedure:
Following the procedure of Harrison et al., J.Chem.Soc., 1963, 2930-2937, 15 g benzimidazolin-2-one is boiled under reflux for 31/2 hours with 150 ml phosphoryl chloride, dry hydrogen chloride being passed through the refluxing mixture for the last three hours of the reaction. The excess phosphoryl chloride is removed at about 40 mm and the residue treated with about 40 ml of ice water. The cold acid solution is filtered, and the insoluble unreacted benzimidolin-2-one is washed with dilute hydrochloric acid, then with water. The filtrate and washings are made just alkaline, as determined by a litamus test, by the addition of dilute ammonia solution. After thorough cooling, crude 2-chlorobenzimidazole is collected, washed with water and dried. The reaction sequence yields 0.5 g of unreacted benzimidazolin-2-one and 15.6 g of title compound which has a m.p. of 180° C. (softens, bubbles, then resolidifies).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH2:15][CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:15][CH3:16])[C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN1c2cc(Cl)nc(=O)n2CC1(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (100 mg, 0.501 mmol) and iodoethane (94.0 mg, 0.601 mmol) in acetonitrile (4 mL) was added Cs2CO3 (326 mg, 1.00 mmol). The reaction mixture was stirred at 90° C. for 1 h, filtered and concentrated to afford the crude product (110 mg) as a brown solid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[N:13]3[C:8]([CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)=[C:7](C(O)=O)[C:6](C(O)=O)=[C:5]3[C:4]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH3:2].N1C2C(=CC=CC=2)C=CC=1>[Cu]>[CH2:1]([C:3]1[C:12]2[N:13]3[C:8](=[CH:7][CH:6]=[C:5]3[C:4]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[CH3:2]
Reactant: CCc1c(-c2ccc(OC)cc2)c2c(C(=O)O)c(C(=O)O)c3cc(OC)cc1n32
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: CCc1c(-c2ccc(OC)cc2)c2ccc3cc(OC)cc1n32
Temperature: 170 °C
Yield: 77.3 %

Procedure:
A mixture of 4-ethyl-6-methoxy-3-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid (1.75 g, 4.45 mmol), copper powder (0.4 g), and 90 ml of freshly purified quinoline was heated to 170° C. for eight hours in a nitrogen atmosphere. The copper catalyst was filtered off and the filtrate acidified with 6M hydrochloric acid and extracted with ether. The washed and dried (magnesium sulfate) extract was evaporated and the residue triturated with petroleum ether (40-60). The precipitate was filtered off and dried to afford 1.05 g (77%) of the title compound. M.p. 109-11° C. 1H-NMR (DMSO-d6, 200 MHz) δ: 1.38 (t, 3H), 3.18 (q, 2H), 3.85 (s, 3H), 4.02 (s, 3H), 7.12 (d, 1H), 7.14 (d, 2H), 7.60 (d, 1H), 7.70-7.80 (m, 4H). (Compound 3).
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[NH:21][C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.[CH3:29]I.[H-].[Na+].O>CN(C=O)C>[N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH3:29])[C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2ccccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(-c2ccc(N3CCn4c3nc3ccccc34)cc2)c2ncccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (57 mg) and methyl iodide (0.012 mL) in DMF (2.0 mL) was added sodium hydride (62 mg) (60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 1 h, and then added H2O. The precipitate was collected and washed with MeOH to give 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (43 mg) as white powder.
Reaction SMILES: [Na].[CH2:2]([OH:14])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].C1(S(O[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])(=O)=O)C=CC=CC=1.C1C=CC=CC=1.[Na]>>[CH2:12]([OH:13])[CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:14][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33]
Reactant: OCCOCCOCCOCCO
Reactant: O=S(=O)(OCCOCCOCCO)c1ccccc1
Agent: [Na]
Solvent: c1ccccc1
Product: OCCOCCOCCOCCOCCOCCOCCO

Procedure:
Dissolve one equivalet of sodium in at least 5 equivalents of tetraethylene glycol and then add one equivalent of triethylene glycol monobenzenesulfonate. Heat the resulting solution at 100° to 150° C. until the elimination of sodium benzene sulfontate is substantially complete. Remove the insoluble sulfonate salt by filtration and fractionally distill the resultiing product in vacuo to obtain heptaethylene glycol as the higher boiling fraction.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][CH2:7][NH:8][CH3:9])=[O:4].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][N:8]([CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:10])([F:11])[F:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCCCCCBr
Reactant: CNCCNC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(C)CCNC(=O)C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-N-[2-(methylamino)ethyl]acetamide (5 g) in DMF (50 ml) were added ethyl 7-bromoheptanoate (3.6 ml) and potassium carbonate (7.7 g) and stirring was continued at room temperature for 18 hr. Potassium carbonate was removed by filtration and saturated aqueous sodium bicarbonate and water was added to the filtrate, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried with sodium sulfate, and concentrated. The residue was dissolved in toluene and purified by passing through the silica gel column (eluent; hexane to hexane-ethyl acetate (4:1) to ethyl acetate) to obtain the titled compound as a crude material (7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)[CH2:12]Br)[NH:8][N:7]=1)=[O:5])[CH3:2].[C:15]([NH2:18])(=[S:17])[CH3:16]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:18]=[C:15]([CH3:16])[S:17][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CC(N)=S
Reactant: CCOC(=O)c1cc(C(=O)CBr)[nH]n1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2csc(C)n2)[nH]n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of 5-(2-bromoacetyl)pyrazole-3-carboxylic acid ethyl ester (5.30 g), thioacetamide (1.60 g), and ethanol (100 ml) was stirred at 60° C. for 30 minutes and concentrated. The residue was dissolved in 50 ml of 2N HCl solution, and washed with ethyl ether (2×50 ml). The aqueous solution was separated and neutralized with solid NaHCO3. The mixture was then extracted with ethyl acetate (233 100 ml). The ethyl acetate solution was dried over sodium sulfate and concentrated to afford 3.46 g of 5-(2-methylthiazol-4-yl)pyrazole-3-carboxylic acid ethyl ester as pale yellow solids, mp 141-142° C. NMR: 1.41 (t, 3H), 2.78 (s, 3H, thiazolyl methyl), 4.42 (q, 2H), 7.15 (s, 1H, thiazolyl H), 7.47 (s, 1H, 4-pyrazolyl H).
Reaction SMILES: [C:1]([C:3](=[CH:5][CH2:6]Cl)[CH3:4])#[N:2].[S:8]1([C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12](=[O:13])[NH:11]1)(=[O:10])=[O:9].[Na]>CN(C)C=O>[O:10]=[S:8]1(=[O:9])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:12](=[O:13])[N:11]1[CH2:6][CH:5]=[C:3]([C:1]#[N:2])[CH3:4]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C#N)=CCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C#N)=CCN1C(=O)c2ccccc2S1(=O)=O
Yield: 66.3 %

Procedure:
18.2 g (150 millimoles) of 2-cyano-4-chlorobut-2-ene were slowly added dropwise to 20.0 g (100 millimoles) of sodium saccharin in 100 ml of absolute dimethylformamide, while stirring thoroughly. The reaction mixture was stirred for a further 4 hours at 40° C., after which the precipitated sodium chloride was filtered off and the filtrate was evaporated down under reduced pressure to about 30 ml. After 400 ml of water had been added, the oil initially formed slowly crystallized. The crystals were filtered off under suction, recrystallized from ethanol and dried in a drying oven under reduced pressure at 50° C. to give 17.4 g (66%) of 4-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-2-cyanobut-2-ene of melting point 107°-108° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:41])[CH2:20][N:21]2[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:24]3[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=3[C:22]2=[O:40])[CH2:14][CH2:13]1.[ClH:42]>C(O)(=O)C.O1CCOCC1>[ClH:42].[C:29]([CH2:28][CH:25]1[C:24]2[CH:36]=[CH:37][CH:38]=[CH:39][C:23]=2[C:22](=[O:40])[N:21]([CH2:20][C:19]([NH:18][CH:15]2[CH2:14][CH2:13][CH:12]([CH2:11][NH:10][C:2]3[NH:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH2:17][CH2:16]2)=[O:41])[CH2:27][CH2:26]1)([OH:31])=[O:30]
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)NC2CCC(CNc3nc4ccccc4[nH]3)CC2)C(=O)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)CC1CCN(CC(=O)NC2CCC(CNc3nc4ccccc4[nH]3)CC2)C(=O)c2ccccc21

Procedure:
Analogously to Example II, the t-butyl ester (Example V) in glacial acetic acid was cleaved using 4N HCl in dioxane. After freeze-drying, 0.45 g of white amorphous hydrochloride remained; ESI-MS [M+H+]: 504.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[C:8]2[C:9]3[CH:31]=[CH:30][S:29][C:10]=3[C:11](=[O:28])[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[C:14]([CH3:19])=[CH:15][C:16]=1[O:17][CH3:18].IC>C1COCC1>[Br:6][C:7]1[C:8]2[C:9]3[CH:31]=[C:30]([CH3:2])[S:29][C:10]=3[C:11](=[O:28])[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:13]=2[C:14]([CH3:19])=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1cc(C)c2c(c1Br)c1ccsc1c(=O)n2COCC[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1Br)c1cc(C)sc1c(=O)n2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a stirred solution of diidopropylamine (85 μL, 0.6 mmol) in THF (2.5 mL) at −78° C. was added n-BuLi (2.5 M, 0.24 mL, 0.60 mmol) and the reaction mixture was stirred at 0° C. for 10 min then cooled to −78° C. A solution of 9-bromo-8-methoxy-6-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)thieno[2,3-c]quinolin-4(5H)-one (0.23 g, 0.50 mmol) in THF (1 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. Iodomethane (93 μL, 1.5 mmol) was added and the reaction mixture was stirred at −78° C. for 2 h and quenched by the addition of satd. aq. ammonium chloride and extracted with dichloromethane. The organics were dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by column chromatography (silica, heptane/ethyl acetate) to afford the desired product (0.13 g, 55%) as a white solid: ESI MS m/z 468 [C20H26BrNO3SSi+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:36][O:37][C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[CH:17]=[N:18][C:19]2[N:20]([N:30]=[CH:31][C:32]=2[C:33](O)=[O:34])[C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[O:15])[CH2:10][CH2:9]3.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:36][O:37][C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[CH:17]=[N:18][C:19]2[N:20]([N:30]=[CH:31][C:32]=2[C:33]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:34])[C:21]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[O:15])[CH2:10][CH2:9]3
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 48.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)-7-(3-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.070 g, 0.140 mmol) obtained in step 4 and ethanesulfonamide (0.076 g, 0.699 mmol), the title compound (0.040 g, 48%) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([OH:6])[C:4]#[CH:5].[C:12]1([C:18](Br)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([O:6][C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:4]#[CH:5]
Reactant: C#CC(O)C(C)(C)CCCC
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C#CC(OC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)CCCC

Procedure:
Treatment of 23.1 g. (0.150 mole) of 4,4-dimethyl-1-octyn-3-ol (Example 149) with 56.5 g. of triphenylmethyl bromide in 150 ml. of pyridine and purification of Florisil®, all as described in Example 127 gives the title compound, m.p. 75°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:9]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][N+:16]([O-:38])=[CH:17][CH:18]=3)[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:9]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-pyridine were dissolved in 3 mL of dichloromethane and 80 mg (0.52 mmol) of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature for 4 hours, diluted with the same solvent and washed with aqueous sodium hydrogenocarbonate. The organic layer was then dried over sodium sulphate and evaporated to afford, after crystallization from ethylacetate, 49 mg (47%) of the title compound.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[Cl:36][CH2:37][CH2:38][NH2:39].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([NH:39][CH2:38][CH2:37][Cl:36])=[O:31])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NCCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Reaction time: 1 h
Yield: 70.4 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (66 mg, 0.15 mmol) synthesized in Example (66g), 2-chloroethylamine hydrochloride (34 mg, 0.30 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) were dissolved in dichloromethane (10 mL), and WSCI•HCl (31 mg, 0.16 mmol) was added at room temperature, followed by stirring for 1 hour under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (60 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-60%) to afford the desired product (56 mg, yield 79%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(=O)([O-])O.[Na+].BrC1C=CC(S(O[CH2:31][CH2:32][CH:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[OH:34])(=O)=O)=CC=1>COCCOC>[CH:35]1([CH:33]([OH:34])[CH2:32][CH2:31][N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:10][CH2:11]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=S(=O)(OCCC(O)C1CCCCC1)c1ccc(Br)cc1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC2CCN(CCC(O)C3CCCCC3)CC2)nc1
Yield: 61.1 %

Procedure:
A mixture of 4-(5-methylpyridin-2-yl)aminopiperidine (394 mg, 2 mmol), sodium hydrogencarbonate (277 mg, 3.2 mmol) and 3-cyclohexyl-3-hydroxypropyl 4-bromobenzenesulfonate (932 mg, 2.4 mmol) in 1,2-dimethoxyethane (10 mL) was refluxed for 8 hours. After then adding 5 g of NH silica Chromatorex DM1020 to the reaction mixture, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 g NH silica Chromatorex DM2035, hexane:ethyl acetate=1:1) to obtain the title compound as a light yellow solid (405 mg) (59.6% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]1([C:21]#[CH:22])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1[OH:20])(=[O:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@@:6]1([C:21]#[CH:22])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1[O:20][S:24]([CH3:23])(=[O:26])=[O:25])(=[O:3])[CH3:2]
Reactant: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a pyridine (4 mL) solution of 12 (76 mg, 0.247 mmol) was added methanesulfonyl chloride (57 μL, 0.74 mmol) at 0° C., and the mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (60 mL×3/20 mL). Silica gel column chromatography (CHCl3/MeOH=100/0-100/1) of the organic layer gave 13 (95.0 mg, 100%) as a foam: 1H NMR (CDCl3) δ1.96 (3H, d, J6,Me=1.2 Hz, Me), 2.16 (3H, s, Ac), 2.38 (1H, ddd, Jgem=16.0 Hz, J1′,2′a=3.5 Hz and J2′a,3′=0.7 Hz, H-2′a), 2.70 (1H, s, ethynyl), 3.11 (1H, s, Ms), 3.19 (1H, ddd, Jgem=16.0 Hz, J1′,2′b=8.4 Hz and J2′b,3′=5.5 Hz, H-2′b), 4.48 (1H, d, Jgem=11.3 Hz, H-5′a), 4.53 (1H, d, Jgem=11.3 Hz, H-5′b), 5.27-5.28 (1H, m, H-3′), 6.52 (1H, dd, J1′,2′a=3.5 Hz and J1′,2′b=8.4 Hz, H-1′), 7.33 (1H, d, J6,Me=1.2 Hz, H-6), 8.86 (1H, brs, NH); FAB-MS m/z 387 (M++H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:13](OCC)(=[O:17])[C:14]([O-])=[O:15]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][C:14](=[O:15])[C:13](=[O:17])[NH:10]2
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: CCOC(=O)C(=O)[O-]
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
4-Trifluoromethyl-o-phenylenediamine (8.0 grams) was added to 80 ml. of ethyl oxalate and the resulting mixture was heated to reflux and refluxed for two hours. A precipitate formed during this period. The reaction mixture was then cooled to room temperature and filtered to separate the precipitate, m.p. 344°-346° C. (dec.) The product was identified as the expected 6-trifluoromethyl-2(1H), 3(4H)-quinoxalinedione, by IR, TLC, NMR, and microanalysis.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[S:18][C:17]([CH3:22])=[N:16][C:15]=3[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].[NH4+].[Cl-]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[S:18][C:17]([CH3:22])=[N:16][C:15]=3[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)=[O:11])=[CH:9][C:2]=1[CH3:1]
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccc(C#N)c(C)c1)c1ccccc1-2
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc(CN)c(C)c1)c1ccccc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
A solution of 2-methyl-4-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulene-6-carbonyl)-benzonitrile from Example E124.1 (190 mg, 0.53 mmol) in methanol (15 ml) at room temperature was treated with cobalt(II) chloride hexahydrate (275 mg, 1.15 mmol). The mixture was stirred for 20 min then cooled down to 0° C. Sodium borohydride (200 mg, 5.3 mmol) was added portionwise and the mixture was stirred for 20 h at room temperature. Saturated NH4Cl (2 ml) was added dropwise and the mixture was stirred for 30 min then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloromethane) to yield the title compound (100 mg, 52%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([CH:16]=1)[NH2:15].[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH:15][C:18](=[O:20])[CH3:19])[CH:16]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C)c(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triethylamine (2.9 g, 14.4 mmol) and 5-methoxy-2-methylaniline (1.0 g, 7.2 mmol) in DCM (30 mL) at 0° C., was added acetyl chloride (0.57 g, 7.2 mmol) dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution, and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to give N-(5-methoxy-2-methylphenyl)acetamide as needle-shaped crystals. The crude product was used in the next step without further purification.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]([O:41][CH2:42][C:43]3[S:47][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:45][CH:44]=3)[CH2:39][CH2:38][S:37]2(=[O:53])=[O:52])=[CH:32][CH:31]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[C:24]([C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH:40]([O:41][CH2:42][C:43]3[S:47][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:45][CH:44]=3)[CH2:39][CH2:38][S:37]2(=[O:53])=[O:52])=[CH:34][CH:35]=1)(=[O:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(O)c1ccc(N2C(OCc3ccc(C(=O)OC)s3)CCS2(=O)=O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(N2C(OCc3ccc(C(=O)OC)s3)CCS2(=O)=O)cc1
Reaction time: 16 h
Yield: 101.2 %

Procedure:
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (44 mg, 0.104 mmol) was added to a solution of the alcohol 14 (42 mg, 0.087 mmol) in CH2Cl2 (2 mL) at 23° C. After stirring for 16 h the reaction mixture was diluted with CH2Cl2 and filtered. The filtrate was concentrated in vacuo and purification of the residue by flash column chromatography (silica gel, 1:1 hex/EtOAc) gave 41 mg (98%) of the ketone 16.