Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2

Procedure:
A nitrogen flushed mixture of heptyl-carbamic acid 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.378 g., 1 mmol) and 10% Pd—C (0.02 g.) in absolute ethanol (20 ml) was shaken in a par apparatus at room temperature (38° C.) under 55 psi pressure of hydrogen for 4 hours. Pd—C was then discarded through filtration. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed with methanol: dichloromethane (1:99) to give 2b; yield: 0.25 g. (84.6%), m.p.: 67° C., C17H26N2O2; 1H NMR δ ppm (CDCl3): 0.88 (bs, 3H), 1.20-1.30 (m, 7H, 1.56 (bs, 3H), 1.88-1.93 (m, 2H), 2.74 (t, 2H), 3.23-3.28 (m, 4H), 3.66-3.76 (m, 1H), 4.89 (bs, 1H), 6.40-6.44 (m, 1H), 6.68-6.71 (m, 2H); IR vmax (KBr) (cm−1): 561, 665, 768, 815, 887, 976, 1149, 1223, 1308, 1353, 1506, 1621, 1699, 2362, 2857, 2930, 3763.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.C([O-])(O)=O.[Na+].[I:16]I.OS([O-])(=O)=O.[Na+]>O>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:16])[CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: II
Reactant: OCc1ccc(O)c(Cl)n1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: OCc1cc(I)c(O)c(Cl)n1
Yield: 62 %

Procedure:
2-Chloro-6-(hydroxymethyl)-3-pyridinol (C10) (11.6 g, 72.7 mmol) and NaHCO3 (18.3 g, 218 mmol) are added to 200 mL water. The mixture is stirred until homogeneous, the flask is placed in an ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is stirred over the weekend at rt. The pH of the mixture is adjusted to 3 with 2N NaHSO4, and the mixture is extracted with 4×50 mL EtOAc. The combined organic layer is dried over anhydrous MgSO4, is filtered and the filtrate is concentrated in vacuo to a yellow solid. The crude solid is washed with EtOAc to provide 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C12) as an off-white solid (62% yield), and the filtrate is concentrated to a small volume and is chromatographed over 250 g silica gel (230-400 mesh) eluting with 2.5:4.5:4:0.1 EtOAc/CH2Cl2/hexane/acetic acid. The desire fractions are combined and concentrated to afford an additional pure C12 (12% yield). MS (EI) for C6H5ClINO2, m/z: 285(M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10](O)[C:11]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[C:12]=2[N:26]=1.P(OCC)(OCC)OCC>CN(C)C=O>[ClH:1].[ClH:1].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[C:12]=2[N:26]=1
Reactant: On1c(-c2c(Cl)cccc2Cl)nc2c1-c1ccncc1Nc1ncccc1-2
Agent: CCOP(OCC)OCC
Solvent: CN(C)C=O
Product: Cl
Product: Clc1cccc(Cl)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Temperature: 25 °C
Yield: 241.4 %

Procedure:
2-(2,6-Dichlorophenyl)imidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepin-3(8H)-ol (15.2 g, 0.0384 mol) in N,N-dimethylformamide (250 mL) was treated with triethyl phosphite (26.3 mL, 0.153 mol) and the solution was heated to reflux for 2.5 hours. The solution was allowed to cool to room temperature and was concentrated in vacuo. The residual yellow solid was collected by filtration (using 2 L of acetonitrile to wash). The yellow powder was then dissolved in 250 mL of 0.5 N aqueous hydrochloric acid and 50 mL of acetonitrile. The dark red solution was freeze dried for 16 hours to afford the desired product as an orange-red powder (14.0 g, 85%). 1H NMR (400 MHz, d6-DMSO): δ 8.81 (s, 1H), 8.09 (d, J=6.2 Hz, 1H), 8.03 (s, 1H), 7.94 (dd, J=5.0, 1.6 Hz, 1H), 7.69-7.57 (m, 5H), 6.86 (dd, J=7.5, 4.9 Hz, 1H). LCMS calculated for C19H12Cl2N5 (M+H)+: m/z=380.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][NH:19][C:20]([C:22]1[CH:27]=[C:26](OC2C=CC([N+]([O-])=O)=C([N+]([O-])=O)C=2)[CH:25]=[CH:24][N:23]=1)=[O:21]>CN(C=O)C>[CH3:18][NH:19][C:20]([C:22]1[CH:27]=[C:26]([O:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:16][CH:15]=2)[CH:25]=[CH:24][N:23]=1)=[O:21]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CNC(=O)c1cc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(OCc3ccccc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred RT slurry of NaH (2.24 g of 60% oil dispersion, 55.9 mmol) in 40 mL DMF was added 4-benzyloxyphenol (11.2 g, 55.9 mmol). The mixture was stirred for 10 min before adding 4-chloro-pyridine-2-carboxylic acid methylamide (Example 2 Step A, 3.18 g, 18.6 mmol). The reaction was stirred at RT for 5 min, then at 75° C. for 2 h, and finally at 85° C. for 6 h. The reaction was cooled to RT, quenched with saturated aqueous NaHCO3, then diluted with Et2O and 6 N NaOH. The layers were separated, and the organic layer was washed twice with 6 N NaOH, once with brine, dried over Na2SO4, filtered, and concentrated in vacuo, to yield the title compound as a light salmon-colored solid. MS (MH+)=335.1; MW Calc'd 334.38 for C20H18N2O3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(OC)cc1
Product: COC(=O)c1nc(C)sc1-c1ccc(OC)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-methoxy-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.90 min; [M+H]+=263.93.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH3:8][C:9]([CH3:11])=[O:10].C(O)C.[ClH:15]>C[Si](C)(C)N[Si](C)(C)C.O>[ClH:15].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:9]([OH:10])([CH3:11])[CH3:8])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: CC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(O)P(=O)(O)CCCN
Temperature: 25 °C

Procedure:
A suspension of 1.23 g 3-aminopropylphosphonous acid in 25 ml of hexamethyldisilazane is heated to reflux under an inert gas for 20 hours. After this time a clear solution results and the reaction mixture is cooled to room temperature under inert gas and 50 ml of anhydrous acetone is added and an exothermic reaction results. The reaction mixture is allowed to cool to room temperature and the volatile components removed in vacuo to afford a clear oil. This oil is dissolved in 50 ml of a 2.0M hydrochloric acid solution in water and washed with 2×100 ml of dichloromethane and 1×100 ml of ether. The aqueous layer is evaporated to dryness to give a semi-solid residue which is co-evaporated with water (10×20 ml) and absolute ethanol (10×20 ml yielding 3-aminopropyl(2-hydroxyprop-2-y)phosphinic acid hydrochloride m.p. 159°-161° as a white solid. This is suspended in absolute ethanol and treated with propylene oxide. Filtration and drying of the solid affords 3-aminopropyl(2-hydroxyprop-2 -yl)phosphinic acid; m.p. 243°-244°.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])=[O:4].O=C[C@@H]([C@@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O

Procedure:
The present inventors assiduously continued to study in order to obtain a crystalline sugar from a mixture containing D-psicose and D-allose obtained in high yield by the reaction of L-rhamnose isomerase (L-RhI).
Reaction SMILES: [F:1][C:2]1([F:14])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]1([F:13])[F:12].[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.O1CCOCC1.I(O)(=O)(=O)=O>O.CO>[F:13][C:3]1([F:12])[O:4][C:5]2[CH:11]=[CH:10][C:9]([B:15]([OH:19])[OH:16])=[CH:8][C:6]=2[O:7][C:2]1([F:1])[F:14]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: FC1(F)Oc2ccccc2OC1(F)F
Agent: [O-][I+3]([O-])([O-])O
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: OB(O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2,2,3,3-Tetrafluoro-1,4-benzodioxane (484 mg), bis(pinacolato)diboron (295 mg), [Ir(COD)(OMe)]2 (15.4 mg) and 4,4′di-tert-butyl-2,2′-dipyridyl (12.5 mg) were mixed. 1,4-Dioxane (0.5 mL) was added in a nitrogen atmosphere and stirred at 100° C. for two hours. MeOH (0.5 mL) was added to the reaction solution, and metaperiodic acid (1.06 g) was added in four portions under ice-cooling. Water was added to the reaction solution, followed by extraction with ethyl acetate and concentration. The resulting mixture was purified by silica gel column chromatography to give 2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl-boronic acid (230 mg, 39%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[O-]CC.[Mg+2:34].[O-]CC.CCCCCCC>C(O)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[Mg:34]
Reactant: [Mg+2]
Agent: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: CC[O-]
Solvent: CC(C)O
Solvent: CCCCCCC
Product: [Mg]
Temperature: 25 °C

Procedure:
To 40.81 g of losartan of Example 1 in 235 ml of i-propanol, 6.07 g magnesium ethoxide were added, and stirred at reflux temperature overnight. Reaction mixture was hot filtered, 650 ml n-heptane were added, and cooled to room temperature for the product to precipitate. It was filtered and washed with 110 ml n-heptane, and dried in vacuo at 50° C. to yield 37.9 g losartan magnesium.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)[C:12]2[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8].CC([O-])(C)C.[K+].Cl>CN(C=O)C>[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:24][CH:25]=2)[C:12]2[C:13](=[O:17])[N:14]([CH2:2][C:3]#[N:4])[CH:15]=[CH:16][C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: N#CCCl
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccn(CC#N)c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.79 g of chloroacetonitrile in 5 ml of DMF is added dropwise at 20°, with stirring, to a solution of 3.82 g of 2-butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine and 1.17 g of potassium tert-butylate in 20 ml of DMF. The mixture is stirred at 20° for a further 30 min and poured on to ice, hydrochloric acid is added to pH 6 and the mixture is worked up in conventional manner to give 2-butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-5-cyanomethyl-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine, m.p. 64°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[OH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:37][CH2:36]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCC(O)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-hydroxy-piperidine. ES-MS m/e (%): 470 (M+H+, 100).
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(CO)cccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(CCl)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)indoline-1-carboxylate (230 mg, 0.92 mmol) in dichloromethane (3 mL), thionyl chloride (0.123 mL, 1.02 mmol) was added dropwise at 0° C. and stirred for 1 h. Then the mixture was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated under reduced pressure and dried under high vacuum to yield the title compound (217 mg, crude). The compound was directly used for the next step. [TLC Rf=0.86 (ethyl acetate/hexane 20:80)].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([CH3:20])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[CH3:20][C:13]1[CH:12]=[C:11]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(C=O)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 104.5 %

Procedure:
4-Hydroxybenzaldehyde (945 mg, 7.7 mmol), 4-fluoro-2-methyl-1-nitrobenzene (1.0 g, 6.4 mmol), and K2CO3 (1.77 g, 12.8 mmol) were stirred in 55 mL dimethylformamide at 100 degrees Centigrade for 18 hours. The reaction was cooled to room temperature, diluted with ethylacetate, extracted two times with 1N NaOH, and rinsed with brine. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.72 g crude 4-[(3-methyl-4-nitrophenyl)oxy]benzaldehyde, which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26]>CN1CCCC1=O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:27])([NH2:28])[CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(N)CN
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(N)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.6 mL, 47 mmol) was added slowly to a solution of 2,4-dichloro-3-nitroquinoline (10.0 g, 41.1 mmol) in anhydrous 1-methyl-2-pyrrolidinone (40 mL). The reaction mixture was cooled to 0° C. with an ice bath. A solution of 1,2-diamino-2-methylpropane (4.1 g, 47.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (5 mL) was added dropwise over a period of 15 minutes while maintaining the temperature of the reaction mixture below 4° C. After the addition was completed the ice bath was removed and the reaction mixture was allowed to stir at ambient temperature for 4 hours. The reaction mixture was slowly poured into vigorously stirred warm water (300 mL). The resulting suspension was stirred for 1 hour and then cooled to 13° C. by adding ice. The solid was isolated by filtration and then washed with cold water until the filtrate was clear to provide 12.1 g of N1-(2-chloro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine as a damp yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].Br[CH2:11][C:12]1[CH:25]=[CH:24][C:23]2[C:22](=[O:26])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=1.[I:28][CH3:29]>CN(C=O)C.C(#N)C>[I-:28].[CH3:29][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([C:13]2[C:14]3[C:15](=[O:27])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22](=[O:26])[C:23]=3[CH:24]=[CH:25][C:12]=2[CH3:11])=[CH:4]1
Reactant: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Reactant: CI
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ccc2c(c1-[n+]1cn(C)c(Cl)c1Cl)C(=O)c1ccccc1C2=O
Product: [I-]
Temperature: 80 °C

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) were combined in a round bottom flask. Acetonitrile (2 mL) was added and the mixture was stirred at reflux for 30 min, dissolving the remaining solid. Concurrently, 2-(Bromomethyl)anthraquinone (0.40 g, 1.33 mmol) was added to 30 mL acetonitrile and stirred at reflux for 30 min, partially dissolving the solid. The solution in the initial flask was added to the 2-(bromomethyl)anthraquinone mixture, and the solution was returned to reflux for 3 h. The mixture was filtered hot, and a precipitate quickly formed in the tan filtrate. The precipitate was collected by a second filtration and washed with cold acetonitrile to yield a yellow powder. This solid (0.50 g, 1.0 mmol) will be dissolved in DMF and heated at 80° C. Iodomethane (0.62 mL, 10.0 mmol) will be added slowly and the reaction mixture will be heated for 12 h. Removal of the volatile components under reduced pressure will yield the product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:27])[C:17](=[CH:28][O:29][CH2:30][CH3:31])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:32]([O:27][C@H:18]1[C:17](=[CH:28][O:29][CH2:30][CH3:31])[CH2:16][C@H:15]2[C@H:14]3[C@H:23]([CH2:22][CH2:21][C@:19]12[CH3:20])[C:24]1[CH:25]=[CH:26][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH2:12][CH2:13]3)(=[O:34])[CH3:33]
Reactant: CCOC=C1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC=C1C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]2(C)[C@H]1OC(C)=O
Yield: 86 %

Procedure:
A solution of 3 (194 mg), acetic anhydride (1 mL) in pyridine (3ml) was stirred at rt overnight under N2. Reaction was poured into saturated aqueous NaHCO3 (150 mL) and extracted with CH2Cl2 (3×, 100 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on a 2×20 cm column of silica gel using hexanes/EtOAc (4:1) as eluent gave 183 mg (86%) of 4 as a white solid: TLC, T-2, Rf0.67.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][S:9]([OH:12])(=O)=[O:10].CN(C=O)C.S(Cl)([Cl:20])=O>>[ClH:20].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][S:9]([Cl:20])(=[O:12])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)CCc1ccccn1
Solvent: CN(C)C=O
Product: Cl
Product: O=S(=O)(Cl)CCc1ccccn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
2-(2-Pyridyl)ethanesulfonic acid (1.00 g) was suspended in thionyl chloride (5 ml). Catalytic amount of DMF was added to the suspension. The mixture was stirred at 50° C. for 30 minutes, and was concentrated in vacuo. The resulting solid was recovered and washed with Et2O to give 1.41 g of 2-(2-pyridyl)ethanesulfonyl chloride hydrochloride as a solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH2:25]([Mg]Br)[CH3:26]>O1CCCC1.C(OCC)C.[Cl-].[Na+].O>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:19])=[O:20])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH2:25][CH3:26]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 0.3 g (0.7 mmol) of material from Example 45 in 4 mL of tetrahydrofuran at ambient temperature was added 0.5 mL (1.5 mmol) of a 3.0M solution of ethylmagnesium bromide in ethyl ether. The mixture was stirred for 16 hours, diluted with 5 mL of half saturated brine and extracted four times with 5 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (15 g silica gel, 50% ethyl acetate/hexane) of the residue afforded 0.1 g (42%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O>>[CH2:21]([CH:18]([N:13]1[C:12]([C:32]2[S:31][CH:35]=[CH:34][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH2:19][CH3:20])[CH3:22]
Reactant: CCC(CC)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1cccs1
Product: CCC(CC)n1nc2c(c1-c1cccs1)CCNCC2
Yield: 37.2 %

Procedure:
The title compound (35 mg) was prepared as in Example 177, Steps C and D, using 148 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 122 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H23N3S, 289.16; found, m/z 290.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.72-7.67 (m, 1H), 7.25-7.21 (m, 1H), 7.13-7.09 (m, 1H), 4.01-3.94 (m, 1H), 3.43-3.38 (m, 2H), 3.34-3.28 (m, 2H), 3.20-3.14 (m, 2H), 2.86-2.80 (m, 2H), 1.95-1.85 (m, 2H), 1.79-1.69 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.CCN(CC)CC>CO.C(Cl)Cl.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][NH2:11])=[CH:6][CH:7]=1
Reactant: NCC#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: NCC=Cc1ccc(Cl)cc1
Yield: 74.1 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-prop-2-ynylamine (14.0 g) in 200 mL each of MeOH and CH2Cl2 was added Et3N (1.2 mL) and Lindlar catalyst (1.4 g) and the resulting suspension was stirred under a H2 balloon. The reaction was followed by TLC (i.e., thin layer chromatography) using 6% methanol-dichloromethane as eluent and once completed, filtered through a CELITE pad, concentrated and purified by chromatography to provide 10.5 g of 3-(4-chloro-phenyl)-allylamine. MS: m/e 168.6 (MH+)
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COCOCc1cc(C(=O)C2CC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1ccnc(COCOC)c1)C1CC1

Procedure:
To a suspension of 60% sodium hydride (1.09 g) in THF (30 mL) was added ethyl diethylphosphonoacetate (6.46 mL) at 0° C., and then cyclopropyl(2-((methoxymethoxy)methyl)pyridin-4-yl)methanone (1.20 g) was added. The reaction mixture was heated under reflux for 2 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.36 g) as a pale-yellow oil.