Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].[I-].[K+].[F:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>CN(C)C=O>[F:18][C:19]1[CH:20]=[C:21]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[CH:27][CH:28]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Temperature: 95 °C

Procedure:
27.6 g of finely-pulverulent potassium carbonate, 18.2 g of ethyl 2-chloroethylcarbamate and 1 g of powdered potassium iodide are added to a solution of 22.2 g of 4-(3,5-difluorophenoxy)phenol in 80 ml of dimethylformamide. The reaction mixture is heated for 16 hours at 95° C., with stirring. After this, the reaction mixture is filtered, the filtrate is poured into 400 ml of water, and the mixture is extracted repeatedly with diethyl ether. The combined organic phases are washed with water and dried over sodium sulfate, and the solvent is distilled off. The residue is purified by chromatography over silica gel (eluent: n-hexane/diethyl ether 3:1), which gives the pure ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate as a colourless compound which soon crystallizes and has a melting point of 54°-56° C. The 1H-NMR spectrum agrees with the indicated structure.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:15])[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=1.[CH2:16]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:21](O)=O)[CH3:17]>>[CH2:16]([C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:5]=3)[N:15]=2)[CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH3:17]
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Reactant: Cc1cc(C(=N)NO)cc(CC(C)C)n1
Product: CCc1cc(-c2nc(-c3cc(C)nc(CC(C)C)c3)no2)cc(C)c1O

Procedure:
2-Ethyl-4-[3-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenol is prepared from N-hydroxy-2-isobutyl-6-methyl-isonicotinamidine and 3-ethyl-4-hydroxy-5-methyl-benzoic acid; LC-MS: tR=0.90 min, [M+1]+=352.17.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=2[N+:16]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[NH2:16][C:8]1[CH:9]=[C:10]([C:13](=[O:15])[CH3:14])[CH:11]=[CH:12][C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C2CCCCC2)c([N+](=O)[O-])c1
Agent: Cl
Product: CC(=O)c1ccc(C2CCCCC2)c(N)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Stannous chloride dihydrate (15.8 g, 0.07 mol) is added to a solution of 1-(4-cyclohexyl-3-nitrophenyl)ethanone (5.8 g, 0.0235 mol) in concentrated hydrochloric acid (35 mL) at 0-5° C. The reaction mixture is slowly brought to 60-65° C. and is stirred at this temperature for 15 minutes. After cooling to room temperature the reaction mixture is extracted with ethyl acetate (3×100 mL). The pH is adjusted to 8.0-9.0 using solid sodium bicarbonate. After washing with water (1×15 mL) the organic layer is dried over sodium sulfate and concentrated under reduced pressure to yield the crude, which is purified by column chromatography (230-400 mesh; ethyl acetate:n-hexane, 3:7) to give 1-(3-amino-4-cyclohexylphenyl)ethanone.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH:22]=[O:23]>O>[CH2:2]([O:4][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH:22]=[O:23])[CH3:3]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: CCO
Agent: [Na]
Solvent: O
Product: CCOC1=C(C=O)C(c2ccccc2)Oc2ccccc21
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1.7 g sodium is allowed to react with 150 ml absolute ethanol. After complete disappearance of sodium, one adds 13.5 g 4-chloro-3-formyl-flav-3-ene. After stirring 30 minutes at 40° C., 300 ml of water is added and a precipitate is formed, filtered, washed with water and dried. The solid is crystallized in hexane. Pure 4-ethoxy-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 80°-82° C.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:4](=[O:7])[NH:5][N:6]=1.Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:5]1[C:4](=[O:7])[N:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:2]([Br:1])=[N:6]1
Reactant: COC(=O)CCl
Reactant: O=c1[nH]nc(Br)n1Cc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)Cn1nc(Br)n(Cc2ccccc2F)c1=O

Procedure:
300 mg (1.1 mmol) of the compound from Example 135A are stirred under reflux for 2 hrs together with 150 mg (1.38 mmol) of methyl chloroacetate and 168 mg (1.21 mmol) of potassium carbonate in 10 ml acetonitrile. After cooling, the mixture is diluted with ethyl acetate and treated with 1 N hydrochloric acid. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulphate and freed of the volatile components on the rotary evaporator. The residue is dried under high vacuum. The product thus obtained (360 mg, purity ca. 73% by LC/MS) is used in the next synthetic step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10]CC)=O.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C1(C)C(C)=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:10]
Reactant: Nc1ccncc1
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1)c1c(O)c2sccc2[nH]c1=O
Temperature: 140 °C
Yield: 66.6 %

Procedure:
A mixture of 2.48 g (10.4 mmols) of ethyl 4,5-dihydro-7-hydroxy-5-oxothieno[3,2-b]pyridine-6-carboxylate [J. Chem. Res. (S), 6 (1980); J. Chem. Res. (M), 113 (1980)], 1.01 g (10.7 mmols) of 4-aminopyridine, 50 ml of xylene and 10 ml of dimethylformamide was heated at 140° C. for an hour. After completion of the reaction, insoluble matters were filtered and tritylated with dimethylformamide with heating to give 1.99 g (yield: 67%) of Compound 2.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[C:14]2[S:13][N:12]=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O>O1CCCC1>[S:13]1[C:14]2[C:6]([C:4]([NH2:1])=[O:3])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=[N:12]1
Reactant: COC(=O)c1cccc2nnsc12
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc2nnsc12

Procedure:
In an autoclave, under pressure and at room temperature, 17 g of ammonia ispassed into a solution of 19.4 g of benzo-1,2,3-thiadiazole-7-carboxylic acid methyl ester in 70 ml of tetrahydrofuran. The solution is then heatedand maintained at 80°-90° C. for approximately 20 hours, an internal pressure of 55·105Pa max. building up. Partial concentration by evaporation is then carried out and the resulting precipitate is filtered off, washed with cold tetrahydrofuran and dried. 14.9 g of beige crystals having a melting point of 270°-272°C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[N+:10]([C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1)(=[O:20])=[O:21]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Yield: 89.5 %

Procedure:
Using o-anisidine (1.0 ml, 8.55 mmol) and 3-nitrobenzenesulfonyl chloride (1.95 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.36 g (89.5%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3F)CC2)cc1-c1ccc(Cl)cc1

Procedure:
105 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(2-fluorophenyl)piperazine (50 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:42])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:20][C:19]=1[CH3:41])(C)(C)C>ClCCl>[CH3:41][C:19]1[CH:20]=[C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH2:15][CH2:14][C:13]([OH:42])=[O:12]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid tert-butyl ester from Example E76.1 (80 mg, 0.17 mmol) in dichloromethane (10 ml). The mixture was stirred for 2 h at room temperature, concentrated in vacuo and azeotroped with dichloromethane to yield the title compound (71 mg, 100%).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])=[O:16])([O:3][CH3:4])=[O:2].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:16])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCC(=O)Nc1ccccc1O
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCC(=O)OC

Procedure:
When (44) and 4-bromobutyronitrile are reacted under the conditions of step (A), above, (45) is obtained as a waxy solid. Conversely, reacting (44) with ethyl 4-bromobutyrate as in step (A) yields (8).
Reaction SMILES: [CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15](C(OC(C)(C)C)=O)[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCCC(=O)c1ccccc1
Reaction time: 4 h
Yield: 34.9 %

Procedure:
Dissolve 3-[(phenacyl)ethylamino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.79 g, 1.57 mmol) in methylene chloride (5 mL) and add, by dropwise addition, trifluoroacetic acid (5 mL). Stir for 4 hours and pour carefully into saturated sodium hydrogen carbonate (100 mL). Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo to giveas yellow oil. Recrystallize (ethyl acetate/hexane) to give the title compound (0.23 g, 36%); mp 203°-5° C.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([O:10]C)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO>[C:3]([NH:1][NH2:2])(=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NN
Reactant: CCCCCC(=O)OC
Solvent: CO
Product: CCCCCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 271.5 %

Procedure:
Under nitroqen, a solution of 262 g (8 2 mol) of anhydrous hydrazine in 1300 mL of methanol was cooled to 0° C. and treated with 885 g (6.8 mol) of methyl caproate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 7 h. The reaction was concentrated in vacuo; recrystallization from toluene gave 707 g (80%) of caproic acid hydrazide as a colorless solid: mp 72.5°-73.9° C.; NMR (CDCl3) δ 0.82 (t, J=7 Hz, 3H), 1.15-1.33 (m, 4H), 1.51-1.64 (m, 2H), 2.10 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 7.56 (br s, 1H). A 5.0 g (39 mmol) sample of the hydrazide was dissolved in 40 mL of methanol and treated with 11.2 g (78 mmol) of ethyl iminocaproate [P. Reynaud and R. C. Moreau, Bull. Soc., Chim. France, 2997 (1964)-which. was only about 50% pure by NMR] under nitrogen. The reaction was stirred at reflux for 2 days and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (48:52) gave 7.56 g (92%) of 3,5-dipentyl-1H-1,2,4-triazole as a colorless solid: mp 66°-68° C.; NMR (CDCl3) δ 0.88 (t, J=7 Hz, 6H), 1.24-1.41 (m, 8H), 1.66- 1.81 (m, 4H), 2.72 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 210 (100), 166 (14); HRMS. Calcd for M+H: 210.1970. Found: 210.1964.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[C:9]([NH2:17])=[C:8]([CH:18]([CH3:20])[CH3:19])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>ClC1C=CC=CC=1Cl>[N:1]1([C:6]2[N:7]=[C:8]([CH:18]([CH3:20])[CH3:19])[C:9]3[NH:17][C:21](=[O:22])[C:13]4=[N:14][CH:15]=[CH:16][N:12]4[C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)c1nc(-n2ccnc2)nc(-n2ccnc2)c1N
Solvent: Clc1ccccc1Cl
Product: CC(C)c1nc(-n2ccnc2)nc2c1[nH]c(=O)c1nccn12
Temperature: 25 °C

Procedure:
Combine 2,4-bis(1H-imidazol-1-yl)-6-(2-propyl)pyrimidin-5-amine (6 g, 22.3 mmol) with 4.5 g (27.8 mmol) of carbonyldiimidazole in 150 mL of 1,2-dichlorobenzene and heat at reflux under N2 for 2 hours. Cool to ambient temperature. Filter the precipitate and wash with CH2Cl2. Dissolve the solids in 500 mL of 10% HCl, treat with charcoal, filter, and make the filtrate basic with NH4OH. Filter the resulting precipitate, wash with water and then with acetone to provide 2-(1H-imidazol-1-yl)-4-(2-propyl)imidazo[2,1-h]pteridin-6(5H)-one; NMR (DMSO+CF3CO2D): δ1.32 (d, 6), 3.84 (m, 1), 7.15 (s, 1), 7.67 (s, 1), 8.04 (s, 1), 8.5 (s, 1) and 8.69 (s, 1 ) ppm.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:13]1[S:9][C:10]([C:14]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CC1(c2nccs2)CCCCC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ncc(Br)s2)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
N-Bromosuccinimide (0.33 g, 1.87 mmol) was added to a solution of the product from Step 1 (300 mg, 1.56 mmol) in DMF (5 ml) and the resulting reaction mixture was stirred at room temperature for 2 hrs. 2 aliquots of N-bromosuccinimide (0.33 g, 1.87 mmol) were added over a period of 23 hrs before addition of saturated aqueous Na2S2O3 (10 mL). The mixture was then extracted with EtOAc (2×20 mL) and the combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (gradient elution 7% to 60% EtOAc in Hexanes) to afford 1-(5-bromo-1,3-thiazol-2-yl)cyclohexanecarbonitrile (96 mg, 0.35 mmol, 22.7% yield) as a pale yellow oil. MS ESI: [M+]+ m/z 272.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.C(N(CC)CC)C.[Cl:33][CH2:34][C:35](Cl)=[O:36]>ClCCl>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12)=[O:36]
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=O)CCl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
To a round bottom flask charged with 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 47.2 mg, 0.139 mmol) was added dichloromethane (697 μL) and triethylamine (35.0 μL, 0.251 mmol). Chloroacetyl chloride (12.20 μL, 0.153 mmol) was added dropwise. The reaction mixture was stirred at rt for 16 h. Additional chloroacetyl chloride (12.20 μL, 0.153 mmol) was added. The reaction mixture was diluted with dichloromethane. The organics were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 4-(2-Chloroacetamido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (58.5 mg, 101% yield) was isolated as an orange paste. Material was used in subsequent reactions with no further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:28](=[O:32])/[CH:29]=[CH:30]/[CH3:31].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH:30]([CH3:31])[CH2:29][CH:28]=[O:32])=[O:15])[CH3:14]
Reactant: C/C=C/C=O
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCCCc1ccccc1)C(C)CC=O
Temperature: 0 °C
Yield: 92 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.34 ml, 0.0024 mole), trimethyl silylchloride (0.30 ml, 0.0024 mole) and crotonaldehyde (0.20 ml, 0.0024 mole). The reaction mixture was stirred at reflux temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 5% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a yellow oil (0.60 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]2[O:12][C:11](=[O:13])[C@@:10]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]1([C@H:34]([N:36]=[C:37]=[O:38])[CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:20]([C:7]1[C:8]([OH:12])=[C:9]([C@@:10]2([C:14]([F:16])([F:15])[F:17])[O:18][C:37](=[O:38])[N:36]([C@@H:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[CH3:35])[C:11]2=[O:13])[CH:19]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@@H](N=C=O)c1cccc2ccccc12
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2c(c1)[C@](O)(C(F)(F)F)C(=O)O2
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@H](c1cccc2ccccc12)N1C(=O)O[C@@](c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)(C(F)(F)F)C1=O
Yield: 37.9 %

Procedure:
(R)-(+)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (100 mg, 0.3 mmol), (R)-(−)-1-(1-naphthyl)ethyl isocyanate (58 uL, 0.33 mmol), and 4-dimethylaminopyridine (3.7 mg, 0.03 mmol) were heated at reflux in toluene (1 mL) for 1 h under nitrogen. The resulting solution was evaporated to dryness and the residue purified by chromatography on silica gel with a gradient of ethyl acetate in heptane from 0% to 100% in 20 min. and then with heptane/DCM 3:1. One obtained 60 mg (37%) of white crystals. Crystals suitable for X-ray analysis were obtained by slow evaporation of a solution in dichloromethane.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[CH3:49][C@@H:50]1[CH2:55][O:54][CH2:53][CH2:52][NH:51]1>>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][C@H:50]2[CH3:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C[C@@H]1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H]1COCCN1C(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 3, Step B) and (R)-3-methylmorpholine (EXAMPLE 12, Step B) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19ClN4O4S, 446.1; m/z found, 445 [M−H]−. HPLC (reverse phase): RT=8.54 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.05 (d, J=1.8 Hz, 1H), 9.04 (br s, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.56 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.91 (dd, J=8.4, 7.4 Hz, 1H), 7.56 (br s, 1H), 7.01-6.98 (m, 2H), 4.4-4.2 (br m, 1H), 3.90-3.82 (m, 1H), 3.68-3.62 (m, 1H), 3.51 (dd, J=11.5, 2.7 Hz, 1H), 3.40-3.20 (m, 3H), 1.31-1.23 (br m, 3H).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13](I)[CH2:12]1.Cl[C:19]1[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=1>[Zn].O1CCCC1>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:19]2[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=2)[CH2:12]1
Reactant: CC1CCCC(I)C1
Reactant: CSc1nsc(Cl)n1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CSc1nsc(C2CCCC(C)C2)n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
1.31 g of zinc foil (99.998%) and 190 mg of 1,2-dibromoethane was added into 2 ml of tetrahydrofurane under nitrogen atmosphere and the mixture was heated in an oil bath at 65° C. for 1 minute. After cooling to room temperature, 0.1 ml of trimethylsilyl chloride, 2.14 g of 3-methylcyclohexyl iodide and 10 ml of tetrahydrofuran were added to the mixture, and the mixture was exposed to ultrasonic wave in a water bath for 4 hours. Further, 1.31 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 390 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex and 10 ml of tetrahydrofuran were added in the mixture, and the reaction mixture was stirred for 3.5 days at room temperature. The reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 790 mg of 5-(3-methylcyclohexyl)-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2nc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc2ccccc2cc1CBr
Temperature: 25 °C
Yield: 33.1 %

Procedure:
To a solution of 2,3-dimethylquinoline (0.50 g, 3.2 mmol) in carbon tetrachloride (40 ml) benzoyl peroxide (100 mg) and N-bromosuccinimide (1.14 g, 6.4 mmol) were added. The reaction mixture was refluxed for 4 hours, and then cooled to room temperature. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate/petroleum ether as the eluent to give 0.25 g of 3-bromomethyl-2-methylquinoline.