Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([F:29])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>CN(C)C=O.C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)=[CH:21][C:22]=1[F:29]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ccnc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Yield: 55.3 %

Procedure:
7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline (190 mg) was dissolved in N,N-dimethylformamide (5 ml) and triethylamine (1 ml). Palladium hydroxide (40 mg) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/methanol (20/1) to give 75 mg (yield 56%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:44][CH2:43][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][N:19]([CH2:28][C:29]5[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=5)[C:32]([O:34]C(C)(C)C)=[O:33])[C:18]4=[O:42])[CH2:16][CH2:15]3)[C:6]=2[CH:45]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:44][CH2:43][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][N:19]([CH2:28][C:29]5[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=5)[C:32]([OH:34])=[O:33])[C:18]4=[O:42])[CH2:16][CH2:15]3)[C:6]=2[CH:45]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccc(Cl)cc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccc(Cl)cc54)CC3)C2=O)c1
Yield: 24 %

Procedure:
A solution of tert-butyl 3-((8-(3-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (100 mg, 0.16 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo and the crude residue was purified using preparatory high performance liquid chromatography to afford the acetate salt of the title compound as a white solid (22 mg, 24%); 1H NMR (400 MHz, DMSO-d6): 1.61 (d, 2H, J=13.2 Hz); 1.83 (t, 2H, J=6.8 Hz); 2.37 (t, 2H, J=7.2 and 6.8 Hz); 2.54-2.58 (m, 2H); 2.67-2.72 (m, 4H); 3.85 (t, 2H, J=6.8 Hz); 4.58 (s, 2H); 4.61 (s, 2H); 6.77 (t, 1H, J=7.6 and 7.2 Hz); 6.85 (d, 2H, J=7.2 Hz); 6.98-7.01 (m, 2H); 7.20-7.24 (m, 3H); 7.47-7.53 (m, 2H); 7.86-7.88 (m, 2H); 11.01 (bs, 1H); MS for C31H32ClN5O4 m/z 574 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[S:24](=[O:38])(=[O:37])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[N:31]=[CH:30]2)[C:17]([O:19][CH3:20])=[O:18]>>[Cl:8][C:7]1[C:2]([N:25]([CH2:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH3:36])[N:31]=[CH:30]3)[S:24]([C:23]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:13])(=[O:38])=[O:37])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)c(C)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(C(F)(F)F)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 3-methyl-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 26).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:27][CH2:26]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[N:8]2[CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:27][CH2:26]2)=[CH:4][CH:3]=1
Reactant: BrCCCOC1CC1
Reactant: CC1(C)C(=O)Nc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCCOC2CC2)c2cc(Br)ccc21
Temperature: 70 °C

Procedure:
To a suspension of 6-bromo-3,3-dimethylindolin-2-one (example 14a, 300 mg, 1.25 mmol) and Cs2CO3 (814 mg, 2.5 mmol) in DMF (2 ml) was added a solution of (3-bromopropoxy)cyclopropane (447 mg, 2.5 mmol) in DMF (0.5 ml). The reaction mixture was heated to 70° C. for 3 hours. The reaction mixture was filtered through sintered glass and concentrated. The crude material was purified by flash chromatography on silica gel using ethyl acetate as eluent. The title compound was obtained as orange viscous oil (360 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:16][NH:17][C:18](=[O:23])[C:19]([O:21]C)=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH3:34]CO>O>[CH3:34][N:17]([CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18](=[O:23])[C:19]([OH:21])=[O:20]
Reactant: CCO
Reactant: COC(=O)C(=O)NCC(C#Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(C#Cc2ccccc2)CN(C)C(=O)C(=O)O)cc1OC1CCCC1

Procedure:
A solution of (+,-)-methyl 2-(3-cyclopentyloxy-4-methoxyphenyl)-4-phenyl-but-3-ynyloxamate (100 mg, 0.24 mmol) in hot EtOH (3 ml) was treated with 2.5N NaOH (0.5 ml). The reaction was diluted with H2O, acidified with Hcl, and extracted with EtOAc. The extracts were washed with H2O, dried and the solvent evaporated. The residue was recrystallized from MeCN, and gave the titled compound, 42 mg (44%). mp 157-159°. 1H NMR (400 MHz, CDCl3 +DMSO-D6) δ 7.63 (t, 1 H), 7.45 (m, 2 H), 7.30 (m, 4 H), 6.97 (m, 2 H), 6.85 (d, 1 H), 4.79 (m, 1 H), 4.07 (t, 1 H), 3.84 (s, 3 H), 3.74 (m, 1 H), 3.62 (m, 1 H), 1.78-1.98 (m, 6 H), 1.61 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:27][CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:25][CH3:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 67 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (200.0 mg, 0.517 mmol) in pyridine (1.0 mL) was added acetic anhydride (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 5.5 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-50% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from ethanol/n-hexane to give the title compound as a colorless powder (148.4 mg, 0.346 mmol, 67%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[NH:29]1[C:33]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)=[N:32][N:31]=[N:30]1>>[NH:32]1[C:33]([C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:36][CH:35]=2)=[N:29][N:30]=[N:31]1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2nnn[nH]2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(tetrazol-5-yl)-aniline Rf value: 0.5 (silica gel, methylene chloride/ethanol=5:1) C25H20N6O3
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)CCO3)S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-(3-{[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12w, and 4-fluorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ7.79 (m, 2H), 7.14 (m, 3H), 7.03 (d, 1H), 6.88 (m, 2H), 6.79 (s, 1H), 6.71 (d, 1H), 6.58 (d, 1H), 4.51 (t, 2H), 4.25 (s, 2H), 4.21 (s, 2H), 3.64 (s, 3H), 3.08 (t, 2H), 2.80 (t, 2H), 2.50 (t, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18]O)[CH:12]=[CH:11]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42]N1C(=O)CCC1=O>ClCCl>[Br:42][CH2:18][CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][CH:7]=[C:6]2[O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:12]=1
Reactant: COCCOc1cccc2ccc(CC(CO)C(C)C)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOc1cccc2ccc(CC(CBr)C(C)C)cc12
Reaction time: 4 h

Procedure:
A solution of 0.30 g of 2-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-3-methylbutan-1-ol in 10 ml of dichloromethane at 0° C. is admixed with 0.29 g of triphenylphosphine and 0.20 g of N-bromosuccinimide. After 4 hours, the reaction mixture is concentrated by evaporation to a volume of approx. 3 ml, diluted with hexane, clarified by filtration and then concentrated fully by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5](OC(C)C)[O:4]1.[P:12]([O:21]C(C)C)([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15].P(Cl)(Cl)Cl>[Cl-].[Zn+2].[Cl-]>[Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([P:12]([O:17][CH:18]([CH3:20])[CH3:19])([O:13][CH:14]([CH3:16])[CH3:15])=[O:21])[O:4]1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CC(C)O[C@@H]1OC[C@@H](CBr)O1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClP(Cl)Cl
Product: CC(C)OP(=O)(OC(C)C)[C@@H]1OC[C@@H](CBr)O1
Temperature: 0 °C
Reaction time: 10 h
Yield: 72 %

Procedure:
To the mixture of cis and trans 4-(bromomethyl)-2-isopropoxy-1,3-dioxolane (example 2) (6.13 g, 9:1 of isopropoxy:methoxy) was added triisopropyl phosphite (4.43 mL, 18.0 mmol, 0.66 eq.), phosphorus trichloride (0.784 mL, 8.99 mmol, 0.33 eq.) and zinc chloride (few milligrams) at 0° C. The mixture was stirred at 0° C. for 2 hr and at room temperature for 10 hr. The crude mixture of cis and trans isomers in a 2:5 ratio was purified by flash chromatography on silica gel using dichloromethane:ethyl acetate 4:1 as eluant to give the cis isomer (0.242 g), a mixture of cis and trans isomers (3.13 g) and the trans isomer (3.15 g) for a total yield of 72%. Several chromatographic purifications were performed to obtain the cis and trans isomers in pure form.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26]CC=C)=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]1(OC2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH2:35][CH:30]=[CH2:31])[C:20]=3[OH:26])=[O:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc(Cl)cc1NC(=O)Cc1ccc(OC)c(OC2CCCC2)c1
Product: C=CCc1cc(Cl)cc(NC(=O)Cc2ccc(OC)c(OC3CCCC3)c2)c1O

Procedure:
A solution of N-(3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline (33 grams, 0.079 mol) in 330 milliliters of diphenyl ether was heated at 180° for 6.5 hours. This reaction mixture was combined with a second reaction mixture containing N-(3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline and 250 milliliters of diphenyl ether which had been heated at 180° for 20 hours.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH2:9]([N:11]=[C:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:20])=[CH:13]1)[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([N:11]([CH2:9][CH3:10])[C:12]1[CH:13]=[C:14]([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH:17]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCN=C1C=C(C)CC(C)(C)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(C(=O)COC(C)=O)C1=CC(C)(C)CC(C)=C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 1076.8 %

Procedure:
2-Acetoxyacetyl chloride (6.42 g, 4.7 mmol) is added slowly to a mixture of 1A (7.62 g, 4.2 mmol) and toluene (50 ml), which is cooled to −5° C. After the addition is complete, the mixture is stirred for a further 1 hour at −5° C., then allowed to warm to room temperature and stirred for a further 1.5 hours. The reaction mixture is then cooled down to −3° C. and a mixture of triethylamine (6.5 ml, 4.7 mmol) and toluene (25 ml) is added slowly to the mixture. The mixture is stirred for a further 16 hours, during which time the temperature is gradually allowed to rise to room temperature. The mixture is filtered, and the filtrate is washed three times with water, dried over sodium sulfate and evaporated in vacuo to give the crude product (12.0 g, 89%) as an oil. A portion of this crude material (4 g) is purified by flash column chromatography, eluting with a mixture of ethyl acetate and petroleum ether (1:4) to give pure product (2.3 g, equivalent to 51% overall), with m.p. 38-40° C. NMR analysis of this indicates that the product has a purity of about 88 mol %, the impurity consisting mainly of two isomeric products.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[C:5]#[N:6].C1C(=O)N([Br:19])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:19][C:8]1[C:7]([CH3:11])=[C:4]([C:3]([O:2][CH3:1])=[CH:10][CH:9]=1)[C:5]#[N:6]
Reactant: COc1cccc(C)c1C#N
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)c(C)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxy-6-methylbenzonitrile (3.6 g, 24 mmol) in TFA (25 mL) was added NBS (6.5 g, 36 mmol) and stirred at room temperature for 2 hours. Analysis of the reaction mixture by LC indicated complete bromination of the starting material. The solution was concentrated in vacuo and the resulting crude was dissolved in EtOAc and washed with brine, then dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (Hexanes:EtOAc=1:1) to provide the title product.
Reaction SMILES: [CH2:1]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:12]1O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Ni]>[CH2:1]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC1CCCC(CCCCCCCCCC)C1O
Agent: [Ni]
Product: CCCCCCCCCCC1CCCC(CCCCCCCCCC)C1

Procedure:
137 Grams of 2,6-didecyl-cyclohexanol were hydrogenated with 14 gm of Girdler nickel 49A. 71 Grams of the hydrocarbon 1,3-didecyl-cyclohexane were recovered.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[O:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][NH2:32])[CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:32][CH2:31][CH:27]2[CH2:28][CH2:29][CH2:30][O:25][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: NCC1CCCOC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CCCOC2)cn1
Yield: 25 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using (tetrahydro-2-H-pyran-3-yl)methanamine hydrochloride instead of methylamine, to the title compound (33 mg, 25%) which was obtained as a white solid after crystallisation from ethyl acetate:hexane. MS: m/e=408.4 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[Cl:17][C:18]1[N:23]=[C:22]2[CH:24]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[S:26][C:21]2=[CH:20][CH:19]=1>>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:27]([C:25]3[S:26][C:21]4[C:22](=[N:23][C:18]([Cl:17])=[CH:19][CH:20]=4)[CH:24]=3)(=[O:28])=[O:29])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)cs1

Procedure:
The title compound is prepared from 4-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-thiophene-2carbonitrile hydrochloride as described in EXAMPLE 1, Part E using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride. The product is triturated with Et2O/CH2Cl2 /hexanes to give a white solid.
Reaction SMILES: C(O)(=O)C.[Cl-].[NH4+:6].[F:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20](=[NH:23])OC)=[N:12]1>>[F:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20]([NH2:6])=[NH:23])=[N:12]1
Reactant: [NH4+]
Reactant: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: [Cl-]
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12

Procedure:
The solution of methyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate in methanol obtained from Example 5A is mixed with 33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride and stirred under reflux overnight. The solvent is evaporated in vacuo, the residue is thoroughly triturated with acetone, and the precipitated solid is filtered off with suction. It is added to 2 l of water, 31.8 g of sodium carbonate are added while stirring, the mixture is extracted three times with a total of 1 l of ethyl acetate, and the organic phase is dried with magnesium sulphate and evaporated in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:21][CH2:22][N:23]=3)[C:8]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[N:9][C:10]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][CH2:32][CH2:33][S:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)(=[O:36])=[O:35].O>CN(C=O)C>[N:37]1([S:34]([CH2:33][CH2:32][CH2:31][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:7]([CH2:21][CH2:22][N:23]=4)[C:8]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)=[N:9][C:10]=3[CH:11]=2)(=[O:36])=[O:35])[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1
Reactant: O=S(=O)(CCCCl)N1CCOCC1
Reactant: O=C(NC1=Nc2cc(O)ccc2C2=NCCN12)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1=Nc2cc(OCCCS(=O)(=O)N3CCOCC3)ccc2C2=NCCN12)c1cccnc1
Temperature: 120 °C
Yield: 26.1 %

Procedure:
To N-(8-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Example 2-5 in WO2004029055, 250 mg, 0.001 mol) and K2CO3 (1.1 g, 0.008 mol) in DMF (5 ml) was added 4-[(3-chloropropyl)sulfonyl]morpholine (Intermediate E, 204.0 mg, 0.001 mol) to a sealed tube and heated to 120° C. for 3 h. The reaction was poured into water and extracted with CH2Cl2. Organic layers dried with MgSO4, filtered and concentrated. The residue was purified using silica gel flash chromatography (100% EtOAc, then 0-20% MeOH/CH2Cl2) to provide the title compound (130 mg, 33%). TLC: Rf=0.21 in 10% MeOH/CH2Cl2, HPLC MS RT=1.81 min., MW=499.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.22 (2H, m), 3.17 (4H, m), 3.26 (2H, m), 3.64 (4H, m), 4.18-4.29 (4H, m), 4.56 (2H, m), 7.22 (1H, d), 7.74 (1H, s), 7.89 (1H, m), 8.12 (1H, d), 8.81 (1H, m), 8.95 (1H, dd), 9.44 (1H, s).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[CH3:13][O:14][NH2:15].O.O.O.C([O-])(=O)C.[Na+]>CO.O>[CH3:13][O:14][N:15]=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: CON
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
In 3.8 l of methanol was dissolved 176 g of isatin while heating, and a solution of 100 g of O-methylhydroxylamine hydrochloride and 136 g of sodium acetate trihydrate in 400 ml of water was added thereto. The resulting mixture was stirred at room temperature for 10 minutes, followed by concentration. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated to give 192 g (91%) of 3-methoxyiminoindolin-2-one. The resulting crude product was used in the subsequent reaction without being purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][CH2:26][O:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:25][CH2:26][O:27][CH3:28])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Product: COCCn1ccc(-n2c(C)nc(C#Cc3cccc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=382.3, 384.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and 2-bromoethyl-methylether.