Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:26][N:25]([C:27](=[O:44])[CH2:28][N:29]([CH2:37][CH2:38][C:39]3[NH:43][N:42]=[N:41][CH:40]=3)C(=O)OC(C)(C)C)[CH2:24][C:22]=2[N:23]=1>ClCCl>[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:26][N:25]([C:27](=[O:44])[CH2:28][NH:29][CH2:37][CH2:38][C:39]3[NH:43][N:42]=[N:41][CH:40]=3)[CH2:24][C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)N(CCc1cnn[nH]1)CC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNCCc1cnn[nH]1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Add trifluoroacetic acid (3 mL) slowly to a 0° C. solution containing tert-butyl {2-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-oxoethyl}[2-(1H-1,2,3-triazol-5-yl)ethyl]carbamate (0.15 g; 1.0 equiv; 0.297 mmoles) in dichloromethane (1 mL). Stir for 2 hours, then warm to ambient temperature and stir for 30 minutes. Concentrate the mixture and dissolve the residue in dichloromethane (20 mL). Add saturated sodium bicarbonate (20 mL), brine (20 mL), and water (50 mL), and extract with dichloromethane (6×20 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]-2-{[2-(1H-1,2,3-triazol-5-yl)-ethyl]amino}ethanone (0.093 g; 77%) as a yellowish foam: MS (m/z): 405(M+1).
Reaction SMILES: [CH3:1][N:2]([CH:21]([CH3:23])[CH3:22])[C:3]1[CH:20]=[N:19][C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][O:11][C:5]=2[N:4]=1.[Br:24]N1C(=O)CCC1=O.C(#N)C>O>[Br:24][C:20]1[C:3]([N:2]([CH3:1])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7][C:6]=2[N:19]=1
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC(C)N(C)c1nc2c(nc1Br)CN(C(=O)OC(C)(C)C)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A mixture of tert-butyl 3-[methyl(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (1.0 g), N-bromosuccinimide (608 mg) and acetonitrile (20 mL) was stirred at room temperature for 16 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 3→30% ethyl acetate/hexane) to give the title compound (915 mg, 74%) as a colorless oil.
Reaction SMILES: O[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.S(Cl)([Cl:15])=O.Cl>>[Cl:15][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: OCC1COc2ccccc2O1
Agent: Cl
Product: ClCC1COc2ccccc2O1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
202 g (1.21 mols) of 2-hydroxymethyl-1,4-benzodioxan are introduced into a 1 liter flask equipped with a stirrer, condenser and dropping funnel, and 288 g (2.42 mols) of thionyl chloride are run in dropwise. Violent evolution of HCl is observed. The mixture is heated under reflux until HCl ceases to be evolved, that is to say for 1 hour 30 minutes. The mixture is then distilled in vacuo after having driven off the excess thionyl chloride. 175.5 g (yield: 77.2%) of 2-chloromethyl-1,4-benzodioxan are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][OH:15])=[N:9]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[C:6]([CH:16]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[O:15])=[N:9]1
Reactant: Cc1cc(CO)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(C=O)nn1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1
Yield: 61.5 %

Procedure:
A solution of alcohol 4 (0.57 g, 1.3 mmol) and 0.5 M Dess-Martin periodinane (9.05 mL, 4.1 mmol) in CH2Cl2 (25 mL) was stirred under N2 atmosphere at RT for 3 h. The reaction mixture was quenched with a 10% aqueous solution of Na2S2O3 (10 mL) and extracted with more CH2Cl2 (10 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and the volatiles were removed in vacuo. The residue was purified by MPLC (5 g SiO2 cartridge, eluent 70% iso-hexane-30% CH2Cl2) to give aldehyde 5 0.3 g (64%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20](C)C)[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:26][C:27]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH3:35][N:33]([CH3:34])[C:32]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[F:26]
Reactant: CN(C)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1F
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(F)c(N(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and [2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-dimethyl-amine (stage 151.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.59 min (Method A); M+H=432 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.13-8.08 (m, 2H), 7.99-7.94 (m, 1H), 7.80-7.77 (m, 1H), 7.57-7.54 (m, 1H), 7.28-7.23 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.89 (s, 6H), 1.96 (s, 3H))
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([NH:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[S:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(Cl)cc2Cl)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Cl)cc3Cl)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(2,4-dichloro-phenyl)-thiazol-2-ylamine hydrobromide with 0.32 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and extracted three times with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.50 g of N-[4-(2,4-dichloro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CCOCC>[C:28]([Si:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc(I)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](OCc1cccc(I)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of 3-iodo-benzyl alcohol (4.68 g, 20 mmol) in CH2Cl2 (40 mL) is added imidazole (1.49 g, 22 mmol) and t-butyldiphenylsilyl chloride (5.74 g, 22 mmol). The resulting mixture is stirred for 1 h diluted with ether washed with water and brine, dried over MgSO4 and concentrated to give the title compound as an oil (9.41 g). MS (EI) 472 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:16])=[CH:9][CH:8]=1)[CH3:2].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]([CH3:38])=[C:34]([CH2:36]Cl)[N:35]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([O:16][CH2:36][C:34]2[N:35]=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:30][CH:29]=3)[O:32][C:33]=2[CH3:38])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1OCC2)OCC
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)c2c1OCC2)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (example 125 a]) was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole (example 123 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-2-ethoxy-propionic acid as white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>CCOCC>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(Cl)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.56 g of phenyl chloroformate in 50 ml of ether was added dropwise to a stirred solution of 2.55 g of 3-chloroaniline in 35 ml of ether. The mixture was stirred for one hour at room temperature and then filtered. The filtrate was evaporated and the residue crystallized from hexane to yield phenyl N-(3-chlorophenyl)carbamate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:8]([N:2]([CH2:3][CH2:4][CH2:5][OH:6])[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCI
Reactant: CNCCCO
Product: CCCCCCCCCCCCN(C)CCCO
Yield: 96 %

Procedure:
A solution of 3-(methylamino)propanol (5.71 g, 64.0 mmol, S. Koepke, R. Kupper, and C. J. Michejda, J. Org. Chem., 44, 2718,1979)), and iodododecane (7.58 g, 25.6 mmol) was reacted as described in example 1 to give 6.33 g (96%) of the title material as an oil, b.p. 100-105° C./0.04 torr.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([CH:15]([C:21]([OH:23])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1CN(C(=O)OCc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C(=O)O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 13.43 g (38.33 mmol) of diethyl (1-benzyloxycarbonyl-3-azetidinyl)malonate dissolved in 130 ml of ethanol was added 38.44 ml of 1N potassium hydroxide ethanol solution, followed by overnight stirring at room temperature. After evaporation of the solvent, the resulting residue was mixed with 10% citric acid aqueous solution, extracted with chloroform (200 ml×3) and then dried over anhydrous sodium sulfate. By evaporating the solvent, quantitative amount of the title compound was obtained.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)c1
Yield: 75.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-(chloromethyl)-4-methylpyridine (0.53 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained.
Reaction SMILES: [C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][C:3]([CH3:5])=[CH2:4].C(Cl)(Cl)[Cl:18]>C(OCC)C>[C:1](=[O:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[O:2][C:3]([Cl:18])([CH3:5])[CH3:4]
Reactant: C=C(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(Cl)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
The isopropenyl carbonate from step 88a (7.5 g, 33.6 mmol) was dissolved in a mixture of ethyl ether (100 mL) and chloroform (100 mL). The mixture was cooled to 0° C. and then bubbled with HCl gas. After standing at room temperature for 16 hours the mixture was purged with nitrogen to remove the excess HCl, and the solvent was evaporated to give the title compound (8.0 g, 92%): 1H NMR (CDCl3, 300 MHz) δ2.11 (s, 6H), 7.39-7.44 (m, 2H), 8.27-8.32 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][C:20]=2[O:29][CH3:30])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:33])=[CH:12][C:13]([CH3:32])([CH3:31])[NH:14]2.Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:29][CH3:30])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:33])=[CH:12][C:13]([CH3:31])([CH3:32])[NH:14]2
Reactant: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)C(C)=CC(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2-1, 424 mg, 0.888 mmol) was dissolved in 1,4-dioxane (5 mL), 4N HCl/1,4-dioxane solution (666 μL) was added thereto, and then the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (150 mL). The mixture was washed with water (100 mL, twice) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (241.7 mg) as a colorless solid. (Yield 63%)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([N+:24]([O-:26])=[O:25])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])=[C:8]2[C:20]([O:22][CH3:23])=[O:21].[CH3:27]I.OS([O-])(=O)=O.[Na+]>CN(C)C=O>[CH3:3][O:4][C:5]1[C:6]([N+:24]([O-:26])=[O:25])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:27])[C:9]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])=[C:8]2[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C=Cc1[nH]c2ccc(OC)c([N+](=O)[O-])c2c1C(=O)OC
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1c(C(=O)OC)c2c([N+](=O)[O-])c(OC)ccc2n1C
Temperature: 60 °C

Procedure:
This synthesis was carried out under an atmosphere of dry N2. To a stirred suspension of NaH (2.9 g) in dimethylformamide (145 ml) were added 9.34 g (28 mmol) methyl 5-methoxy-3-methoxycarbonyl-4-nitro-2-indoleacrylate (15). Thereupon the whole mixture was heated at 45°-50° C. When the evolution of H2 had ceased methyliodide (25 ml) was added to the dark red solution. During an additional (1 h) heating of the reaction mixture at 60° C., the colour of the solution turned to yellow. After cooling this mixture was poured into cold (0° C.) 10% NaHSO4 aq. Yellow crystals separated, which were collected by filtration, washed with water and ethanol, and finally dried in vacuo at 50°-60° C.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Br:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Brc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3Br)CC2)c(OC)nc1C
Yield: 58 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-bromophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1)=[O:17]>C(Cl)Cl.[OH-].[Na+]>[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:13][C:6]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)ccn1
Temperature: 170 °C

Procedure:
3,4-Dinitrophenol (12.3 g, 66.8 mmol) and 4-chloro-pyridine-2-carboxylic acid methylamide prepared similarly as described in patent WO 00/42012 (less than 7.79 g, 45.7 mmol, due to contaminant) in an open 50 mL round-bottom flask provided with stir bar and fitted with running water condenser. The reaction was heated at 150° C. for 1 h and at 170° C. for 16 h. The reaction was cooled to RT and dissolved in CH2Cl2 and 2N NaOH (aq). The layers were separated, and the organic layer was washed with a mix of brine and 2 N NaOH. The aqueous layers were back-extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a hexanes-to-hexanes/EtOAc gradient, to yield the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[CH3:20][NH:21][C:22]([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:22]([N:21]([CH3:20])[C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:19])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Reactant: CNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid was reacted with N,2-dimethylpropan-2-amine (CAN 94896-77-2) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=333.5 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([O:13][CH3:14])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A suspension of 2.3 g (12.81 mmol) of 6-chloronicotinoyl chloride and 1.53 g (15.37 mmol) of N,O-dimethylhydroxylamine in 46 mL of dichloromethane was cooled to 0° C. After dropwise addition of 5.36 mL (38.4 mmol) of triethylamine the resulting reaction mixture was warmed to RT and stirred for further 16 h. The mixture was subsequently washed with water (40 mL), 5% citric acid (40 mL), water (40 mL), and brine (40 mL). The organic layer was dried with Na2SO4, filtered, and the solvent was evaporated at reduced pressure yielding the titled compound as an oil. Amount 2.30 g. Yield 89%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1cccc(Br)n1
Temperature: 80 °C

Procedure:
2,5-Dibromopyridine (2.0 g, 8.4 mmol) was dissolved in 1,4-dioxane (2 mL) and a solution of hydrazine hydrate (500 mg, 8.4 mmol) in 1,4-dioxane (15 mL) was added dropwise by syringe pump. The reaction was heated to 80° C. for 16 h. The solvents were removed in vaccuo and the residue was chromatographed on silica gel eluting with hexanes:EtOAc (1:1) to afford 2-bromo-6-hydrazinopyridine as a brown solid. MS (ESI) 187.0 (M++H), 189.0 (M+H+2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].Br[CH:35]1[CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[CH:35]1([S:9]([C:7]2[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])(=[O:11])=[O:10])[CH2:38][CH2:37][CH2:36]1
Reactant: BrC1CCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)C2CCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 115 °C

Procedure:
Under argon, sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (150 mg, 65 μmol; purity about 21%) was suspended in a pressure-proof glass tube in DMF (1 ml). Molecular sieve (4 Å, 20 mg) and bromocyclobutane (100 μl, 1088 μmol, 16.7 eq.) were added. The sealed tube was heated at 115° C. for 15 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column; mobile phase: acetonitrile/water+0.1% TFA). After lyophilization, the title compound was obtained as a solid (15.5 mg, purity according to LC-MS 90%, 41% of theory).