Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+:3].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:55][CH2:56][CH3:57])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:7])[CH3:6].C(=O)=O>O.O1CCOCC1>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:55][CH2:56][CH3:57])[N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:12]=1[C:13]([O-:15])=[O:14])([CH3:6])[CH3:7].[Li+:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1nc(C(C)(C)O)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 20 h

Procedure:
A solution of 2.65 g of lithium hydroxide monohydrate in 158 ml of water was added, whilst ice-cooling, to a solution of 30 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 18(a)] in 344 ml of dioxane, and the resulting mixture was stirred at 5°-10° C. for 20 hours. At the end of this time, small pieces of dry ice were added to the mixture, which was then concentrated by evaporation under reduced pressure to a volume of about 100 ml. Ethyl acetate and sodium chloride were added to the concentrate, and the mixture was stirred. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure, to give lithium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate as a glass. 6.08 g of potassium carbonate were added, whilst ice-cooling, to a solution of whole of this lithium carboxylate in 160 ml of N,N-dimethylacetamide, and then a solution of 11.2 g of 4-chloromethyl -5-methyl -2-oxo-1,3-dioxolene (74% purity) in 26 ml of N,N-dimethylacetamide was added dropwise, whilst ice-cooling, to the mixture. The resulting mixture was stirred at 50° C. for 3 hours. At the end of this time, water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was crystallized in diisopropyl ether, to give 29.3 g of the title compound as crystals, melting at 98°-100° C. (with decomposition).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:17](=[S:21])[S:18][S:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[S-:22][S-].[Na+].[Na+].O>CN(C)C=O>[SH:22][C:20]1[S:19][S:18][C:17](=[S:21])[C:16]=1[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=1
Reactant: [S-][S-]
Reactant: CC(C)(C)c1cc(-c2cssc2=S)cc(C(C)(C)C)c1O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2c(S)ssc2=S)cc(C(C)(C)C)c1O
Temperature: 100 °C

Procedure:
33.8 parts of 4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione and 40 parts of a 2.5 molar solution of sodium disulphide were dissolved in 40 parts of dimethylformamide and warmed at 100°C for 15 minutes. 500 parts of water were then added, the mixture extracted several times with ether to remove any starting material, and then 60 parts of 3N hydrochloric acid solution were added slowly with stirring. The solid was filtered giving 27 parts of 5-mercapto-4-(3,5-di-t-butyl-4-hydroxyphenyl)-1,2-dithiole-3-thione m.p. 182°C which gave the following elemental analysis:
Reaction SMILES: [C:1]1([S@@:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[N:9][Si](C)(C)C)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+]>CO.O>[C:1]1([S@@:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[NH:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C[S@@](=O)(=N[Si](C)(C)C)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: O
Product: CCOC(=O)C[S@](=N)(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
A solution of Ethyl [S-phenyl-N-(trimethylsilyl)sulfonimidoyl]acetate (18.7 mmol, obtained as crude oil from step 2) in MeOH—H2O (10:1, 7.5 mL) was treated with cesium fluoride (0.25 g, 1.65 mmol) in one portion. The reaction mixture was heated to 50° C. and stirred for 2 hours. The reaction mixture was concentrated, the residue absorbed to silica gel and purified by chromatography (silica gel, EtOAc-Hexane, Et3N 0.1%). The product containing fractions were concentrated to give the title compound as a pale yellow oil (1.65 g, 39% for steps 1-3).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:34])[C@H:13]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:14](CC1C=CC=CC=1)[CH3:15].[H][H]>[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:34])[C@H:13]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[NH:14][CH3:15]
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Reactant: [H][H]
Agent: [Pd]
Product: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1

Procedure:
A methanolic solution of Nα-benzyl-Nδ-Boc-Nα-methylornithinyl 2-naphthyl ether (D) was reduced with hydrogen, over 5% palladium-on-carbon, to afford titled product: 1H NMR (400 MHz, CDCl3) δ1.44 (s, 9H), 1.63 (m, 2H), 1.95 (m, 2H), 2.53 (s, 3H), 2.95 (m, 1H), 3.09 (m, 2H), 4.01 (dd, J=10.7; 6.7 Hz, 1H), 4.12 (dd, J=10.5; 4.4 Hz, 1H), 7.19 (m, 2H), 7.35 (t, J=9.1 Hz, 1H), 7.45 (t, J=8.9 Hz, 1H), and 7.75 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1C=CC=CC=1>[Cl:8][C:4]1[N+:3]([O-:9])=[C:2]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1CCNCC1
Reactant: [O-][n+]1c(Cl)cccc1Cl
Solvent: c1ccccc1
Product: [O-][n+]1c(Cl)cccc1N1CCCCC1

Procedure:
A solution was prepared by dissolving 10 grams (0.061 mole) of 2,6-dichloropyridine-N-oxide in 100 milliliters of benzene at 35 C. To this solution was added dropwise 10.3 grams (0.122 mole) of piperidine. Upon completion of the piperidine addition, the reaction mixture was refluxed for 2 hours. At the completion of the reaction, the insoluble material contained in the reaction mixture was removed by filtration and benzene thereafter distilled off. The oily residue which remained was taken up in hexane. The 6-chloro-2-(piperidino)pyridine-N-oxide product was recovered by recrystallization from hexane and recovered in a yield of 7.5 grams. The product melted at 38°-41°C. and was found upon analysis to have carbon, hydrogen, chlorine and nitrogen contents of 54.5, 5.9, 19.9 and 12.9 percent, respectively, as compared with the theoretical contents of 56.8, 6.1, 16.7 and 13.2 percent, respectively, calculated for the above named compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][CH2:19][CH3:20])[N:6]2[CH2:13][C:14](=[NH:17])[NH:15][OH:16].[Cl:21][C:22]1[CH:27]=[C:26]([C:28](Cl)=O)[CH:25]=[C:24]([Cl:31])[N:23]=1>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][CH2:19][CH3:20])[N:6]2[CH2:13][C:14]1[N:17]=[C:28]([C:26]2[CH:25]=[C:24]([Cl:31])[N:23]=[C:22]([Cl:21])[CH:27]=2)[O:16][N:15]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)nc(Cl)c2)n1
Temperature: 120 °C

Procedure:
Synthesized as described for Examples 32A-32B using 2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with 2,6-dichloro-4-pyridinecarbonyl chloride (0.021 g, 0.1 mmol) and TEA (0.012 g, 0.12 mmol) and heated at 120° C. for 1 h in the microwave: 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 2H), 7.96 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 5.87 (s, 2H), 2.91 (t, 2H), 1.67-1.54 (m, 2H), 0.92 (t, 3H); MS (ES) m/z 447 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:15])=[C:5]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[Cl:14][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[C:3]([CH2:2][NH:1][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1c(Cl)ccc(CN)c1F
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.3 %

Procedure:
To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (0.540 g, 2.5 mmol) in THF (5 mL) was added pivaloyl chloride (0.335 g, 2.79 mmol) and TEA (0.1 mL) and the reaction mixture was stirred for 2-3 h at RT. Excess of solvent was removed under vacuum and the residue was diluted with water, extracted with EtOAC and concentrated to afford 0.500 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 1.31 (t, J=7.5 Hz, 3H), 4.26 (d, J=5.1 Hz, 2H), 4.39 (q, J=6.6 Hz, 2H), 7.33-7.43 (m, 2H), 8.13 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]=O)[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:17]#[N:18].[CH:21]1([NH:24][C:25]2[S:26][CH2:27][C:28](=[O:30])[N:29]=2)[CH2:23][CH2:22]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:21]1([NH:24][C:25]2[S:26]/[C:27](=[CH:15]\[C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][C:6]([C:17]#[N:18])=[C:5]4[O:4][CH2:3][C:2]([CH3:20])([CH3:19])[CH3:1])/[C:28](=[O:30])[N:29]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)COc1c(C#N)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(NC2CC2)=N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)COc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(2,2-dimethyl-propoxy)-6-formyl-quinoline-3-carbonitrile (example 67b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(2,2-dimethyl-propoxy)-quinoline-3-carbonitrile. LC-MS m/e 407 (MH+).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:14]2[CH2:13][CH2:12][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:8]=2[S:7][CH:6]=1.CO>CN(C)C=O>[C:21]1([CH:9]2[C:8]3[S:7][CH:6]=[C:5]([C:2]#[N:3])[C:14]=3[CH2:13][CH2:12][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:10]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N1CCc2c(Br)csc2C(c2ccccc2)C1)C(F)(F)F
Reactant: N#C[Cu]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1csc2c1CCN(C(=O)C(F)(F)F)CC2c1ccccc1

Procedure:
A mixture of copper (I) cyanide (0.45 g) and 3-bromo-8-phenyl-5,6,7,8-tetrahydro-6-trifluoroacetyl-4H-thieno[2,3-d]azepine (1.0 g) in dry dimethylformamide (10 ml) was heated under reflux for 5 hours. After allowing to cool to room temperature methanol (35 ml) was added and the mixture stirred vigorously, filtered and the filtrate evaporated to a yellow oil. Chromatography on silica eluting with diethylether gave the nitrile product, m.p. 107°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CC(=O)O)cc1O
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(O)c1

Procedure:
The stirred solution of 2-(3-Hydroxy-4-methoxyphenyl)acetic acid (9.82 g, 53.90 mmol) and p-Toluenesulfonic acid monohydrate (1.15 g, 6.0 mmol) in abs ethanol (100 ml) was refluxed for 4 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[O:4]1.C(O)[CH2:19][OH:20]>>[N+:12]([C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([OH:4])=[C:10]([O:11][CH2:3][CH2:19][OH:20])[CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(O)c(OCCO)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
0.2 mol (13.2g) of potassium hydroxide pellets (85%) is added to 100 ml of ethylene glycol which has been heated beforehand to 50° C. 0.1 mol (21.2g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added in a single portion to this solution. The heating is maintained for 2 hours.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>CN(C)C1C=CN=CC=1.O1CCOCC1>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([O:15][CH2:16][CH3:17])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:7][CH:6]=1)[CH3:14]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OC(=S)N(C)C)cc1)OCC
Temperature: 100 °C
Yield: 101.8 %

Procedure:
A mixture of ethyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (100.8 g, 0.423 mol), triethylamine (83.4 g, 115 ml, 0.824 mol), 4-dimethylaminopyridine (5.2 g, 42.3 mmol) and dimethylthiocarbamoyl chloride (62.6 g, 0.507 mol) in dioxane (640 ml) was stirred and heated at 100° C. for 10 h in nitrogen atmosphere. The solid was filtered off, washed with dioxane and the filtrates were evaporated in vacuo. The residue was dissolved in dichloromethane (600 ml), the solution was washed with water (3×250 ml), dried (MgSO4) and passed through column of silica gel (Fluka 60, 500 g). The column was washed with 500 ml dichloromethane, collected dichloromethane solutions were evaporated to yield 140.1 g (˜100%) of 3-(4-dimethylthiocarbamoyloxy-phenyl)-2-ethoxy-propionic acid ethyl ester as an oil, which was used to next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+:22]>CN(C)C=O>[C:5]([NH:6][C:2](=[N:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1)[S:3][CH3:4])#[N:22]
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSC(=Nc1nc(C)c(-c2cc(C)ccn2)s1)NC#N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)-thiazole (410 mg) and potassium carbonate (415 mg) in N,N-dimethylformamide (10 ml) was added dimethyl N-cyanodithioimino-carbonate (292 mg), and the mixture was stirred at 100° C. for 1 hour. The mixture was poured into a saturated aqueous solution of ammonium chloride. Then the precipitate was collected by filtration, purified by column chromatography (silica gel 30 g, 0 to 3% methanol in dichloromethane) and recrystallized from 2-propanol to give N-cyano-N′-(4-methyl-5-(4-methylpyridin-2-yl) thiazol-2-yl)-S-methylisothiourea (0.08 g).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C@H:13]([C@H:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[CH2:14][OH:15]>ClCCl>[CH3:12][C@H:13]([C@H:16]([CH3:20])[CH2:17][CH2:18][CH3:19])[CH:14]=[O:15]
Reactant: CCC[C@@H](C)[C@@H](C)CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC[C@@H](C)[C@@H](C)C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
Pyridinium chlorochromate (27.35 g, 126.9 mmol) and neutral alumina (96 g, 3.5 g per gram of pyridinium chlorochromate) in dry dichloromethane (200 mL) was stirred under nitrogen for 0.25 hours. (2R,3R)-2,3-Dimethyl-hexan-1-ol (5.0 g, 38.46 mmol) in dichloromethane (60 mL) was added and the resulting dark slurry was stirred at room temperature for 3 hours. The slurry was filtered through a short pad of silica eluting with excess dichloromethane. Evaporation of the solvent afforded the titled compound (4.1 g, 84% yield) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.8 (m, 3H) 0.9 (d, J=6.6 Hz, 3 H) 1.0 (d, J=6.6 Hz, 3 H) 1.2 (m, 4 H) 1.8 (m, 1 H) 2.2 (m, 1 H) 9.6 (s, 1 H).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([NH:42][C:19]([C:14]2[N:15]([CH3:18])[N:16]=[CH:17][C:13]=2[NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])=[O:21])[CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Agent: Cl
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol) and tert-butyl-3-aminopyrrolidine-1-carboxylate hydrochloride (23 mg, 103 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (28 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:27])[N:12]([CH2:25][CH3:26])[CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23]C)[CH:19]=3)[CH2:14]2)=[CH:6][CH:5]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:27])[N:12]([CH2:25][CH3:26])[CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH2:14]2)=[CH:8][CH:9]=1
Reactant: CCN(C(=O)Oc1ccc(OC(F)(F)F)cc1)C1CCc2cc(OC)ccc2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN(C(=O)Oc1ccc(OC(F)(F)F)cc1)C1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of ethyl-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid 4-trifluoromethoxy-phenyl ester (898.6 mg; 2.19 mmol) in anhydrous CH2Cl2 (8 mL) was cooled to −78° C., a 1.0 M solution of boron tribromide-CH2Cl2 (6.57 mL, 6.57 mmol) was added slowly. Upon completion of the addition, the reaction mixture was allowed to warm to RT, quenched with MeOH (10 mL) and stirred for an additional 2 h. The solvents were evaporated, and the residue was purified by flash chromatography with hexane-EtOAc (2.5:1) to give 649.4 mg (75%) of ethyl-(6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid 4-trifluoromethoxy-phenyl ester as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:9]1[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=4[O:13][CH3:14])[CH:4]=3)[CH2:21][CH2:20]1)=[CH:4]2
Reactant: C1CNCCNC1
Reactant: COc1cc2cc(CCl)ccc2c(OC)c1OC
Product: COc1cc2cc(CN3CCCN(Cc4ccc5c(OC)c(OC)c(OC)cc5c4)CC3)ccc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxynaphthalene (607 mg) and homopiperazine (108 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5](O)=[O:6].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.N.Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5]([NH2:21])=[O:6]
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2)c(Br)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2cccc(F)c2)c(Br)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A mixture of 3-bromo-4-(3-fluorophenoxy)benzoic acid (step 2, 550 mg, 1.77 mmol) and 1,1′-carbonyldiimidazole (430 mg, 2.65 mmol) in N,N-dimethylformamide (10 mL) was stirred at 60° C. for 1 h. After cooling to 0° C., 25% ammonia solution was added slowly to the mixture. The resulting mixture was stirred at room temperature for 16 h. The mixture was pored into 2 M hydrochloric acid (100 mL) and the whole was extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to give 441 mg (80%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.14 (1H, d, J=2.2 Hz), 7.74 (1H, dd, J=8.6, 2.2 Hz), 7.36–7.27 (1H, m), 6.97–6.59 (6H, m).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH2:28][O:29]C(=O)C2C=CC=CC=2)([CH2:18][O:19]C(=O)C2C=CC=CC=2)[O:7][C@H:6]1[N:38]1[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]1=[O:40])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@H:9]1[C:8]([CH2:18][OH:19])([CH2:28][OH:29])[O:7][C@@H:6]([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O[C@H]1[C@H](n2cc(C)c(=O)[nH]c2=O)OC(COC(=O)c2ccccc2)(COC(=O)c2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a stirred solution of nucleoside 4 (9.00 g, 0.014 mol) in methanol (130 cm3) was added sodium methoxide (3.87 g, 0.0716 mol). The reaction mixture was stirred at room temperature for 4 h and then neutralised with dilute hydrochloric acid. The mixture was evaporated to dryness under reduced pressure followed by coevaporation using toluene (15 cm3×3). The residue was purified by silica gel column chromatography using dichloromethane/methanol (4–1 5% methanol, v/v) as eluent to give nucleoside triol 5 (4.82 g, 89%) as a white solid material after evaporation of the solvents under reduced pressure.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]([CH3:18])=[CH2:17]>CC(C)=O>[CH3:17][C:16](=[CH2:15])[CH2:18][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)CC(C(C)=O)C(C)=O
Temperature: 50 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
A mixture of acetylacetone (2.5 g, 25 mmol), K2CO3 (3.45 g, 25 mmol) and 3-bromo-2-methylpropene (2.5 mL, 25 mmol) in acetone (80 mL) is stirred at 50° C. for 3 days. The mixture is filtered, the filtercake washed with few acetone and the filtrate evaporated to give 2.48 g of 3-(2-methyl-allyl)-pentane-2,4-dione as a dark oil that is used without further purification in subsequent steps; LC-MS: tR=0.87 min, [M+1]+=155.26.