Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:11]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH:9]=[CH:10]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (712 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as white powder (505 mg, yield 57%).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(COC)OC.C[Si]([C:21]([F:24])([F:23])[F:22])(C)C.[F-].[Cs+]>CCCCCC.ClCCl>[F:22][C:21]([F:24])([F:23])[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnccn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: COCCOC
Product: O=C(c1cnccn1)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of pyrazine carboxylate methyl ester is dissolved in an inert solvent, for example monoglyme (dimethoxyethane). To this solution is added a mixture of trimethylsilyltrifluoromethane and dry caesium fluoride. After about 12-24 hours, at a temperature of about room temperature, the solvent is removed under reduced pressure. The residue is dissolved in a mixture of an inert solvent, for example tetrahydrofuran, and an organic acid, for example acetic acid, and the mixture is treated with tert-butylammonium fluoride. The reaction is conducted at a temperature of about room temperature for about 3 hours. When the reaction is substantially complete, the compound of formula (18) is isolated by conventional means, for example by diluting with water, extracting the product into an inert solvent, for example ethyl acetate, washing with a solution of a mild inorganic base, for example sodium bicarbonate, and drying. Removal of the solvent under reduced pressure provides a crude compound, which can be purified by trituration with an inert solvent, for example a mixture of dichloromethane and hexane, to give a compound of formula (18), 2,2,2-trifluoro-1-(pyrazin-2-yl)ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([O:22]C(=O)/C=C\N3C=NC(C4C=C(C(F)(F)F)C=C(OC)C=4)=N3)=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[NH2:45][NH2:46]>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:45][NH2:46])=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(-c2ncn(/C=C\C(=O)OC(=O)/C=C\n3cnc(-c4cc(OC)cc(C(F)(F)F)c4)n3)n2)cc(C(F)(F)F)c1
Reactant: NN
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 50-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (isobutyl carbonic) (Z)-3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic anhydride was cooled at 0° C. and added Hydrazine hydrate (0.911 g, 5.7 eq.). Reaction mixture was stirred at 0° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 50% EtOAc-hexane as mobile phase. SM Rf=0.6 and Product Rf=0.4. Reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.920 g of Crude compound which was used for next step without further purification.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:17][CH2:16]1.C([O-])(=O)C.[Na+]>O>[CH3:11][O:10][C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:19][CH2:20]1)=[O:9]
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: COC(=O)c1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccccc1NCCN1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A mixture of 0.93 g of methyl anthranilate, 2 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine, 0.88 g of sodium acetate and 5 mL of H2O was stirred for 24 h at reflux. After cooling at room temperature, the mixture was extracted with EtOAc, the organic phase dried on Na2SO4, evaporated to dryness and the residue purified via flash chromatography (CH2Cl2 --MeOH 98:2) giving 0.41 g (18%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])(=[O:5])=[O:4].[CH2:19]([O:22][C:23]([N:25]1[C@H:29]([CH2:30][C:31]2[S:35][C:34]3=[CH:36][N:37]=[C:38]([CH3:39])[N:33]3[CH:32]=2)[CH2:28][C@H:27]([S:40][C:41]2[C@H:42]([CH3:58])[C@@H:43]3[C@@H:53]([C@H:54]([OH:56])[CH3:55])[C:52](=[O:57])[N:44]3[C:45]=2[C:46]([O:48][CH2:49][CH:50]=[CH2:51])=[O:47])[CH2:26]1)=[O:24])[CH:20]=[CH2:21]>ClC(Cl)C>[F:1][C:2]([F:18])([F:17])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:19]([O:22][C:23]([N:25]1[C@H:29]([CH2:30][C:31]2[S:35][C:34]3=[CH:36][N:37]([CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])[C:38]([CH3:39])=[N+:33]3[CH:32]=2)[CH2:28][C@H:27]([S:40][C:41]2[C@H:42]([CH3:58])[C@@H:43]3[C@@H:53]([C@H:54]([OH:56])[CH3:55])[C:52](=[O:57])[N:44]3[C:45]=2[C:46]([O:48][CH2:49][CH:50]=[CH2:51])=[O:47])[CH2:26]1)=[O:24])[CH:20]=[CH2:21]
Reactant: CC(C)(C)[Si](C)(C)OCCOS(=O)(=O)C(F)(F)F
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(C)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(Cl)Cl
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(C)n(CCO[Si](C)(C)C(C)(C)C)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(t-Butyldimethylsilyloxy)ethyl trifluoromethanesulfonate (20.4 mg) is added to a solution of 32.4 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 31-a), in 0.5 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 2 hr. The excess reagent is removed by evaporation under reduced pressure to give allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-[2-(t-butyldimethylsilyloxy)ethyl]-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethanesulfonate as a brown oil. Acetic acid (0.0033 ml) and 0.056 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of this compound in 0.5 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for one hr. Dry ethanol (0.5 ml) is added thereto. Triphenylphosphine (5.8 mg), 0.012 ml of morpholine, and 3.2 mg of tetrakis(triphenylphosphine)palladium(0) are successively added to the mixture, and the mixture is stirred in an argon atmosphere at room temperature for one hr. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 3 ml of THF and dried in vacuo to give a yellow powder which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 4.62 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10]OC(=O)C1C=CC=CC=1.[SH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Sc1ccccn1
Reactant: Cn1c([N+](=O)[O-])cnc1COC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c([N+](=O)[O-])cnc1CSc1ccccn1
Temperature: 80 °C

Procedure:
26.1 Grams (0.1 mol) of 1-methyl-2-benzoyloxymethyl-5-nitro-imidazole were dissolved while stirring in 150 ml of dimethylformamide; then 11.1 g (0.1 mol) of 2-mercaptopyridine and 13.8 g of potash (free from water and powdered) were added. A very faintly exothermic reaction was perceptible only. The reaction mixture was heated to 80°C for 1 hour, whereupon the color of the mixture changed from yellow toward light brown and a white precipitate formed. The mixture was then cooled to room temperature and the end product was precipitated by stirring it into about 500 ml of ice water. The product was suction-filtered, thoroughly washed with water and recrystallized from about 3000 ml of isopropanol. 18.0 Grams (72 % of the theoretical yield) of 1-methyl-2-(2-pyridylthiomethyl)-5-nitro-imidazole were obtained as a faintly yellow crystallized powder, m.p. 146°-147°C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.[CH3:41][C:42]1[C:43]([N:58]2[CH2:67][CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]2[CH3:68])=[N:44][C:45]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:46][C:47]=1[CH2:48]O>C(Cl)Cl>[CH3:41][C:42]1[C:43]([N:58]2[CH2:67][CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]2[CH3:68])=[N:44][C:45]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:46][C:47]=1[CH2:48][O:32][C:31](=[O:33])[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28]
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(COC(=O)CNC(=O)OC(C)(C)C)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), N-t-butoxycarbonylglycine(27.8 mg, 0.158 mmol) and triethylamine(23.9 μl 0.171 mmol) were added to a suspension of 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol) in anhydrous methylene chloride(1 ml). The reaction mixture was stirred for 1 day at room temperature, washed with water. The separated organic layer was concentrated and the residual oil was purified by a silica gel column chromatography (dichloromethane/methanol 20/1) to give the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][C@@H:9]1[C@H:10]1[C@@H:12]2[CH:11]1[Si:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].[K+].C1C[O:26]CC1>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:10]2[C@H:12]([CH:11]2[Si:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:13]([C:14]([OH:15])=[O:26])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H]2C[C@@H]1[C@@H]1C([Si](C)(C)C)[C@@H]12
Agent: [F-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)[C@H]2C([Si](C)(C)C)[C@H]21
Temperature: 60 °C
Yield: 100 %

Procedure:
A mixture of (1S,2R,4R,5R)-7-oxo-3-trimethylsilanyl-6-aza-tricyclo[3.2.1.0(2,4)]octane-6-carboxylic acid tert-butyl ester (1.7 g, 5.7 mmol) and potassium fluoride on alumina (2.10 g, 14.1 mmol) in THF (38 mL) was heated to about 60° C. for about 18 h. The mixture was cooled to ambient temperature and filtered through Celite®. The Celite® pad was rinsed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure to afford (1R,2S,4R,5R)-4-(tert-butoxycarbonylamino)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylic acid (1.82 g, 100%): LC/MS (Table 2, Method a) Rt=2.62 min; MS m/z: 312 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH3:17])=[CH:4][CH:3]=1.[ClH:19].Cl.[NH2:21][CH2:22][CH2:23][O:24][NH2:25].N1C=CC=CC=1>C(O)C>[ClH:19].[ClH:19].[NH2:21][CH2:22][CH2:23][O:24][N:25]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH3:17]
Reactant: Cc1nccn1CCCC(=O)c1ccc(F)cc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nccn1CCCC(=NOCCN)c1ccc(F)cc1
Reaction time: 3 h
Yield: 116 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(2-methyl-1-(1H)-imidazolyl)-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.18 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 3.2 g (70%) of product, mp 219°-221° C. (dec).
Reaction SMILES: [CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[H][H]>O1CCCC1.[Ru]>[CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:5]1[NH2:6]
Reactant: [H][H]
Reactant: Nc1ccccc1C1CC1C1CC1
Agent: [Ru]
Solvent: C1CCOC1
Product: NC1CCCCC1C1CC1C1CC1
Temperature: 25 °C

Procedure:
0.289 g of Ru/C (5%) are added to a solution comprising 3.00 g (17.31 mmol) 2-[1,1′-Bi(cyclopropyl)-2-yl]anilin in 20 ml of tetrahydrofuran, and the mixture is hydrogenated with 100 bar of hydrogen at 120° C. for 20 hours. After cooling to room temperature, the catalyst is filtered off through Celite 545 and the product is concentrated under reduced pressure. This gives 3.01 g (96%) of 2-[1,1′-Bi(cyclopropyl)-2-yl]cyclohexanamine having a purity of 96% according to MSD-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH:42]([NH2:45])([CH3:44])[CH3:43]>C(Cl)Cl>[CH:42]([NH:45][C:5]1[N:4]=[C:3]([O:2][CH3:1])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1)([CH3:44])[CH3:43]
Reactant: CC(C)N
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(NC(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A solution of Example C2 (0.13 g, 0.309 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.09 g, 0.37 mmol), stirred at RT overnight, treated with isopropyl amine (0.5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-isopropyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (63 mg, 47%). MS (ESI) m/z: 432.2 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.ClC(Cl)C(OC(=O)C(Cl)Cl)=O.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][CH:25]=1>ClC(Cl)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([C:25]1[O:26][C:27]([CH3:29])=[CH:28][C:24]=1[CH3:23])=[O:11]
Reactant: O=C(O)CCCc1cccs1
Reactant: Cc1coc(C)c1
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1cc(C)c(C(=O)CCCc2cccs2)o1
Temperature: 50 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
In 50 ml of dichloroethane were dissolved 8.51 g (0.05 mole) of 4-(2-thienyl)butyric acid and 14.39 g (0.06 mole) of dichloroacetic anhydride. To the resulting solution was added 0.065 mole of 3,5-dimethylfuran and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 7 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure to obtain 2-[4-(2-thienyl)butyryl]3,5-dimethylfuran.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Cl)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.22 (2H, s), 5.73 (1H, d, J=1.6 Hz), 7.30-7.35 (3H, m) 7.41-7.43 (1H, m), 7.47 (1H, s), 7.57 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.72 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H11ClN4O, 311. Found, 311.
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl:6][C:7]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[N+:15]([O-:17])=[O:16])[CH:10]=[C:9]([F:18])[CH:8]=1>O1CCOCC1>[Cl:6][C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][N+:15]([O-:17])=[O:16])[CH:10]=[C:9]([F:18])[CH:8]=1
Reactant: O=[N+]([O-])/C=C/c1cc(F)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: O=[N+]([O-])CCc1cc(F)cc(Cl)c1
Yield: 58.5 %

Procedure:
Add sodium borohydride (0.75 g, 19.7 mmol) to a solution of 1,4-dioxane (10 mL) and absolute ethanol (2.5 mL) in a room temperature water bath. Next add 1-chloro-3-fluoro-5-((E)-2-nitrovinyl)-benzene (1.5 g, 8.98 mmol) in 1,4-dioxane (10 mL) dropwise and stir at room temperature for 1 hour (Bhattacharjya, Synthesis, 1985, 886-997). Add ice chips, glacial acetic acid (2 mL), water (2 mL), concentrate and dilute in dichloromethane/water. Wash the dichloromethane layer with water, saturated aqueous sodium chloride, dry (sodium sulfate), filter and purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes) to give the desired compound as an oil (1.07 g 70%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:28][C@@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20][CH2:19]4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc2c(c1)CCC[C@@H]2NC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and (S)-1,2,3,4-tetrahydro-1-naphthylamine (74 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (9 mg) and a syn-form compound (14 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1.[C:14]([N:18]1[C:23](=[O:24])[C:22]([Cl:25])=[C:21](O)[CH:20]=[N:19]1)([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:14]([N:18]1[C:23](=[O:24])[C:22]([Cl:25])=[C:21]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]([OH:11])[CH3:10])=[CH:12][CH:13]=2)[CH:20]=[N:19]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CC(O)COc1ccc(CO)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(O)COc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
To solution of the product of Example 6B (269 mg, 1.48 mmol) and 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (250 mg, 1.23 mmol) dissolved in anhydrous THF (18.5 mL) was added solid PPh3 (485 mg, 1.85 mmol) and DIAD (0.358 mL, 1.85 mmol). After completion of addition the reaction mixture continued to stir at room temperature. After 20 hours, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (1:1 pentane:ethyl acetate) to provide the desired product (234 mg, 0.634 mmol) in 51% yield. 1H (CDCl3 7.71 (1H, s), 7.33 (2H, d, 600 MHz): δ J=8.7 Hz), 6.94 (2H, d, J=8.7 Hz), 5.24 (2H, s), 4.19 (1H, m), 3.95 (1H, dd, J=9.2, 3.1 Hz), 3.81 (1H, dd, J=9.2, 7.7 Hz), 1.62 (9H, s) 1.29 (3H, d, J=6.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:20])[CH:16]=3)[CH:11]2[CH3:21])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CN(C)C=O>[ClH:9].[CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:20])[CH:16]=3)[CH:11]2[CH3:21])=[N:4][C:5]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(N2CCc3cc(Cl)ccc3C2C)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(Cl)ccc3C2C)c1C
Product: Cl
Yield: 5.2 %

Procedure:
The same procedures as in Step 2 of Example 3 above were repeated using 5,6-dimethyl-2-chloro-4-(1-methyl-6-chloro- 1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.1 g, 0.31 mmol) prepared in Step 1 above, dimethylformamide (5 ml), and 4-fluoroaniline (0.07 ml, 0.74 mmol) to afford 7 mg (53%) of the titled compound.