Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][SH:2].[CH3:3][C:4]1[C:5]([N+]([O-])=O)=[C:6]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:3][C:4]1[C:5]([S:2][CH3:1])=[C:6]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(C)c(C)c1[N+](=O)[O-]
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C)c(C)c1SC
Temperature: -10 °C
Reaction time: 72 h

Procedure:
A solution of methanethiol (22 ml) in dry dimethyl formamide was added to a mixture of ethyl 3,4-dimethyl-2-nitrobenzoate (21.54 g) and potassium carbonate (20.02 g) in dry dimethyl formamide while maintaining the temperature below -15° C. The mixture was stirred at -10° C. for 0.5 hours and at room temperature for 3 days. Water was added and the mixture was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane (8:1) to give ethyl 3,4-dimethyl-2-methylsulphenylbenzoate (21.25 g) as a clear oil, NMR (CDCl3) 1.4(t,3H), 2.3(s,3H), 2.35(s,3H), 2.55(s,3H), 4.4(q,2H), 7.1(d,1H), 7.2(d,1H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH:8]1[CH:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9]1=[O:21])([CH3:4])[CH3:3].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].C(O)(=O)C>O1CCCC1>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH:8]1[CH:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][CH:9]1[OH:21])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(=O)C1CO[Si](C)(C)C(C)(C)C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC1CC(O)C1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Yield: 61.5 %

Procedure:
2,3-Bis(((1,1-dimethylethyl)dimethylsilyl)oxymethyl)cyclobutanone (10.2 g, 28.4 mmol) from Step B was dissolved in tetrahydrofuran (THF) and the solution was cooled to -78° C. under a nitrogen atmosphere. To the THF solution at -78° C. was slowly added, with stirring, 31 mL (31 mmol) of potassium tri-sec-butylborohydride (sold by Aldrich Chemical Company as a 1 M solution in THF under the registered trademark K-Selectride®. After stirring for 0.5 h at -78° C., the reaction mixture was allowed to warm to 0° C. and it was stirred for 40 minutes at 0° C. One equivalent (1.9 mL) of glacial-acetic acid was added and the reaction mixture was concentrated in vacuo to approximately 50 mL. The concentrate was diluted with 1 L of methylene chloride and the resultant solution was washed with 400 mL of 5% aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to a syrup. The syrup (15.5 g) was chromatographed on a 4.5×45 cm silica gel column eluted @2-5 psi with 2 L of methylene chloride. All fraction containing the desired product were combined and concentrated. The residue (10 g) was rechromatographed as described above to give 6.3 g (62% yield) of the title compound as a syrup; 1H NMR (CDCl3) δ 0.07 (d, 12H), 0.92 (d, 18H), 2.01 (m, 1H), 2.13 (m, 2H), 2.25 (m, 1H), 2.40 (m, 1H), 3.35 (d, 1H), 3.55 (m, 2H), 3.86 (dd, 1H), 3.98 (dd, 1H); MS DCI-NH3M/Z: 361 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[C@:13]3([CH2:22][C@:21]3([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)[CH:23]([CH3:25])[CH3:24])[C:12]2=[O:33])[CH:5]=1.[C-:35]#[N:36].[Na+]>O1CCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[C@:13]3([CH2:22][C@:21]3([C:26]3[CH:31]=[CH:30][C:29]([C:35]#[N:36])=[CH:28][CH:27]=3)[CH:23]([CH3:25])[CH3:24])[C:12]2=[O:33])[CH:5]=1
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CN2C(=O)[C@@]3(C[C@]3(c3ccc(I)cc3)C(C)C)c3cc(F)ccc32)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2C(=O)[C@@]3(C[C@]3(c3ccc(C#N)cc3)C(C)C)c3cc(F)ccc32)c1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A solution of (1S,2S) and (1R,2R)-methyl-3-((-5′-fluoro-2-(4-iodophenyl)-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoate (1.35 g, 2.4 mmol), NaCN (240 mg, 4.9 mmol), CuI (50 mg, 0.3 mmol) and Pd(PPh3)4 (140 mg, 0.12 mmol) in tetrahydrofuran (9.0 mL) was stirred at 65° C. for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo. Purification by flash column chromatography eluting with Hexane/ethyl acetate (8:1 to 4:1) to afford light yellow oil (500 mg, yield 45.5%) LC/MS m/e calcd. for C29H25FN2O3: 469, observed (M+H)+: 469.2
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CS(O[CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1
Reactant: CN1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1ccccc1Br
Product: CN1CCC(Oc2ccccc2Br)CC1

Procedure:
The title compound was prepared from 2-bromophenol and 1-methylpiperidin-4-yl methanesulphonate in a similar manner to Example 134 (b) except that the compound was purified by cation exchange chromatography eluting with ammonia/methanol mixtures.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([Cl:11])=[CH:4][N:3]=1.Br[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=2)[C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: OB(O)c1cc(Cl)ncc1Cl
Reactant: Cc1cnc(Br)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(-c2cc(Cl)ncc2Cl)c(C)c1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of 2,5-dichloropyridin-4-ylboronic acid (75.6 g, 0.4 mol), 2-bromo-3,5-dimethylpyridine (56.2 g, 0.3 mol), Pd(dppf)Cl2 (13.5 g, 17 mmol) and K3PO4.3H2O (162 g, 0.6 mol) in dioxane (600 mL) and H2O (120 mL) was stirred at reflux under N2 atmosphere overnight. TLC (petroleum ether/EtOAc=10:1) showed that the reaction was complete. After cooling to room temperature, the mixture was filtered. Water (500 mL) was then added to the filtrate. The mixture was extracted with dichloromethane (500 mL×3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc=50:1 to 30:1) to give title compound (20 g, 26%) as a yellow solid. 1H NMR (400 MHz, MeOD): δ 8.54 (s, 1H), 8.31 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 2.41 (s, 3H), 2.15 (s, 3H); m/z for C12H10Cl2N2 253.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH-].[Na+].[C:12]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]=[C:22](SC)[S:23][CH3:24])(=[O:20])=[O:19].O>CN(C)C=O>[C:12]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:22](=[N:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[S:23][CH3:24])(=[O:19])=[O:20]
Reactant: CSC(=NS(=O)(=O)c1ccccc1-c1ccccc1)SC
Reactant: Cc1cc(C)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CSC(=Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
12.3 g of 2-amino-4,6-dimethylpyrimidine was suspended in 300 ml of dimethylformamide, and 4 g of sodium hydroxide (oily 60%) was added. The mixture was stirred at room temperature for 1 hour. Furthermore, 33.7 g of dimethyl N-(2-biphenylylsulfonyl)carbonimidodithioate was added, and the mixture was stirred at room temperature for a day and night. The reaction mixture was poured into 2 liters of water, and filtered. When the filtrate was made weakly acidic, white crystals precipitated. The crystals were collected by filtration, and recrystallized from ethanol to give 29.2 g of the desired 1-(2-biphenylylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)2-methylisothiourea of the following formula, mp. 154°-157° C.: ##STR18##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C(=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([F:11])[CH:7]=3)[N:1]=2)=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2nc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A suspension of 2-amino-5-fluorobenzamide (154 mg, 1.0 mmol), 4-tert-butylbenzaldehyde (162 mg, 1.0 mmol) and sodium disulfite (194 mg, 1.02 mmol) in N,N-dimethylacetamide (2 ml) is heated to 150° C. and stirred at this temperature for 3 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration, washed with water and dried under vacuum to afford 2-(4-tert-butyl-phenyl)-6-fluoro-3H-quinazolin-4-one as light grey solid;
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:54](=[O:55])[N:6]2[C:7]([C:41]([O:43]CC3C=CC([N+]([O-])=O)=CC=3)=[O:42])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15]([CH3:17])[C@H:14]([C:18]([N:20]4[CH2:23][CH:22]([N:24](C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[C:25](=[NH:27])[CH3:26])[CH2:21]4)=[O:19])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:25]([NH:24][CH:22]1[CH2:21][N:20]([C:18]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:54](=[O:55])[N:6]4[C:7]=3[C:41]([OH:43])=[O:42])[CH2:16][N:15]2[CH3:17])=[O:19])[CH2:23]1)(=[NH:27])[CH3:26]
Reactant: [H][H]
Reactant: CC(=N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)C1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CC(=N)NC1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)C1
Yield: 61.4 %

Procedure:
453 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[3-[N-(4-nitrobenzyloxycarbonyl)-N-acetimidoylamino]azetidin-1-ylcarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 21 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and 500 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated at room temperature for 1.5 hours in an atmosphere of hydrogen. The catalyst was then removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure. The residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 40 ml). Of the fractions obtained by solution with 8% by volume aqueous acetonitrile, the one containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to give 166 mg of the title compound as a powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([CH:10]=1)[NH2:9])([O-:3])=[O:2].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([NH:9][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1cc([N+](=O)[O-])ccc1O
Yield: 30 %

Procedure:
The N-[5-nitro-2-hydroxyphenyl]-N′-phenyl urea was prepared from the 5-nitro 2-hydroxy aniline and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (100 mg, 30%). 1H NMR (CD3OD): d 9.48 (s, 1H, NH), 9.07 (d, J=1.56 Hz, NH), 8.55 (s, 1H), 7.80 (dd, 1H, J=6.25 Hz and J=1.56 Hz), 7.50 (d, 2H, J=6.25 Hz), 7.30 (t, 2H, J=6.25 Hz), 7.01 (m, 2H). EI-MS m/z 273 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29](O)=[O:30])=[N:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)=[O:30])=[N:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)C(Cc2ccc(OCc3ccccc3)cn2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
A mixture of methyl 4-(aminomethyl)benzoate (2 g, 10 mmol), 3-(5-(benzyloxy)-pyridine-2-yl)-2-(tert-butoxycarbonylamino) propanoic acid (1.04 g, 11 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (2 g, 10.4 mmol) in 50 mL dichloromethane was stirred at room temperature for 2 h (monitored by TLC). The mixture was extracted with water and dried over magnesium sulfate. The residue was purified by chromatography (EA:Hex=1:1) to give the title compound (1.5 g, 49%). NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.31 (s, 9H, Boc), 2.90 (m, 2H, CH2), 3.81 (s, 3H, OMe) 4.30 (m, 2H, CH2), 4.33 (m, 1H, CH), 5.12 (s, 2H, OBn), 6.97-7.09 (d, 1H, J=3.5 Hz, Ar—H), 7.15 (d, 1H, J=8.53 Hz, Ar—H), 7.24˜7.46 (m, 8H, Ar—H), 7.84, (d, 2H, Ar—H, J=8.24 Hz), 8.24 (br, 1H, NH), 8.43 (br, 1H, NH).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][C:18]([CH3:22])([CH3:23])[C:19]([O:1][CH2:2][C:3]2[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=2)=[O:20])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cnc(CO)s1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(COC(=O)C(C)(C)Oc2ccc(Cl)cc2)s1

Procedure:
Using the procedure of Example 3, methyl 2-hydroxymethyl-thiazole-5-carboxylate and p-chlorophenoxy-isobutyric acid chloride were reacted in toluene and triethylamine to obtain methyl 2-[α-(p-chlorophenoxy)-α,α-dimethylacetoxymethyl]-thiazole-5-carboxylate melting at 80° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH3:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([N:24]2[CH2:25][CH2:26][N:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:28][CH2:29]2)[CH3:23])=[CH:18][CH:17]=1
Reactant: C[C@H](c1ccc(Br)cc1)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](c1ccc(Br)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (251 mg, 1.13 mmol), (R)-1-[1-(4-bromophenyl)ethyl]piperazine (obtained as described in Example 270, preparation of starting materials, 304 mg, 1.13 mmol) and DIPEA (0.20 mL, 1.13 mmol) in DMF (3 mL) were stirred and heated at 80° C. for 1 hour. The resulting solution was cooled to ambient temperature then quenched with water (10 mL) to give a pale brown precipitate. The precipitate was collected by filtration, washed sequentially with water, acetonitrile and ether and dried under vacuum to afford 6-[4-[(1R)-1-(4-bromophenyl)ethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (437 mg, 85%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][C:6]([CH2:10][OH:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18](O)=[O:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:11][CH2:10][C:6]12[CH2:9][C:2]([NH:1][C:18]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][N:12]=3)=[O:19])([CH2:8][CH2:7]1)[CH2:3][CH2:4][CH2:5]2
Reactant: NC12CCCC(CO)(CC1)C2
Reactant: O=C(O)c1cnccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC12CCCC(CO)(CC1)C2)c1cnccn1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To a solution of (5-aminobicyclo[3.2.1]octan-1-yl)methanol (327 g, 2.1 mmol) and pyrazine-2-carboxylic acid (260 mg, 2.1 mmol) in DMF (10 mL) was added DIEA (680 mg, 5.22 mmol), followed by HATU (800 mg, 2.1 mmol). After stirring at room temperature for an hour, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under rescued pressure to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2/1) to afford 540 mg (100%) of the title compound, N-(5-(hydroxymethyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide as a colorless oil. ESI-MS m/z: 262 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:18]2[CH2:20][CH2:19]2)[N:3]=1.[I:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[CH:18]1([C:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:7]=[C:2]([N:25]3[CH:26]=[C:22]([I:21])[N:23]=[CH:24]3)[N:3]=2)[CH2:20][CH2:19]1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nc(C3CC3)c2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C3CC3)nc(-n3cnc(I)c3)c2)cc1

Procedure:
The title compound was prepared 2-chloro-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.33) (1.0 g, 3 mmol) and commercially available 4-iodo-imidazole (0.782 g, 4 mmol) according to the general procedure IVa. Obtained as a yellow solid (1.44 g, 93%). MS (ISP) 456.2 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CN(C)C=O.O>[Br:1][C:2]1[N:3]([CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(Br)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of methyl 2-bromo-1H-indole-3-carboxylate (1.0 g, 4.0 mmol) in dimethylformamide was added sodium hydride (0.32 g, 8.0 mmol, 60% in oil) under ice bath. The resulting mixture was stirred at room temperature for 0.5 hour. Then (1-bromoethyl)benzene (1.1 g, 6.0 mmol) was added in portion slowly. Then the mixture was stirred at room temperature for 1 hour. After the reaction, it was diluted with water (100 mL), and the product was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by column Chromatography (silica gel: ethyl acetate:petroleum ether=1:8) to give the pure product methyl 2-bromo-1-(1-phenylethyl)-1H-indole-3-carboxylate (1.1 g, 75%) as a yellow oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]12[CH2:18][C:13]3([CH3:19])[CH2:14][CH:15]([CH2:17][C:11]([CH3:20])([CH2:12]3)[CH2:10]1)[CH2:16]2.[OH-].[Na+]>O>[CH3:19][C:13]12[CH2:14][CH:15]3[CH2:17][C:11]([CH3:20])([CH2:10][C:9]([C:1]4([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]4)([CH2:16]3)[CH2:18]1)[CH2:12]2
Reactant: Oc1ccccc1
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC12CC3CC(C)(C1)CC(C1(O)C=CC=CC1)(C3)C2
Yield: 37 %

Procedure:
Into a 2 liter flask equipped with a thermometer, a Dimroth condenser, an inlet for nitrogen gas and a stirrer, 77.4 g (0.822 moles) of phenol and 20.0 g (0.0822 moles) of 1-bromo-3,5-dimethyladamantane were placed. A stream of nitrogen gas was introduced into the flask, and the resultant mixture was heated under the refluxing condition in an oil bath for 30 minutes. Then, 800 ml of water was added, and the obtained mixture was heated under the refluxing condition in an oil bath for 10 minutes to obtain a fluid separated in two layers. The fluid was cooled in an ice bath, and the lower layer having an orange color was solidified to obtain a white solid substance. The white solid substance was taken out by decantation, stirred twice in 500 ml of a 2% aqueous solution of sodium hydroxide and twice in 500 ml of water and then filtered, and 7.8 g of 4-(1-(3,5-dimethyladamantyl)phenol was obtained (the yield: 37%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C(O)(=O)C.[Br:22]N1C(=O)CCC1=O.O>[Cl-].[Na+].O>[Br:22][C:6]1[S:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[C:3]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1scc(C)c1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1sc(Br)c(C)c1NC(=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a stirred mixture of methyl 4-methyl-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (11.7 g, 43.8 mmol) and acetic acid (150 mL) was added 1-bromopyrrolidine-2,5-dione (15.6 g, 88.0 mmol) at room temperature. Then, this mixture was stirred at 80° C. for 6 h. After cooling to room temperature, the mixture was poured into water (600 mL) and brine (300 mL). The precipitate was collected by filtration, washed with water, dried under vacuum to afford the title compound (9.40 g, 62%) as a white solid: