Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@:4]2([O:6][CH2:5]2)[CH2:3]1.[CH2:22]([O:24][C:25]1[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[CH3:23]>CO>[CH2:22]([O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][CH2:5][C@:4]2([OH:6])[CH2:7][CH2:8][CH2:9][C@@:2]([CH2:10][N:11]3[C:15]4[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)([CH3:1])[CH2:3]2)=[CH:27][CH:26]=1)[CH3:23]
Reactant: CCOc1ccc(N)cn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Solvent: CO
Product: CCOc1ccc(NC[C@]2(O)CCC[C@](C)(Cn3cnc4ccc(C#N)cc43)C2)cn1
Temperature: 120 °C

Procedure:
A 5 mL microwave vial was charged with 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (150 mg, 0.533 mmol),6-(ethyloxy)-3-pyridinamine (221 mg, 1.599 mmol) and MeOH (4 mL). The reaction mixture was stirred and heated to 120° C. for 24 h. The reaction mixture was concentrated down to afford an oil. The oil was purified by silica gel (40 g) loading and initially elluting in DCM through to 6% MeOH/DCM over 18 column volumes to afford 1-{[(1S,3S)-3-({[6-(ethyloxy)-3-pyridinyl]amino}methyl)-3-hydroxy-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile as an colorless oil. MS (m/z) 420 (M+H+).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[N:15]1([CH2:19][C@@H:20]([NH2:32])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:19][C@@H:20]([NH:32][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: N[C@H](CN1CCC1)c1ccc(F)c(C(F)(F)F)c1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(F)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 62 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethylamine to give the title compound as a white solid. LC/MS [390 (M+H)].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[Br:28][C:29]1[CH:30]=[C:31]([C:35]2([NH2:38])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[Br:28][C:29]1[CH:30]=[C:31]([C:35]2([NH:38][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]4[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=4)[N:3]=3)[CH2:36][CH2:37]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NC1(c2cccc(Br)c2)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4cccc(Br)c4)CC3)nc(OCC(F)(F)F)n2)cc1
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To a solution of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1156 mg, 2 mmol) in THF (10 mL) was added 1-(3-bromophenyl)cyclopropanamine (424 mg, 2.000 mmol) and Hunig's Base (1.747 mL, 10.00 mmol). The resulting mixture was stirred for 16 h. After concentration, the residue was purified by Biotage eluting with 20% ethyl acetate in hexane to give 400 mg (35%) of the desired product as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH:13]=C)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I([O-])(=O)(=O)=[O:16].[K+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:5]([O:4][CH2:3][C@H:2]([CH3:1])[CH2:12][CH:13]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(C)COCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](CC=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.7 %

Procedure:
A 250 mL round-bottomed flask, equipped with a magnetic stirring bar and a thermometer was fitted with a septum and a nitrogen inlet. The apparatus was charged with benzyl 2-methyl-4-penten-1-yl ether (2.39 g, 12.5 mmol) in 75 mL of acetone and 25 mL of water. Osmium tetroxide (0.833 mL of an 0.15 M aqueous solution, 0.125 mmol) was added in one portion, followed by potassium periodate (6.04 g, 26.2 mmol) in three equal portions. The resulting slurry was stirred for 6 hours at room temperature and decanted into a 500 mL separatory funnel. The aqueous layer was extracted with 3×200 mL of diethyl ether. Each washing was stirred over the solids for 5 minutes, washed with 150 mL of saturated aqueous sodium thiosulfate and 100 mL of saturated aqueous sodium chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated and chromatographed (4×20 cm column; 4:1 hexane:ethyl acetate) to afford 1.94 g (81%) of aldehyde 4 as a colorless oil. Rf =0.37 (4:1 hexane:ethyl acetate).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][CH2:18][C:17]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C>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.CO>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][CH2:18][C:17]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: Ic1ccc(N2CCC3(C2)OCCO3)nc1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2ccc(N3CCC4(C3)OCCO4)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 3.0 g of 2-benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine, 1.07 g of (3R)-3-ethynyl-3-quinuclidinol, 82 mg of tetrakis(triphenylphosphine)palladium (0), 68 mg of cuprous iodide, 2.0 ml of triethylamine and 7 ml of methanol was stirred at room temperature overnight in a nitrogen atmosphere. The reaction solution was partitioned between aqueous dilute ammonia-ethyl acetate, washed with washed with water, dried over anhydrous magnesium sulfate and then concentrated. 10 ml of tetrahydrofuran was added to the residue to dissolve under heating, and to the mixture was added 15 ml of ethyl acetate. The mixture was filtered through 10 g of NH-silica gel, washed with ethyl acetate, and concentrated. The residue was crystallized from ethyl acetate, to give 2.79 g of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>C1(C)C(C)=CC=CC=1>[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH:16][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1cc(C)cc(N)c1
Solvent: Cc1ccccc1C
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(O)cc2)c1
Temperature: 160 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxyphenylacetic acid (20.0 g, 131 mmol) and 3,5-dimethylaniline (15.9 g, 131 mmol) in xylene (100 mL) was stirred for three days at 160° C. with a Dean Stark trap. The mixture was cooled to room temperature and filtered. The solid product obtained was washed with hexane (200 mL), 10% sodium bicarbonate solution (250 mL), water (200 mL), 10% hydrochloric acid (200 mL), and then water (200 mL). The beige solid was air dried to yield 27.7 g, 82.7%. mp 183-185° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4F)nc23)CC1
Yield: 73.6 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.053 mMol) 2,4-difluorobenzoyl chloride, 0.012 gm (77%) of the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[SH:12])=[CH:3][CH:2]=1.[C:13]1(=[O:31])[N:17]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[CH2:20]Cl)[C:16](=[O:26])[C:15]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:14]12>>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[S:12][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]2[C:16](=[O:26])[C:15]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:14]3[C:13]2=[O:31])=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccccc1CCl
Reactant: Sc1nccn1-c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1ccccc1CSc1nccn1-c1ccncc1

Procedure:
1-(4-pyridyl)-2-mercaptoimidazole and 2-phthalimidobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 1-(4-pyridyl)-2-(2-phthalimidobenzylthio)imidazole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:15]=[C:16]=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[N:1]1([C:16]([NH:15][C:7](=[O:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[S:17])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C1COCCN1
Solvent: CC(C)=O
Product: O=C(NC(=S)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of morpholine (1.00 g, 11.5 mmol, 1.00 equiv) in acetone (10 mL). TEA (1.74 g, 17.2 mmol, 1.50 equiv) was added to the reaction, and the resulting solution was stirred for 30 min at 25° C. Benzoyl isothiocyanate (1.87 g, 11.5 mmol, 2.00 equiv) was added dropwise to the reaction at 0° C. The resulting solution was stirred for 30 min at 0° C., then quenched with 20 mL of water. The mixture was extracted with 2×30 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10-1:3) as eluent to furnish 2.30 g (80%) of N-(morpholine-4-carbonothioyl)benzamide as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O=[C:17]1[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:18]1>N1C=CC=CC=1>[C:27]1([C:19]2[CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[N:18]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1
Solvent: c1ccncc1
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc(-c2ccccc2)c1
Reaction time: 0.17 h

Procedure:
With cooling with ice, trifluoromethanesulfonic acid anhydride (3.7 mL) was added to a pyridine (80 mL) solution of methyl 2-oxo-6-phenyl-1,2-dihydropyridine-4-carboxylate (2.8 g), and this was stirred for 10 minutes with cooling with ice, and then at room temperature for 2 hours. With further cooling with ice, trifluoromethanesulfonic acid anhydride (1 mL) was added to it, stirred at that temperature for 5 minutes and then overnight at room temperature. The reaction liquid was concentrated under reduced pressure, then ethyl acetate was added thereto, and the formed precipitate was taken away through filtration. Water was added to the filtrate, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline water. This was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a yellow powder.
Reaction SMILES: [CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.I[CH2:15][C:16]#[N:17].OO>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[C:16]([CH2:15][C:3]1[N:4]2[C:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:1][C:2]=1[C:10]([O:12][CH3:13])=[O:11])#[N:17]
Reactant: N#CCI
Reactant: COC(=O)c1cc2n(c1)CCCC2
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2n(c1CC#N)CCCC2
Yield: 78.4 %

Procedure:
A 500-mL three-neck round-bottomed flask equipped with an addition funnel, thermometer and charged with methyl 5,6,7,8-tetrahydroindolizine-2-carboxylate 101d (6.70 g, 37.4 mmol), iodoacetonitrile (12.5 g, 74.9 mmol), iron (II) sulfate heptahydrate (5.20 g, 18.7 mmol) and dimethyl sulfoxide (250 mL). Hydrogen peroxide (35%, 18.2 g, 187 mmol) was added dropwise to the mixture in 1 h through a syringe pump at room temperature using a water bath. Iron (II) sulfate heptahydrate (2 to 3 equivalent) was added to the reaction mixture in portions to keep the temperature between 25° C. to 35° C., until the color of the reaction mixture is deep red. If TLCs show the reaction not completed, then more hydrogen peroxide (2-3 equivalent) and more iron (II) sulfate heptahydrate (1-2 equivalent) were added in the same manner until the reaction is completed. After that time, the reaction mixture was partitioned between aqueous saturated sodium bicarbonate solution (200 mL) and ethyl acetate (400 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated Sodium thiosulfate solution (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 78% yield (6.40 g) of 101e as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.23 (s, 1H), 4.23 (s, 2H), 3.94 (t, 2H, J=6.5 Hz), 3.81 (s, 3H), 2.74 (t, 2H, J=6.5 Hz), 2.00 (m, 2H), 1.83 (m, 2H); (APCI+) m/z 219.3 (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: O
Solvent: CN(C)C=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: [CH3:1]C(C)([O-])C.[K+].[O:7]=[C:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH2:27][OH:28])=[CH:9]1.CI>C(O)(C)(C)C>[O:7]=[C:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH2:27][OH:28])=[C:9]1[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2CO
Agent: [K+]
Solvent: CI
Solvent: CC(C)(C)O
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 3 h

Procedure:
A mixture of potassium-t-butoxide (5 g) in 100 ml t-butanol is heated to reflux. A solution of 3-oxo-17β-(hydroxymethyl)-4-androstene (10 g) in t-butanol is added followed by a solution of methyl iodide (2.7 g) in t-butanol. Heating is continued for 3 hours. The mixture is then cooled, acidified, and extracted with dichloromethane. The dichloromethane solution is washed with brine, dried, and concentrated to yield 3oxo-17β-(hydroxymethyl)-4-methyl-4-androstene.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[C:29]([CH3:40])[C:28]=1[CH3:41]>>[CH3:40][C:29]1[C:28]([CH3:41])=[C:27]([O:5][CH2:6][C:7]2[C:8]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:9][S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:32]=[CH:31][C:30]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CS(=O)(=O)OCc1c(-c2ccc(C(F)(F)F)cc2)nsc1C(F)(F)F
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(C(F)(F)F)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(4-trifluoromethylphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ7.89 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H), 5.14 (s, 2H), 3.89 (s, 3H), 2.88 (t, J=7.2 Hz, 2H), 2.48 (t, J=7.5 Hz, 2H), 2.22 (s, 3H), 1.76 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H19F6NO3S, 502.1 (M−H). found 502.0.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[NH:11])=[CH:5][C:4]=1[N+:13]([O-])=O.O1CCCC1>[Pd].CO>[ClH:1].[NH2:13][C:4]1[CH:5]=[C:6]([NH:9][C:10]([NH2:12])=[NH:11])[CH:7]=[CH:8][C:3]=1[NH2:2]
Reactant: N=C(N)Nc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: N=C(N)Nc1ccc(N)c(N)c1
Yield: 98.6 %

Procedure:
A mixture comprising N-(4-amino-3-nitrophenyl)guanidine hydrochloride (12.0 g, 51.8 mmol), 10% palladium on carbon (1.0 g), tetrahydrofuran (100 mL) and methanol (100 mL) was hydrogenated at one atmosphere, filtered and concentration in vacuo to provide N-(3,4-diaminophenyl)guanidine hydrochloride (10.3 g, 98% yield) as a dark solid; 1H-NMR (300 MHz, DMSO-d6): 9.4 (s), 7.2 (s), 6.5 (d), 6.3 (s), 6.2 (d), 4.7 (s).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.O1CCCC1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][CH:17]=1>C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:22]([CH2:23][CH3:24])([OH:25])[C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: Clc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(O)(c1ccc(O)cc1)c1cccc(Cl)c1

Procedure:
To a Grignard reactant prepared from 14.6 g. of magnesium turnings and 115 g. of 3-chloro-bromobenzene in 350 ml. of dry tetrahydrofurane a solution of 30.1 g. of 4'-hydroxy-propiophenone in 540 ml. of dry tetrahydrofurane is added dropwise, with stirring under slight reflux. The reaction mixture is slightly boiled for 30 additional minutes, cooled and decomposed by pouring onto a mixture of ice and glacial acetic acid. After separation the organic phase is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Crystallization of the solid residue from a mixture of n-hexane and ethyl acetate yields 42.6 g. of the named compound, melting at 132° to 134° C.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:49])[N:29]([CH:46]([CH3:48])[CH3:47])[CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:49])[N:29]([CH:46]([CH3:47])[CH3:48])[CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1
Reactant: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 67.7 %

Procedure:
A solution of 3-t-butyldiphenylsilyloxy-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (945 mg, 1.38 mmol) (obtained as described in Reference Example 60(2)) in anhydrous tetrahydrofuran (50 ml) were added successively acetic acid (0.10 ml, 1.66 mmol) and a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.66 ml, 1.66 mmol) in an ice bath, and the mixture was stirred in the ice bath for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate ethyl acetate:methanol (10:1) as the eluant to afford 3-hydroxy-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (433 mg, yield 66%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Yield: 74.7 %

Procedure:
Methyl 3-bromo-4-hydroxybenzoate [prepared as per Tetrahedron, 2003, 59, 9173] (3.47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), anhydrous potassium carbonate (3.11 g, 22.5 mmol) was added and the stirred mixture was treated with benzyl bromide (3.08 g, 18.0 mmol) and held at reflux for 5 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 10% ethyl acetate in petroleum ether afforded methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid. 1H NMR (DMSO-d6) 8.12 (1H, d), 7.96 (1H, dd), 7.51 (2H, m), 7.43 (2H, t), 7.35 (2H, m), 5.32 (2H, s), 3.84 (3H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>[Pd]>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[N:7]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Pd]
Product: FC(F)(F)Oc1ccc(-c2nccc(Cl)n2)cc1

Procedure:
The title compound was prepared by palladium-catalyzed arylation of 2,4-dichloropyrimidine and 4-trifluoromethoxyphenyl boronic acid: mp 70-73° C.; 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J=5.6 Hz, 1H), 8.16 (d, J=9.1 Hz, 2H), 7.65 (d, J=5.3 Hz, 1H), 7.36 (dd, J=9.2, 0.9 Hz, 2H); EIMS m/z 274 (M+).