Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.ClCCl.[CH2:19]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34](O)[C:33]([S:40][CH3:41])=[CH:32]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].N1C=CC=CC=1>O.Cl>[CH2:19]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:33]([S:40][CH3:41])=[CH:32]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCCCCCCCc1ccc2cc(O)c(SC)cc2c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCc1ccc2cc(OS(=O)(=O)C(F)(F)F)c(SC)cc2c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 105.7 %

Procedure:
Trifluoromethanesulfonic anhydride (3 ml, 15 mmol) was added to a dichloromethane (50 ml) solution of the obtained 6-decyl-3-methylthio-2-hydroxynaphthalene (3.63 g, 10 mmol) and pyridine (2.5 ml, 30 mmol) at 0° C. This solution was stirred at room temperature for 25 minutes. Then, the mixture was diluted with water (20 ml), and hydrochloric acid (4 M, 20 ml) was added. The mixture was extracted with dichloromethane (30 ml×3). The organic phases obtained by repeating the extraction three times were collected, washed with saturated saline water (30 ml×3), dried with MgSO4, and condensed to obtain 6-decyl-3-methylthio-2-(trifluoromethanesulfonyloxy)naphthalene (compound (4)-81) (4.89 g, 99%).
Reaction SMILES: C(O)CC.Cl.[CH2:6]([O:8][NH2:9])[CH3:7].[CH3:10][N:11]1[C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[CH3:33])=O)=[CH:14][CH:13]=[N:12]1>O>[CH2:6]([O:8][N:9]=[C:16]([C:15]1[N:11]([CH3:10])[N:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][O:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[CH3:33])[CH3:7]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccnn2C)c1
Reactant: CCON
Agent: Cl
Solvent: CCCO
Solvent: O
Product: CCON=C(c1ccccc1COc1cc(C)ccc1C)c1ccnn1C
Yield: 45.9 %

Procedure:
n-Propanol (2 ml) and ethoxyamine hydrochloride (0.18 g, 1.8 mmol) were added to 2-(2,5-dimethylphenoxy-methyl)phenyl 1-methylpyrazol-5-yl ketone (0.20 g, 0.6 mmol), and the mixture was stirred under reflux for 3 days. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.11 g, 50.4%, as colorless crystals) and isomer B (0.10 g, 45.9%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone O-ethyloxime.
Reaction SMILES: [H-].[Na+].Br[C:4]1[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:6]2[N:7]=[C:8]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:10](=[O:13])[C:11]=2[N:12]=1.[CH3:35][OH:36]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[C:10](=[O:13])[C:11]3[N:12]=[C:4]([O:36][CH3:35])[N:5]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:6]=3[N:7]=[C:8]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[CH:15][CH:16]=1
Reactant: O=c1c2nc(Br)n(-c3ccccc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.05 h

Procedure:
A microwave tube is charged with sodium hydride (24.0 mg, 1.0 mmol) and dry methanol. After the reaction mixture is stirred for 3 min, 8-Bromo-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (8.0 mg, 0.015 mmol) is added. The tube is then capped and the mixture is heated in an oil bath for 3 h at 80° C. The reaction mixture is worked up by evaporating the solvent. The crude material is purified by flash chromatography. 1H NMR (CDCl3, 400 MHz) δ 7.63 (m, 4H), 7.43 (m, 1H), 7.28 (m, 4H), 7.11 (d, 2H), 7.03 (m, 1H), 4.25 (s, 3H). HPLC-MS calculated for C24H15Cl3N4O2 (M+H+) 497.0. Found: 497.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[CH:30]([C:33]1[N:37]=[CH:36][O:35][N:34]=1)([CH3:32])[CH3:31].[CH3:38][CH2:39]N(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:38][CH2:39][C:36]4[O:35][N:34]=[C:33]([CH:30]([CH3:32])[CH3:31])[N:37]=4)[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1
Reactant: CC(C)c1ncon1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCc5nc(C(C)C)no5)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (14 mg, 0.033 mmol), 542-chloroethyl)-3-isopropyl-1,2,4-oxadiazole (9 mg, 0.053 mmol) and DIEA (29 uL, 0.17 mmol) in NMP (1 mL) was stirred at 50° C. for 3 days. The crude reaction mixture was purified by RP-HPLC to give 5-Chloro-N2-(4-(1-(2-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl)piperidin-4-yl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 550.3 (M+H+).
Reaction SMILES: [CH2:1]([C@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH2:8][C@H:7]([C:18]([OH:20])=[O:19])[NH:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:28](=[S:30])=[S:29].[CH3:31]I>O.CO>[CH2:1]([C@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH2:8][C@H:7]([C:18]([OH:20])=[O:19])[N:6]1[C:28]([S:30][CH3:31])=[S:29])[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCC[C@@H]1N[C@@H](C(=O)O)Cc2c1[nH]c1ccccc21
Reactant: S=C=S
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCC[C@H]1c2[nH]c3ccccc3c2C[C@H](C(=O)O)N1C(=S)SC
Yield: 75.1 %

Procedure:
In the same manner as described in Example 43, (1RS,3SR)-trans-1-n-butyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.2 g), triethylamine (1.02 g), carbon disulfide (0.39 g), methyl iodide (0.72 g), methanol (14 ml) and water (2 ml) are reacted and treated. The product is recrystallized from aqueous ethanol to give the title compound (1.2 g, 75%), m.p. 99°-102° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N:18]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19]2)=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[O:5].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:31]=O>C(O)C.C(O)(=O)C.CO.[O-2].[O-2].[Mn+4]>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[N:18]([C:15]1[CH:14]=[C:3]3[C:2](=[CH:17][CH:16]=1)[N:1]=[C:31]([C:30]1[CH:33]=[C:34]([F:36])[CH:35]=[C:28]([Cl:27])[CH:29]=1)[N:6]([CH2:7][C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:4]3=[O:5])[CH2:19][CH2:20]2
Reactant: O=Cc1cc(F)cc(Cl)c1
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2CCN3CCC2CC3)ccc1N
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: CC(C)NC(=O)Cn1c(-c2cc(F)cc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Temperature: 95 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
2-Amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)benzamide (Intermediate 7A) (70 mg, 0.20 mmol) was dissolved in ethanol (2 mL) before addition of 3-chloro-5-fluorobenzaldehyde (46.3 mg, 0.29 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a Reactivial® and heated at 95° C. for 24 hours. Reaction mixture was then cooled to room temperature and diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX and concentrated under reduced pressure. The resultant product was re-dissolved in dichloromethane (2 mL), manganese dioxide (33.8 mg, 0.39 mmol) was added and reaction stirred overnight. The sample was then washed with water (5 mL) and extracted into dichloromethane. The organics were separated using a hydrophobic frit. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 2-(6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chloro-5-fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (9.0 mg, 0.018 mmol) 9% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:39])[N:3]=1.C(O)(=O)C.[CH:44](=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH:39][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:3]=1
Reactant: COc1ccc(COc2cccc(N)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(COc2cccc(NCc3ccccc3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 3-(2-amino-6-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate (0.30 g, 0.566 mmol) in methanol (10 mL) including acetic acid (0.03 g, 0.566 mmol) was added benzaldehyde (0.08 mL, 1.133 mmol) followed by sodium cyanoborohydride (0.04 g, 0.566 mmol), and the stirring was continued at 0° C. for 3 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give tert-butyl 3-(2-amino-6-{2-(benzylamino)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate as a yellow amorphous (0.299 g, yield; 85%).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:27]([CH3:32])[C:28]([F:31])([F:30])[F:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.O>CN(C=O)C.C(OCC)(=O)C>[F:29][C:28]([F:30])([F:31])[CH:27]([CH3:32])[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:20][CH:19]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1NCc2ccccc21
Reactant: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C(C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
At 0° C., 222.6 mg (1.67 mmol) of 2,3-dihydro-1H-isoindol-1-one were added to 66.9 mg (1.67 mmol, 60% pure) of sodium hydride in 2 ml of DMF. The mixture was stirred for 30 min, and 600 mg (1.39 mmol) of ethyl 2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate were then added at 0° C. The reaction mixture was stirred for a further 2 h, and water and ethyl acetate were then added. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 108 mg (19% of theory) of the target compound.
Reaction SMILES: [Br-].[C:2]1([PH+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:22]CCC.CCCCCC.[C:32]([O:40][C:41]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:42]=1[C:43]([O:45]C)=O)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([O:40][C:41]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:42]=1[C:43](=[O:45])[CH:22]=[P:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: [Li]CCCC
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc(Cl)ccc1OC(=O)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc(Cl)ccc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a stirred suspension of triphenylphosphonium bromide (2.14 g, 6.0 mmol) in dried THF (30 ml) at room temperature was added 1.6M n-BuLi in hexane (5.25 ml, 8.39 mmol). The orange suspension was stirred for 3 hours. Next, a solution of methyl 2-benzoyloxy-5-chloro-benzoate (0.83 g, 3.0 mmol) in THF (8 ml) was slowly added. The resulting mixture was stirred at 60° C. for 2 hours and filtered after cooled. DCM (100 ml) was added to the filtrate and the combined organic layers were washed with brine (2×80 ml). After filtration and evaporation of the solvent, yellow oil was obtained (2.0 g). They were then purified by chromatography, eluted with EtOAc:hexane/1:1, yielded 0.97 g solids. Rf=0.43. 1H NMR (d6-acetone) δ=7.80-7.52 (20H, m); 7.40-7.20 (1H+1H+1H, m); 5.25 (2H, s); 4.72 (1H, s, trans-H) and 4.62 (1H, s, cis-H). LCMS: (M+1)+=521.2 (RT=5.94 min.)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.Cl.[N:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[S:23][C:22]=1[NH:30][C:31]([NH2:33])=[NH:32].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:10]1([NH:16][C:17]([N:26]2[CH2:27][CH2:28][C:29]3[N:21]=[C:22]([NH:30][C:31]([NH2:33])=[NH:32])[S:23][C:24]=3[CH2:25]2)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: N=C(N)Nc1nc2c(s1)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc2c(s1)CN(C(=O)Nc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.2 mmol) and, after 5 min, phenyl isocyanate (0.11 mmol) are added to a suspension of N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine-2-yl)-guanidine dihydrochloride (0.1 mmol) in dimethylformamide (0.5 ml). The reaction mixture is stirred for another 3 hours at room temperature. Then saturated aqueous sodium carbonate solution is added and extraction is carried out with ethyl acetate. The pure title compound is obtained after drying of the combined organic phases over sodium sulphate and removal of the solvent in a vacuum.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:18]1[CH:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:2]3[CH2:3][CH2:4][N:5]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:6][CH2:7]3)[CH:9]=2)[CH2:15][C:16]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:17]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
5-[3-(piperazin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (100.0 mg, 0.2 mmol) prepared in Step 1, triethylamine (143.0 uL, 1.02 mmol) and methanesulfonyl chloride (35.0 mg, 0.30 mmol) were added to dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 55.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1C.[CH:16](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Br-:1].[CH2:2]([N+:8]1[CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]=1[CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: ClC(Cl)Cl
Reactant: Cc1cccc(C)n1
Reactant: CCCCCCBr
Solvent: Cc1ccccc1
Product: CCCCCC[n+]1ccc(C)cc1C
Product: [Br-]
Reaction time: 8 h

Procedure:
1-Bromohexane (1 equivalent) was dissolved in some toluene in a round bottomed flask flushed with nitrogen. Then, lutidine (1 equivalent) was added and the mixture was heated to reflux. During the reaction, a brown product appeared. The reaction was stopped after 8 hours. Afterwards, the solvent was removed under the reduced pressure. A minimum amount of acetonitrile was added to dissolve the residue and ether was added to precipitate the product. The crude product was washed with ether to afford off-white crystals. The yield of the reaction is 83%. 1H NMR (CDCl3, 200 MHz): δ 0.89 (t, 3H), 1.26 (m), 1.85 (m), 2.64 (s, 3H), 2.93 (s, 3H), 4.81 (t, 2H), 7.75(d, 2H), 9.51 (d, 1H); IR (CHCl3, cm−1): 1398 (C═C), 1635 (C═N), 2975 (N—C).
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]([CH:30]=2)[C:15]([NH:17][C:18]2[C:19]([CH3:29])=[C:20]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:21]([O:23]C)=[O:22])=[O:16])[CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:11]=[CH:12][C:13]([CH3:31])=[C:14]([CH:30]=2)[C:15]([NH:17][C:18]2[C:19]([CH3:29])=[C:20]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:21]([OH:23])=[O:22])=[O:16])[CH2:5]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(O)C3)ccc2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCCC(O)C2)cc1C(=O)Nc1c(C)ccc(C(=O)O)c1C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A solution of aqueous 4N NaOH (2.00 ml) is added to a stirred solution of methyl 3-[[5-(3-hydroxy-1-piperidyl)-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (0.3 g, 0.75 mmol) in THF:MeOH (5 ml:2 ml). After 3 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted with 10% IPA in CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as an off-white solid (0.274 g, 94%). Mass spectrum (m/z): 383.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.CCCCCC>[Si:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)c2occc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)c2occc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 231 %

Procedure:
A mixture of 0.12 gm (0.52 mmol) 5-hydroxymethyl-7-bromobenzofuran 0.070 gm (1.03 mMol) imidazole, and 0.078 gm (0.52 mMol), 0.070 gm (1.03 mMol) imidazole, and 0.078 gm (0.52 mMol) tert-butyldimethylsilyl chloride in 1 mL dimethylformamide was stirred at room temperature for 18 hours. The reaction mixture was diluted with hexane and washed well with water. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 0.41 gm (82%) of 5-tert-butyldimethylsilyloxymethyl-7-bromobenzofuran. This material was reacted essentially as described in EXAMPLE 1 to provide 0.085 gm (24%) 1-(5-tert-butyldimethylsilyloxy-methylbenzofur-7-yl)-2-aminopropane. This material was treated with tetrabutylammonium fluoride in tetrahydrofuran for 1 hour at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the organic phase washed well with water. The remaining organics were concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with dichloromethane containing 2% methanol saturated with ammonia. Fractions containing product were combined and concentrated under reduced pressure to provide 0.028 gm (50%) of 1-(5-hydroxymethylbenzofur-7-yl)-2-aminopropane. The title compound was prepared by reacting this amine with hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2[CH:31]=[CH:32][CH:33]=[N:34]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:34][CH:33]3[CH2:31][CH2:32]3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NC1CC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), cyclopropylamine (15 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C14H18ClN5O2, 324.12. found 324.2.
Reaction SMILES: [NH2:1][N:2]1[C:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[NH:12].[O:13]1C[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(Cl)(=O)CC>O>[NH2:1][N:2]1[C:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[N:12][C:14](=[O:13])[CH2:15][CH3:16]
Reactant: Cc1cccc2sc(=N)n(N)c12
Reactant: C1CCOC1
Agent: CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)N=c1sc2cccc(C)c2n1N

Procedure:
A 3.6 g. portion of 3-amino-2-imino-4-methylbenzothiazoline was dissolved in about 100 ml. of tetrahydrofuran, and 2.2 g. of triethylamine was added. The reaction mixture was cooled in an ice bath, and 2 g. of propionyl chloride, dissolved in 2 ml. of tetrahydrofuran, was added dropwise while the mixture was stirred. After the addition was complete, the reaction mixture was stirred at ice bath temperature for about 3 hours, and was then diluted with an equal volume of water. The tetrahydrofuran was removed under vacuum, and the remaining aqueous mixture was filtered to recover the product. After recrystallization from ethanol, the yield of purified product was 3.2 g. of 3-amino-4-methyl-2-propionyliminobenzothiazoline, m.p. 175°-76°C. The product was identified by nuclear magnetic resonance and ultraviolet analysis and by elemental microanalysis.