Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][CH2:35][C@H:36]([NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[C:37]([OH:39])=O.[NH2:50][C@@H:51]([CH2:69][C:70]1[CH:75]=[CH:74][C:73]([S:76]([CH3:79])(=[O:78])=[O:77])=[CH:72][CH:71]=1)[C:52]([NH:54][C@@H:55]([CH2:62][C:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]=1)[C:56]([C@@:58]1([CH3:61])[CH2:60][O:59]1)=[O:57])=[O:53]>CN(C=O)C.O.CCOC(C)=O>[C:63]1([CH2:62][C@H:55]([NH:54][C:52](=[O:53])[C@@H:51]([NH:50][C:37](=[O:39])[C@@H:36]([NH:40][C:41](=[O:49])[CH2:42][N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH2:35][OH:34])[CH2:69][C:70]2[CH:75]=[CH:74][C:73]([S:76]([CH3:79])(=[O:77])=[O:78])=[CH:72][CH:71]=2)[C:56]([C@@:58]2([CH3:61])[CH2:60][O:59]2)=[O:57])[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]=1
Reactant: O=C(CN1CCOCC1)N[C@@H](CO)C(=O)O
Reactant: C[C@]1(C(=O)[C@H](CC2=CCCCC2)NC(=O)[C@@H](N)Cc2ccc(S(C)(=O)=O)cc2)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(C(=O)[C@H](CC2=CCCCC2)NC(=O)[C@H](Cc2ccc(S(C)(=O)=O)cc2)NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)CO1
Temperature: 25 °C
Yield: 35 %

Procedure:
HATU (502 mg, 1.3 mmol) and DIPEA (1.35 mL) were added to a solution of (S)-3-hydroxy-2-(2-morpholinoacetamido)propanoic acid (225 mg, 0.97 mmol) and (S)-2-amino-N-((S)-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-(methylsulfonyl)phenyl)propanamide (0.88 mmol) in DMF (20 mL) at 0° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and the two layers were separated. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/EtOAc/MeOH=20:10:0.2) to afford (S)-N-((S)-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-(methylsulfonyl)phenyl)propanamide (200 mg, 35% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.33 (d, J=7.2 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.69 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 2H), 5.40 (m, 1H), 5.05 (m, 1H), 4.45-4.70 (m, 2H), 4.30 (m, 1H), 3.57 (m, 4H), 3.50 (m, 2H), 3.22 (m, 1H), 3.20 (s, 3H), 3.10 (m, 1H), 2.80-3.00 (m, 4H), 2.40 (m, 2H), 2.20 (m, 2H), 1.90-2.10 (m, 4H), 1.50-1.70 (m, 3H), 1.37 (s, 3H), 1.00-1.30 (m, 3H). MS (EI) for C31H44N4O9S, found 649.0 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH2:11][S:10][C:9]2=[NH:13])=[CH:5][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH2:11][S:10][C:9]2=[N:13][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][N:6]=1
Reactant: N=C1SCCN1Cc1cnc(Cl)s1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(N=C1SCCN1Cc1cnc(Cl)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2-Chloro-5-thiazolylmethyl)-2-iminothiazolidine (233 mg, 1.0 mmol) and sodium carbonate (120 mg, 1.1 mmol) were dissolved in 10 ml of water, into which, benzoyl chloride (141 mg, 1.0 mmol) dissolved in 5 ml of chloroform was added under cooling with ice, and thereafter stirred at room temperature for 2 hours. The chloroform layer was washed successively with 1% hydrochloric acid and water, dehydrated and dried, chloroform was distilled off, and remaining oil was purified by a silica gel column chromatography to obtain the intended substance. The crude crystal of the intended substance was recrystallized from ethyl acetate. Yield: 101 mg (30%). Melting point: 120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1
Reactant: NC(=O)c1ccc(N)nc1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of 6-aminonicotinamide (524 mg, 3.82 mmol) in TFA (10 mL) was added KNO3 (524 mg, 5.18 mmol) at room temperature with stirring. The resulting solution was stirred at 80° C. for 18 h, cooled to room temperature, then cooled water (100 mL) was added (no precipitate was formed). The resulting acidic aqueous solution was basified to pH 9 with 40% aq NaOH. The precipitate was filtered, washed with cooled water (2×5 mL), and dried to give 160 mg (23%) of 65 as a yellow powder, mp 289°-90° C. 1H NMR (DMSO-d6), 7.430 (s, 1H), 8.078 (s, 1H), 8.285 (bs, 2H, easily exchanged with D20), 8.840 (s, 2H).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[S:14].C([O-])(O)=O.[Na+].Cl>CC(O)C.O>[CH3:11][N:12]1[C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][NH:10][C:13]1=[S:14]
Reactant: CN=C=S
Reactant: NNC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cn1c(-c2cccnc2)n[nH]c1=S
Temperature: 70 °C

Procedure:
Nicotinohydrazide (10 g, 73 mmol) and methyl isothiocyanate (5.6 g, 76 mmol) were mixed in 2-propanol (150 ml) and heated to 70° C. o.n. The reaction was cooled to r.t. and evaporated to dryness. H2O (180 mL) and NaHCO3 (12.8 g, 152 mmol) were added to the residue and the mixture was refluxed o.n. The reaction mixture was cooled to r.t., acidified with concentrated HCl and the title compound, 13.1 g (93%), was collected by filtration. LC-MS (M++1): 193
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:16][CH2:17][C:18]4([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]4)[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([NH2:27])[CH3:26]>O1CCCC1>[CH2:25]([NH:27][CH2:20][C:18]([CH2:17][NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][N:7]2[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:19])[C:21]([F:24])([F:23])[F:22])[CH3:26]
Reactant: FC(F)(F)C1(CNc2cccc3c2cnn3-c2ccccc2)CO1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-phenyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine (1.235 g, 3.7 mmol) in anhydrous tetrahydrofuran (5 ml) was added ethylamine (2M in tetrahydrofuran) (10 ml, 20 mmol). The reaction was stirred at room temperature for approximately 72 hours and then evaporated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCO>CO.[Pd]>[CH3:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]2)=[CH:12][CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: Cc1c(CN2CCN(C)CC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1c(N)cccc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-Methyl-3-nitrobenzyl)-4-methylpiperazine (1.2 g, 4.8 mmol) was dissolved in 50 ml of MeOH, and to this was added a slurry of 10% Pd/C in a minimal amount of EtOH. The reaction mixture was evacuated and purged with H2, and then stirred at room temperature for 3 hours. The mixture was purged with N2 for 30 minutes and then filtered through a pad of celite. Solvent evaporation afforded 2-methyl-3-((4-methylpiperazin-1-yl)methyl)benzeneamine.
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[C:16]([CH2:22]O)=[N:15][C:14]=2[N:13]([CH3:24])[C:11]1=[O:12])(=O)C.S(Cl)([Cl:28])=O>>[OH:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[C:16]([CH2:22][Cl:28])=[N:15][C:14]=2[N:13]([CH3:24])[C:11]1=[O:12]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CO)n2C)n(C)c1=O
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc(CCl)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To thionyl chloride (30 ml) stirred at 0-5° C. was added (R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3,7-dimethylxanthine (6.3 g, 17.9 mmol). After stirring overnight at room temperature, unreacted thionyl chloride and volatile byproducts were evaporated under reduced pressure. To the residual oil was added methanol (300 ml) followed by hydrogen chloride in ether (1.0 M, 20 ml). After stirring for 12 hours, volatile materials were evaporated under reduced pressure to provide (R)-1-(5-hydroxyhexyl)-8-chloromethyl-3,7-dimethylxanthine (5.6 g, 96% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:13])N(OC)C)[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1>O1CCCC1.[Cl-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:13])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-[2-bromo-4-[methoxy(methyl)carbamoyl]phenyl]carbamate (30 g, 83.52 mmol, 1.00 equip) in tetrahydrofuran (400 mL). To the resulting mixture was then added (4-chlorophenyl)magnesium bromide (250 mL, 3.00 equip, 1 M) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with saturated sodium chloride (200 mL). The resulting solution was extracted with ethyl acetate (400 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:petroleum ether in a ratio of 1:20. The solids were collected by filtration. The mother liquor was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield additional tert-butyl N-[2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamate as a light yellow solid. LCMS (ES, m/z) 410 [M+H]+
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:29][CH2:30][C:31](Cl)=[O:32]>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][CH2:6][N:7]([CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)[C:31](=[O:32])[CH2:30][Br:29])[CH3:2]
Reactant: CCOC(CCNCC1OCCO1)OCC
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CCN(CC1OCCO1)C(=O)CBr)OCC

Procedure:
N-(3,3-Diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and bromoacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)-α-bromoacetamide as the residue.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]2[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:8]([CH3:32])[CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]2[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:8]([CH3:32])[CH:7]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(-c2ncc[nH]2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(-c3ncc[nH]3)cc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of ethyl 3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate (100 mg, 0.233 mmol) in THF/H2O (v/v=1/1, 2 mL) was added lithium hydroxide monohydrate (15 mg, 0.350 mmol). The solution was stirred at room temperature overnight. THF was removed under reduced pressure and the resulting aqueous solution was acidified with 10% hydrochloric acid to pH=6.0. The resulting precipitate was isolated by centrifuge, rinsed with water, dried under reduced pressure to afford 3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid as a brown powder (76 mg, 82%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]([C:22]2[S:23][CH:24]=[C:25]([C:27]3[C:28]([O:42][CH:43]4[CH2:46][CH2:45][CH2:44]4)=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]([C:37]([O:39][CH3:40])=[O:38])[C@@H:32]([CH3:41])[CH2:31][CH2:30]4)[N:26]=2)(O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]([C:22]2[S:23][CH:24]=[C:25]([C:27]3[C:28]([O:42][CH:43]4[CH2:46][CH2:45][CH2:44]4)=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]([C:37]([O:39][CH3:40])=[O:38])[C@@H:32]([CH3:41])[CH2:31][CH2:30]4)[N:26]=2)([F:7])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)N1c2ccc(-c3csc(C4(O)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3csc(C4(F)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
(Diethylamino)sulfur trifluoride (DAST) (0.152 g, 0.94 mmol) was added to a −78° C. solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 0.19 mmol) in dichloromethane (4 mL), and the resulting solution stirred for 2 h at −78° C. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 30% ethyl acetate/petroleum ether) to afford (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-fluoro azetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.059 g, 59%) as a yellow solid. MS (ESI, pos. ion) m/z 532 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36]3[N:37]=[CH:38][S:39][CH:40]=3)=[CH:24][C:23]=2[CH2:41][CH3:42])[C:12]=1[CH2:43][CH2:44][CH3:45].B(F)(F)F.CCOCC>C(S)C.C(OCC)C>[CH2:41]([C:23]1[CH:24]=[C:25]([C:36]2[N:37]=[CH:38][S:39][CH:40]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:43][CH2:44][CH3:45])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:46])=[O:2])[CH3:42]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3cscn3)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: FB(F)F
Solvent: CCS
Solvent: CCOCC
Product: CCCc1c(OCCCOc2cc(O)c(-c3cscn3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 67.1 %

Procedure:
A solution of 2-{3-[3-(5-benzyloxy-2-ethyl-4-thiazol-4-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid methyl ester (243 mg, 0.366 mmol) in ethanethiol (7 mL) was treated with boron trifluoride etherate at room temperature for 4 h. The mixture was diluted with diethyl ether, washed once with water, once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 15% ethyl acetate/85% hexane) of the residue provided 131 mg (65%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.88 (d, J=1 Hz, 1H), 7.88 (dd, J=8, 1 Hz, 1H), 7.44 (d, J=1 Hz, 1H), 7.38 (m, 2H), 7.08 (m, 2H), 6.81 (d, J=8 Hz, 1H), 6.68 (d. J=8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J=8 Hz, 1H), 4.21 (t, J=6 Hz, 4H), 3.83 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J=6 Hz, 2H), 1.56 (hextet, J=8 Hz, 2H), 1.19 (t, J=8 Hz, 3H), 0.91 (t, J=7 Hz, 3H); TOF MS ES+ exact mass calculated for C31H34NO6S (p+1): m/z=548.2107. Found: 548.2085.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=O)=[C:4]([S:37]C)[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8]1[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([O:18][CH3:19])[CH:12]=[CH:11]3)[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:24][CH:23]=1)[S:37]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3SC)ccc2c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c3c(ccc2c1)-c1ccc(F)cc1SC3c1ccc(OCCN2CCCCC2)cc1
Yield: 40 %

Procedure:
Dissolve [2-(4-fluoro-2-methylsulfanyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (1.2 g, 2.2 mmol) in dry THF (20 mL). Add lithium aluminum hydride (1M in THF, 2.3 mL, 2.3 mmol) dropwise. After 10 minutes slowly pour the black solution into saturated aqueous ammonium chloride and extract with methylene chloride twice. Dry the combined organic layers with sodium sulfate, filter and concentrate to yield a 2:1 mixture of rotational diastereomers. Dissolve the crude foam in dry THF (15 mL). Add diisopropylethylamine (2.5 mL, 14.4 mmol) and methanesulfonyl chloride (0.45 mL, 5.8 mmol) and heat to reflux under nitrogen. Add more methanesulfonyl chloride (0.45 mL, 5.8 mmol) after 2 hours to drive the reaction to completion. Pour the reaction into saturated aqueous sodium bicarbonate and extract twice with methylene chloride. Dry the combined organic layers with sodium sulfate, filter and concentrate. Purify the residue on silica gel (0% to 3% methanol in methylene chloride) to yield 440 mg (44%) of the title compound: mass spectrum (ion spray) m/z=500.3 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[CH2:7][CH2:8][C:9]([CH3:12])([NH2:11])[CH3:10].C1COCC1.C(=O)([O-])O.[Na+].[C:25](ON1C(=O)CCC1=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH3:14][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[CH2:7][CH2:8][C:9]([NH:11][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:10])[CH3:12]
Reactant: CN(C)CCCN(C)CCC(C)(C)N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Crude N1-(3-(Dimethylamino)propyl)-N1,3-dimethylbutane-1,3-diamine (18.0 g, 31.9 mmol) was dissolved into THF (200 mL). Sodium hydrogen carbonate (14.0 g, 0.167 mol) dissolved in water (200 mL) was added to reaction to give a solution. CbzOSu (7.95 g, 1 equiv, 31.9 mmol) was added in one portion to the reaction and left to stir at room temperature for 16 h. The organic solvent was removed via rotovap and the aqueous concentrated to ˜100 mL. The aqueous was extracted with DCM (2×200 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on a Shimadzu Prep-LC utilizing water/acetonitrile and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. The desired fractions were collected and lyophilized to give a colorless oil (5.57 g, yield: 52.1%). LRMS (ESI+) for C19H33N3O2 (335.3); Found: 336 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.CO/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18].P(Cl)(Cl)(Cl)=O>O.C(O)(=O)C>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1cc(OC)cc(OC)c1
Reactant: CO/C=C/C(=O)OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1c(OC)cc(OC)cc1OC
Reaction time: 3 h
Yield: 90.5 %

Procedure:
1.68 g of 1,3,5-trimethoxybenzene, 2.32 g of methyl trans-3-methoxyacrylate, 0.18 g of water and 6 mL of glacial acetic acid were mixed, 164 mg of phosphorus oxychloride was added into the mixture at an inner temperature of 25° C., the added mixture was stirred for 3 hours at the same temperature to cause a reaction. After completion of the reaction, 36 mL of water was added dropwise into the reaction liquid, and the precipitated crystals were filtrated. The crystals were washed with 20 vol % of aqueous methanol, then, dried to obtain 2.28 g of methyl trans-3-(2,4,6-trimethoxyphenyl)acrylate (white solid). Yield: 91%.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][S:29]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])(=[O:31])=[O:30]>>[OH:26][CH2:27][CH2:28][S:29]([C:32]1[CH:33]=[C:34]([NH:35][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:36]=[CH:37][CH:38]=1)(=[O:30])=[O:31]
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)CCO)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(2-hydroxy-ethanesulfonyl)-aniline [commercially available] according to general procedure II. Yellow solid. MS (ISP) 541.4 [(M+H)+]; mp 205° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[N:31]=[C:30]([C:32]#[N:33])[C:29](Br)=[CH:28][N:27]=1>>[NH2:25][C:26]1[N:31]=[C:30]([C:32]#[N:33])[C:29]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:24])=[CH:28][N:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B(O)O)c(F)c1
Reactant: N#Cc1nc(N)ncc1Br
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing (2′-(N-(tert-butyl)sulfamoyl)-3-fluoro-[1,1′-biphenyl]-4-yl)boronic acid and 2-amino-5-bromo-4-cyanopyrimidine. MS (ESI): mass calcd. for C21H20FN5O2S, 327.08; m/z found, 328.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.64-8.59 (m, 1H), 8.07 (dd, J=7.9, 1.4, 1H), 7.71-7.65 (m, 1H), 7.65-7.59 (m, 2H), 7.57 (s, 2H), 7.45-7.39 (m, 2H), 7.36 (dd, J=7.8, 1.7, 1H), 6.89 (s, 1H), 1.02 (s, 9H).