Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-yl ester, phenylboronic acid, tetrakis(triphenylphosphine)palladium(O) and sodium carbonate in dioxane/water. ES-MS m/e (%): 263 (M+H+, 100).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:25])[CH3:24]>O.ClCCl>[CH3:24][C:23]([NH:16][CH2:15][CH2:14][C:11]1[C:12]2[CH:13]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1)=[O:25]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
The compound V (6.0 g, 0.03 mol) produced as described above and potassium carbonate (5 g) were added to 20 ml of water and 40 ml of dichloromethane, and stirred for 30 minutes. The aqueous layer was removed. The organic layer was cooled to the temperature of 0° C., and acetyl chloride (7.8 g, 0.1 mol) was added dropwise. A reaction was allowed to proceed at room temperature for 1 hour. 100 ml water was then added, and the reaction solution was extracted with dichloromethane (50 ml*3). The organic phases were combined, dried with anhydrous magnesium sulfate, and filtered to remove the drying agent. The filtrate was concentrated under reduced pressure, to give a solid. The solid was recrystallized in a 2:1 toluene/n-hexane mixture, to produce 4.8 g of agomelatine. The yield was 78.5%. The melting point was 107-108° C. (in Literature [2], 109° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].N#N>CO.C1COCC1>[CH2:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:13][CH:12]=2)[CH2:17][CH:8]([NH:7][C:6](=[O:26])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
(1-Benzyl-6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (2.00 g, 4.79 mmol), prepared as described in Example 29A, 4-fluorophenyl-boronic acid (2.01 g, 14.37 mmol) and K2CO3 (2.65 g, 19.16 mmol) in a mixed solvent of THF (50 mL) and MeOH (25 mL) were stirred at RT for 30 min while N2 was allowed to bubble through the mixture, and then PXPd (258 mg, 0.48 mmol) was added. The reaction mixture was heated at 60° C. under N2 for 3 h. After cooling to RT, the solvent was stripped and the residue was diluted with H2O (60 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted with CH2Cl2 (100 mL×3), and the combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried (Na2SO4), filtered and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (0-20%) in hexanes to give the title compound (1.11 g, 54%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(N2CCC(C(=O)OC(C)(C)C)CC2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCC(C(=O)O)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of tert-butyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (0.500 g, 1.535 mmol; this starting material was isolated as a reaction product in Example 1a, Step 1) in anhydrous CH2Cl2 (5 mL) was treated with trifluoroacetic acid (3 mL, 38.9 mmol) and the mixture stirred at RT for 2 h. After this time, the mixture was concentrated on the a rotary evaporator and the resultant residue was neutralized by first treating it with 2 M NaOH and then 0.1 M pH 7 phosphate buffer. The resultant mixture was extracted with EtOAc, and the extract was washed with brine, dried (MgSO4) and concentrated to give 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylic acid (0.45 g, 1.668 mmol, >100% yield) as a pale yellow solid. LC-MS: 270, [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>CN(C)C=O.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of N,N-dimethylformamide and 5 ml of propionic acid is heated up to 150° C. The mixture is maintained at this temperature and stirred for 1.5 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.88 g of raw deferasirox is obtained, i.e. 81% of the theory, with an HPLC purity of 93% and a melting temperature of 255 to 262° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]([OH:54])[CH2:51][O:52][CH3:53])[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:53][O:52][CH2:51][C@@H:50]([OH:54])[CH2:49][O:48][C@H:10]1[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13][NH:8][CH2:9]1
Reactant: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Solvent: CO
Product: COC[C@@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1
Temperature: 25 °C

Procedure:
15.3 g (20.5 mmol) of (3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 70 ml of abs. methanol at 0° C., then 118 ml (236 mmol) of hydrochloric acid in methanol (2.0 molar) were added dropwise at 5° C. max. and thereafter the mixture was warmed to room temperature. After 22 hours the reaction mixture was poured into ice-cold sodium hydrogen carbonate solution (1 l, 60 g sodium hydrogen carbonate) and the product was extracted three times with 500 ml dichloromethane, the organic phases were washed with distilled water, then dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The thus-obtained crude product was chromatographed on silica gel with dichloromethane/methanol (95/5). There were thus obtained 9.3 g (14.4 mmol), 70.2%, (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol as colorless oil; MS: 646.3 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([CH3:13])[CH3:12])[C:5]1=[O:18])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:38]([O:1][C@@H:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([CH3:12])[CH3:13])[C:5]1=[O:18])[CH3:3])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)O)[C@H]1SC
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)c2ccccc2)[C@H]1SC
Reaction time: 1.5 h
Yield: 83 %

Procedure:
In 2 ml of tetrahydrofuran were dissolved (3S, 4R)-3-[(S)-1-hydroxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidin-2-one (105 mg, 0.38 mmole), triphenylphosphine (201 mg, 2 equivalents) and benzoic acid (94 mg, 2 equivalents). To the resulting solution was added little by little a solution of diethyl azodicarboxylate (134 mg, 2 equivalents) in tetrahydrofuran (1 ml) at 20° C. over 10 minutes and then the mixture was stirred at the same temperature for 1.5 hours. The solvent was then distilled off and the residue was dissolved in 3 ml of a 6:1 by volume mixture of benzene and ethyl acetate and left to stand in a refrigerator. The resulting precipitate was filtered off and the filtrate was subjected to thin layer chromatography developed with a 5:1 by volume mixture of benzene and ethyl acetate to afford 119 mg (yield 82%) of the desired product as an oil, containing a small amount of the 1'S-isomer.
Reaction SMILES: [F:1][C:2]([F:26])([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[H-].[Na+].I[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36].O>CS(C)=O>[CH2:36]([C:5]([CH2:4][CH2:3][C:2]([F:26])([F:1])[C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:21])([F:20])[F:19])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=[CH2:30]
Reactant: CCOC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
The diethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-malonate prepared in Step 1 of Example 2 (1.2 g, 3.0 mmol) was slowly added dropwise to a suspension of 60% sodium hydride (288 mg, 12 mmol) in anhydrous dimethyl sulfoxide (20 ml) at 0° C., followed by stirring for 1 hour at room temperature. After 7-iodohept-1-ene (795 mg, 2.5 mmol) was slowly added dropwise, the reaction mixture was stirred for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/40) to give diethyl 2-(6-heptenyl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)malonate (1.08 g, Yield 73%).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[C:17]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19].CN1CCOCC1>C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:17]([N:12]2[C:13]3[C:9](=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:29][CH:28]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CCS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(=O)(=O)CC)cccc21
Reaction time: 0.5 h

Procedure:
Ethanesulfonyl chloride (0.26 g, 2 mmol) was added to a stirred solution of methyl 2-(4-amino-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (0.58 g, 1.7 mmol), as described in Example 3 Step B, and 4-methylmorpholine (0.25 g, 2.5 mmol) in DCM (8 mL) at 0° C. After 30 min, an additional portion of ethanesulfonyl chloride (0.1 g, 1 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE:EA=2:1) to afford the title compound. LC/MS m/z=435.1 [M+H]+.
Reaction SMILES: C([N:8]([C@H:10]([C:20]#[CH:21])[CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])(OC(C)(C)C)=O.[F:22][C:23]1[C:24](I)=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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.[Cu]I>[F:22][C:23]1[C:24]([C:21]#[C:20][C@@H:10]([NH:8][CH3:9])[CH2:11][OH:12])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: C#C[C@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN[C@H](C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)CO
Reaction time: 2.5 h

Procedure:
Using Method C above, (R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne (130 mg, 0.42 mmol) (Example 104C) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated, and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes gradient. The intermediate that resulted from this operation was dissolved directly in 10 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-[4-hydroxy-3-methylamino-1-butynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 28 mg, 38%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)=O.[CH3:17][S:18](C)=O>Cl(O)(=O)(=O)=O>[CH3:17][S:18][C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CS(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1cc(C(C)(C)C)ccc1O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a cold (0°-5° C.) suspension of 4-(1,1-dimethylethyl)phenol (7.5 g., 0.05 mole) and phosphorous oxychloride (8 ml.) in 70% perchloric acid (10 ml.) is added dimethylsulfoxide (3.9 g., 0.05 mole) dropwise with vigorous stirring. The resulting reaction mixture is stirred at 0°-5° C. for 1 hour and at 20° C. for 16 hours and then poured onto crushed ice whereupon a gum separates. Upon warming to 20° C. with vigorous stirring there is obtained a white solid which is collected, washed with cold water, air dried at 20° C. with aspiration and washed with ether. The white solid (10 g., m.p. 160° C.) is added to saturated aqueous potassium chloride (100 ml.) and the resulting mixture, heated at reflux for 4 hours. After standing at 20° C. for 12 hours, the reaction mixture is extracted with ether. The ethereal extract is washed with water and saturated brine, dried over sodium sulfate and filtered. Evaporation of the filtrate in vacuo leaves 2-methylthio-4-(1,1-dimethylethyl)phenol as an analytically pure, colorless oil (5.7 g., 58%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:15]([N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccccc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccccc1-c1nccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add 4M HCl in dioxane (8 mL) to a solution of 3′-(2-fluorophenyl)-2,3,5,6-tetrahydro-[1,2′]-bipyrazinyl-4-carboxylic acid t-butyl ester (1.48 g, 4.13 mmol) in 1,4-dioxane (8 mL), and stir the mixture at room temperature for 3 hr. then at 40° C. for 16 hr. Allow the reaction to cool, filter off the precipitated solid, wash with 1,4-dioxane and dry under reduced pressure at 60° C., to give the title preparation as a yellow solid (960 mg, 70%). MS (ES) m/z=259 [M+H].
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[NH2:44][CH2:45][C:46]([CH3:49])([OH:48])[CH3:47].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([NH:44][CH2:45][C:46]([OH:48])([CH3:49])[CH3:47])=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (1.2 g), N-ethyl-N-(1-methylethyl)propan-2-amine (0.79 mL) and 1-amino-2-methylpropan-2-ol (0.40 g) in DMF (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.03 g), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (294 mg).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]1=[O:20])#[N:2].Cl.N[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:24]=1[SH:31]>C(O)C>[F:29][C:27]1[CH:26]=[C:25]([F:30])[C:24]2[S:31][C:1]([CH2:3][N:4]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[S:7][CH:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]3=[O:20])=[N:2][C:23]=2[CH:28]=1
Reactant: CCOC(=O)CC1Sc2ccccc2N(CC#N)C1=O
Reactant: Nc1cc(F)cc(F)c1S
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1Sc2ccccc2N(Cc2nc3cc(F)cc(F)c3s2)C1=O
Reaction time: 15 h
Yield: 76 %

Procedure:
Ethyl 2-(4-cyanomethyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetate (580 mg) and 474 mg of 2-amino-4,6-difluorothiophenol hydrochloride were added to 4 ml of anhydrous ethanol, the mixture was heated to reflux under argon atmosphere. After 15 hours, the solvent was distilled off. Water was added to the mixture, and extracted with ethyl acetate. After the drying of the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. The resulting oily matter was subjected to alumina column chromatography. Elution with hexane-ehtyl acetate gave 660 mg of the title compound. The structural formula and physical data of this compound are shown in Table 19.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:34][CH2:33][N:32]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:31]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: COc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(C2CCN(C(=O)c3cnoc3-c3ccc(C)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-methoxyphenyl)pyrrolidine oxalat (16.0 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.3 mg). Calcd for C22H22N2O3: 362.1630, found 362.1636.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:10][C:11]=2[I:12])[CH:6]=[CH:7][N:8]=1>C(O)(C)C.C1COCC1>[NH2:1][C:3]1[C:4]2[N:5]([C:9]([CH:13]3[CH2:16][C:15]([CH3:18])([OH:17])[CH2:14]3)=[N:10][C:11]=2[I:12])[CH:6]=[CH:7][N:8]=1
Reactant: N
Reactant: CC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC1(O)CC(c2nc(I)c3c(N)nccn23)C1
Temperature: -78 °C

Procedure:
A solution of 2M ammonia in isopropanol (80 mL) and THF (5 mL) was added to 3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (2.77 g, 7.62 mmol) in a Parr pressure reactor. The mixture was cooled to at −78° C. then ammonia gas was bubbled into the solution for 4-6 min. The reactor was sealed then heated at 110° C. for 15 h. The solvent was then removed in vacuo and the residue purified by chromatography over silica gel eluting with 7% MeOH in DCM to afford desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 3H), 2.32-2.51 (m, 4H), 3.33-3.52 (m, 1H), 6.61 (br.s., 2H), 7.03 (d, J=5.05 Hz, 1H) and 7.62 (d, J=5.05 Hz, 1H).