Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:13]=[C:14]([N:18]2[C:23](=[O:24])[C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[N:21][C:20]3[CH:30]=[CH:31][CH:32]=[N:33][C:19]2=3)[CH:15]=[CH:16][CH:17]=1.O[N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42].C(N=C=NCCCN(C)C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:13]=[C:14]([N:18]2[C:23](=[O:24])[C:22]([CH2:25][CH2:26][C:27]([O:29][N:36]3[C:40](=[O:41])[CH2:39][CH2:38][C:37]3=[O:42])=[O:28])=[N:21][C:20]3[CH:30]=[CH:31][CH:32]=[N:33][C:19]2=3)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)O)nc3cccnc32)c1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Product: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)ON3C(=O)CCC3=O)nc3cccnc32)c1
Reaction time: 24 h
Yield: 84.4 %

Procedure:
To a stirred solution of 4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-3-oxo-2-(2-carboxyethyl)-3,4-dihydropyrido[2,3-b]pyrazine (2.30 g) and N-hydroxysuccinimide (1.15 g) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.20 g) and the resulting mixture was stirred for 24 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution, water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with ether to give 4-[3-[3-(2-methoxyphenyl)ureido]-phenyl]-3-oxo-2-[2-succinimidooxycarbonylethyl)-3,4-dihydropyrido[2,3-b]pyrazine (2.35 g) as a solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.O.C(OCC)C.CC#N.CC#N.Cl[Pd]Cl>[Cl:14][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1
Reactant: Clc1cncc(Cl)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: Clc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 15.9 %

Procedure:
Charge a Schlenk tube under a positive pressure of argon with bis(acetonitrile)palladium (II) chloride (5 mg), 2-dicyclohexylphosphinodiphenyl (21 mg), cesium carbonate (1.69 g, 5.2 mmol) and 3,5-dichloropyridine (0.3 g, 2 mmol) in acetonitrile and stir at room temperature for 25 min (Angew. Chem. Int. Ed. 42, 5993-5996, (2003)). Add phenylacetylene (0.285 mL, 2.6 mmol) and stir at 95° C. for 16 h. Dilute the reaction mixture with water and diethyl ether and separate the phases. Wash the organic layer with water, concentrate and purify the residue by silica gel chromatography, eluting with 50:50 hexanes:dichloromethane to obtain the title compound (68 mg, 16%).
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([OH:18])[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:30])[CH3:29].Cl.[OH-].[Na+]>ClCCl>[Cl:17][C:12]1[N:11]=[C:10]([NH:9][C@H:5]2[CH2:6][CH2:7][CH2:8][C@:3]([CH2:2][NH:1][C:28](=[O:30])[CH3:29])([OH:18])[CH2:4]2)[C:15]([F:16])=[CH:14][N:13]=1
Reactant: CC(=O)Cl
Reactant: NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reaction time: 0.08 h

Procedure:
(1S,3S)-1-(aminomethyl)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol, 46b, (0.19 g, 0.69 mmol) was dissolved in dichloromethane (15 mL) and treated with DIPEA (1.20 mL, 6.91 mmol) and acetyl chloride (0.10 mL, 1.38 mmol). After 5 minutes, the reaction mixture was diluted into 1N HCl (30 mL), and the aqueous layer was brought to a basic pH by addition of 1N NaOH. The resulting suspension was extracted with dichloromethane (50 mL). The organic layer was dried on Na2SO4 and concentrated in vacuo to provide the crude product, which was purified by silica gel chromatography (20-100% EtOAc/hexanes gradient) to afford 195 mg of N-{[(1S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclo-hexyl]methyl}acetamide as a white foamy solid. LCMS RT=2.82 (M+1) 317.33.
Reaction SMILES: [CH:1]([NH:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:3])[CH3:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-]>C(Cl)CCl>[C:16]([N:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)N(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1

Procedure:
A mixture of 3,4-dichlorobenzoic acid, 2-isopropylhydrazide (0.98 g, 0.004 mole) and benzoyl chloride (0.56 g, 0.004 mole) is stirred overnight in 1.2 mL of ethylene dichloride and 6.5 mL of 10% soldium hydroxide. The organic phase is removed and the aqueous mixture is extracted with 25 mL of ethylene dichloride. The organic extracts are combined and concentrated to a yellow oil which is taken up in hot isopropyl alcohol. Cooling the alcohol solution causes precipitation of the title compound as a white crystalline product, which is collected by filtration and has a mp of 157° C.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].C(Cl)Cl.[CH3:15][NH:16][S:17]([Cl:20])(=[O:19])=[O:18]>O>[CH3:11][O:10][C:8]([N:16]([CH3:15])[S:17]([Cl:20])(=[O:19])=[O:18])=[O:9]
Reactant: CNS(=O)(=O)Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)N(C)S(=O)(=O)Cl
Yield: 91 %

Procedure:
158.2 parts of pyridine are added at -10° C., while stirring, to a solution of 188.8 parts of methyl chloroformate in 1,200 parts of methylene chloride. Then 259.2 parts of methylsulfamic acid chloride are added at the same temperature while stirring, and the mixture is stirred for half an hour at 0° C. and for one hour at 25° C. The reaction mixture is then stirred for 6 minutes with 600 parts of water at 5° C. and pH 1. The organic phase is then separated off from the 2-phase mixture formed, and is filtered and subjected to fractional distillation. 341 parts (91% of theory) of N-methoxycarbonyl-N-methylsulfamic acid chloride, of boiling point 49°-51° C./0.13 mbar and nD25 =1.4600, are obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:26][CH2:27][C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:26][CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CCC1CCCCC1)C2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Triethylamine 0.43 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.49 g, and stirred at 0° C. for 40 min. 3-cyclohexyl propionic acid 0.44 ml and WSC 0.59 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 45 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ether. The ether solution was washed with 10% sodium hydroxide solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3(3-cyclohexylpropionyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 20 ml solution of lithium aluminum hydride 0.19 g and refluxed for 1.5 hour. The reaction mixture was cooled, then added ether, water and 10% sodium hydroxide solution, and filtered the insoluble material. The filtrate was extracted with ether and dried by anhydrous sodium sulfate. After removing the drying agent, the filtrate was concentrated in vacuo. The thus obtained residue was purified by means of flash column chromatography (Merck, silica gel 60 230-600 mesh, chloroform-chloroform: acetone=20:1) to obtain the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C@@H:22]2[CH2:26][C@H:25]([F:27])[CH2:24][N:23]2[C:28]([O:30]CC2C=CC=CC=2)=O)[N:8](C)[C:9](=[O:20])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[C:38](OC(=O)C)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([OH:20])[N:8]=[C:7]([C@@H:22]2[CH2:26][C@H:25]([F:27])[CH2:24][N:23]2[C:28](=[O:30])[CH3:38])[N:6]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1nc([C@@H]2C[C@H](F)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc([C@@H]2C[C@H](F)CN2C(C)=O)nc(O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-5-(benzoyloxy)-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine4-carboxylate, dissolved in ethyl acetate was treated with Pd/C 10% (10% w/w) and acetic anhydride (1 eq.) and submitted under H2 atmosphere at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then the suspension was filtered over celite to give the title compound as a 7:3 mixture of rotamers by NMR.
Reaction SMILES: C([O:9][CH2:10][CH2:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[CH:14][CH:13]=1)(=O)C1C=CC=CC=1.C(O[C@@H:30]1[O:47][C@H:46]([CH2:48][O:49]C(=O)C)[C@@H:41]([O:42]C(=O)C)[C@H:36]([O:37]C(=O)C)[C@H:31]1[O:32]C(=O)C)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.ClCCl>[O:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][OH:9])=[CH:25][CH:24]=1)[C@@H:30]1[O:47][C@H:46]([CH2:48][OH:49])[C@@H:41]([OH:42])[C@H:36]([OH:37])[C@H:31]1[OH:32]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(OCCc1ccc(Cc2ccccc2O)cc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCCc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 2-[4-(2-benzoyloxyethyl)benzyl]phenol (0.49 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (1.7 g) in toluene (5.2 mL) and dichloromethane (2.2 mL) was added boron trifluoride diethyl ether complex (0.56 mL), and the mixture was stirred at 25° C. for 8 hours. To the reaction mixture were added ethyl acetate (70 mL) and a saturated aqueous sodium hydrogen carbonate solution (25 mL), and the organic layer was separated. The organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (5 mL) and tetrahydrofuran (2.5 mL), sodium methoxide (28% methanol solution, 0.14 mL) was added to the solution, and the resulting mixture was stirred at 25° C. for 12.5 hours. To the reaction mixture were added ethyl acetate (75 mL) and water (20 mL), and the organic layer was separated. The organic layer as washed with brine (20 mL) and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (7.5 mL), sodium methoxide (28% methanol solution, 0.085 mL) was added to the solution, and the resulting mixture was stirred at 25° C. for 5 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=4/1). The solvent was removed under reduced pressure, diethyl ether was added to the residue, and the resulting precipitates were collected by filtration. The obtained solid was washed with diethyl ether and dried under reduced pressure to give 2-[4-(2-hydroxyethyl)benzyl]phenyl β-D-glucopyranoside (0.47 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][CH:23]([OH:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1.O>CN(C=O)C.C(OCC)(=O)C>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[CH2:28][O:24][CH:23]1[C:18]2[O:17][N:16]=[C:15]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[C:19]=2[CH2:20][CH2:21][CH2:22]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: COc1cc(-c2noc3c2CCCC3O)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2noc3c2CCCC3OCc2cc(F)cc(F)c2)ccc1-n1cnc(C)c1

Procedure:
To the 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-ol (48 mg, 0.15 mmol) in DMF (2 ml) at 0° C., was added NaH (7 mg, 0.18 mmol). The mixture was stirred for 10 min before addition of 1-(bromomethyl)-3,5-difluorobenzene. Stirring was continued for 1 hr before addition of water (3 mL) and extraction with ethyl acetate. The organic phase was washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by preparative TLC using 5% of MeOH in DCM as solvent to afford the title product. 1H NMR (CDCl3) δ: 7.82 (br. s., 1H), 7.53 (s, 1H), 7.30-7.40 (m, 214), 6.89-7.03 (m, 2H), 6.73 (t, J=9.0 Hz, 1H), 4.84 (d, J=12.9 Hz, 1H), 4.76 (d, J=13.7 Hz, 1H), 4.64 (t, J 3.7 Hz, 1H), 3.93 (s, 3H), 2.73-2.82 (m, 1H), 2.57-2.68 (m, 1H), 2.33 (br. s., 314), 2.17-2.26 (m, 1H), 1.87-2.07 (m, 3H). MS(M+H)+=452.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.O.[OH-].[Li+]>CC(O)C.O1CCCC1>[CH2:27]([N:24]1[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:32]5[CH2:44][CH2:43][N:35]6[C:36]7[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=7[CH:42]=[C:34]6[C:33]5=[O:45])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:29]=[C:22]2[CH2:23]1)[CH3:28]
Reactant: CCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a solution of 177a (300 mg, 0.49 mmol) in propan-2-ol (4 mL), tetrahydrofuran (4 mL), and water (1 mL) was added lithium hydroxide (35 mg, 1.47 mmol). The mixture was stirred at room temperature for 0.5 h. It was evaporated and the residue was purified by reverse-phase prep-HPLC to afford 177 (79 mg, 28%) as a white solid. MS-ESI: [M+H]+ 569. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J=5.5 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.39 (s, 1H), 7.33 (d, J=5.5 Hz, 1H), 6.88 (s, 1H), 5.69 (s, 1H), 4.99-4.97 (m, 1H), 4.61-4.60 (m, 1H), 4.48-4.46 (m, 1H), 4.33-4.31 (m, 1H), 4.14-4.06 (m, 4H), 3.87-3.85 (m, 1H), 3.69 (s, 3H), 3.62 (d, J=5.5 Hz, 2H), 2.91 (d, J=5.0 Hz, 2H), 2.63-2.55 (m, 6H), 1.91-1.87 (m, 2H), 1.79-1.78 (m, 2H), 1.17 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:22])=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)[N:34]=[N:33]C=2C=1.[C:37](NN)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C>[CH3:39][C:38]([CH3:41])([CH3:40])[C:37]([C:5]1[C:6]2[C:7](=[N:8][C:9]([CH3:22])=[C:10]([C:19]([NH:33][NH2:34])=[O:20])[C:11]=2[NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]([CH2:1][CH3:2])[N:4]=1)=[O:42]
Reactant: On1nnc2ccccc21
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)c(C)nc21
Reactant: CC(C)(C)C(=O)NN
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1nc(C(=O)C(C)(C)C)c2c(NC3CCOCC3)c(C(=O)NN)c(C)nc21
Reaction time: 18 h
Yield: 79.9 %

Procedure:
Intermediate 60 (0.255 g, 0.84 mmol), EDC (0.225 g, 1.17 mmol) and HOBT (0.136 g, 1.0 mmol) in DMF (5 ml) was stirred at 20° C. for 75 minutes. Pivalic acid hydrazide (0.107 g, 0.92 mmol) was added and stirring continued for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with aqueous sodium hydrogen carbonate then evaporated in vacuo to afford Intermediate 61 as a white solid (0.27 g).). LCMS showed MH+=403; TRET=2.13 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7]C(CCN)=[CH:5][CH:4]=1)#[N:2].C([N:14]([CH2:17][CH3:18])[CH2:15]C)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:18]([CH2:17][N:14]([CH3:15])[C:20](=[O:21])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccc(C#N)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 84.9 %

Procedure:
A mixture of 7 g (47.9 mM) of [(4-cyanophenyl)methyl]methanamine is prepared in 60 ml of DCM and 5.8 g (57.5 mM) of triethylamine are added. The mixture is cooled to 0° C. and a solution of 9.8 g (57.5 mM) of benzyl chloroformate in 20 ml of DCM is added dropwise. The mixture is then agitated for 20 hours at ambient temperature and then washed with a solution of 0.1 N hydrochloric acid, and then with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel in eluting with the aid of a mixture of toluene/ethyl acetate (95/5; v/v). 11.4 g of the desired product are thus obtained as an oil (yield=87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13](=O)[CH2:12][S:11](=[O:17])(=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.[NH2:28]/[C:29](/[CH3:36])=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(O)C>[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]1[C:12]2[S:11](=[O:17])(=[O:16])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C:13]=2[NH:28][C:29]([CH3:36])=[C:30]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC(=O)C1
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
A mixture of 4-N-(t-butyloxycarbonyl)-1,1-dioxo -2,3,4,5,6,7-hexahydro-1,4-thiazepin-6-one (2.00 g, 7.60 mmole) from Example 6, 2,3-dichlorobenzaldehyde (1.33 g, 7.60 mmole) and ethyl 3-aminocrotonate (0.98 g, 7.60 mmole) was heated to reflux in 40 mL of ethanol for 24 hours. The ethanol was removed under reduced pressure and replaced with 85 mL of toluene. The mixture was heated to reflux for 2 hours, cooled to room temperature and filtered to obtain the produce (2.45 g, 61%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=O.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.S(=O)(=O)(O)O.[OH-].[NH4+]>C(O)(=O)C.O.C(Cl)(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[N:7]=[C:24]([C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=1)[CH:15]=[C:13]2[C:12]([OH:17])=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc2ccc(C(F)(F)F)cc12
Reaction time: 0.5 h
Yield: 10 %

Procedure:
4-Trifluoromethylaniline (0.015 mmol, 1.88 mL), pyruvic acid (1.0 eq, 0.015 mmol, 2.04 mL) and 4-trifluoromethylbenzaldehyde were dissolved in acetic acid (10 mL). Concentrated sulfuric acid (10 mL) was cautiously added (exothermic) and stirred for 30 minutes. Chloroform (50 mL) and water (50 mL) were added followed by ammonium hydroxide until the solution was basic to pH paper. The layers were separated and the aqueous solution was extracted with chloroform (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated under vacuum. The solid residue was purified by recrystallization from 95% ethanol to give the title compound as a yellow solid (580 mg, 10%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][C:14]#[N:15])[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)[C:14]#[N:15]
Reactant: N#CCc1coc(-c2ccc(F)cc2)n1
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCC(C#N)c1coc(-c2ccc(F)cc2)n1
Yield: 48 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile and 2-chloro-N,N-dimethylethanamine hydrochloride as described in example 16 step 1b (400 mg, yield 48%). 1H NMR (400 MHz, MeOD) δ 8.10-8.07 (m, 2H), 7.99 (m, 1H), 7.29-7.25 (t, J=8.9 Hz, 2H), 4.24-4.20 (t, J=7.3 Hz, 1H), 2.59-2.46 (m, 2H), 2.29 (s, 6H), 2.23-2.17 (m, 2H). MS (ESI) m/z: Calculated for C15H16FN3O: 273.13. found: 274.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[C:14]([CH3:17])[CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[CH:8]=[N:11][C:12]1[N:16]2[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2ncc3c(Cl)ncnc3n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
The product from Example 1a (1.24 g, 7.01 mmol) in 30 mL of THF was reacted with 5-amino-3-methylpyrazole (0.68 g, 7.01 mmol) in 10 mL of THF under an argon atmosphere by dropwise addition. Stirred at room temperature for 1 hour than added diisopropylethylamine (1.22 mL, 7.01 mmol) dropwise with stirring. Heated overnight at 60° C. Quenched with water and extracted with EtOAc washed with brine and dried over Na2SO4. Filtered and the solvent was removed under vacuum. The product was purified by silica gel chromatography eluting with EtOAc/hexane to give the title compound as a pale yellow solid (405 mg, 29%).
Reaction SMILES: [CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](C(CC)=S)[C:12]=2C)[S:7](=[O:20])(=[O:19])[CH2:6][CH2:5]1)[CH3:2].[OH-:21].[K+].[CH2:23]([OH:25])[CH3:24]>O>[CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:24]([C:23]([OH:21])=[O:25])[C:12]=2[CH3:11])[S:7](=[O:20])(=[O:19])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCO
Reactant: CCSC1CCS(=O)(=O)c2ccc(C(=S)CC)c(C)c21
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CCSC1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Temperature: 60 °C
Yield: 100 %

Procedure:
0.6 Gram (1.5 mmol) of 4-ethylthio-5-methyl-6-ethylthiocarbonylthiochroman-1,1-dioxide, 0.12 g (2.1 mmol) of potassium hydroxide, 3 ml of ethanol and 1 ml of water were stirred under heat at 60° C. for 3 hours. After the completion of the reaction, the solvent was distilled off, 5 ml of water was added, and then 2N hydrochloric acid was added to adjust a pH of 1. Then, the mixture was extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 0.51 g (yield 100%) of 4-ethylthio-5-methyl-6-carboxythiochroman-1,1-dioxide.