Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=1[S:52](Cl)(=[O:54])=[O:53]>C(#N)C>[CH3:42][O:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=1[S:52]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:53])=[O:54]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)c(OC)c1
Yield: 28.2 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0289 g, 0.0626 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2,4-dimethoxybenzenesulfonyl chloride (0.0462 g, 0.195 mmol) to obtain 4-(2,4-dimethoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0117 g, yield 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]([NH2:27])=O)[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]#[N:27])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: COc1ccc(C2Cc3c(C(N)=O)cc(OC)cc3C3CCCCC23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C2Cc3c(C#N)cc(OC)cc3C3CCCCC23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-1-carboxylic acid amide (0.69 g, 0.19 mmol), and triethylamine (0.038 g, 0.38 mmol) in methylene chloride (2.5 ml) at 0-5° C. and add trifluoroacetic anhydride (0.044 g, 0.21 mmol). Let stir at r.t. for 15 minutes. Add water, separate organic layer. Dry over anhydrous sodium sulfate and remove solvent in vacuo to yield preparation 122 (0.066 g, 100%). 1H NMR (CDCl3): 7.24 (d, J=8.8 Hz, 2H), 7.22 (s, 1H), 7.06 (s, 1H), 6.94 (d, J=8.8, 2H), 3.86 (m, 6H), 3.2 (m, 4H), 2.5 (m, 1H), 2.1 (m, 1H), 1.8-0.8 (m, 7H).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH2:16])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27].O>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH:16][C:26](=[O:27])[CH2:25][CH2:24][Cl:23])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCCl
Reactant: C=CCn1c(NN)nc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCn1c(NNC(=O)CCCl)nc2ccccc2c1=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a stirred mixture of 4.50 g of 3-allyl-2-hydrazino-quinazolin-4(3H)-one (0.0208 mol) and 5.75 g of anhydrous potassium carbonate (0.0416 mol; 2 eq) in 100 ml of chloroform at room temperature as added 2.2 ml of 3-chloropropionyl chloride (2.91 g; 0.023 mol; 1.1 eq). Almost immediately, a precipitate appeared and after 1 hr, 50 ml of water were added to the stirred mixture to dissolve any potassium carbonate. The mixture was filtered and the product was washed twice with water then twice with ether, crystallized from ethanol and dried under vacuum over P2O5 at 80° C. to obtain 5.79 g (91% yield) of 3-allyl-2-(2-(3-chloropropionyl)hydrazino)quinazolin-4(3H)-one melting at 151°-153° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[C:17](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.ClCCl>O1CCOCC1>[CH3:17][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nccn2c(C3CCOCC3)ncc12
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nccn2c(C3CCOCC3)ncc12
Yield: 77.2 %

Procedure:
Through a suspension of 8-chloro-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (2.23 mmol, 531 mg) and potassium carbonate (3.35 mmol, 463 mg) in dioxane (1.5 mL) was bubbled nitrogen for 5 minutes and then trimethylboroxine (4.47 mmol, 1.249 mL, 50 wt % solution in tetrahydrofuran) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.223 mmol, 181 mg) were added. After heating the reaction at 100° C. for one hour the reaction mixture was filtered and concentrated in vacuo. Dichloromethane and water were added, the organic layer separated, dried (sodium sulfate) and concentrated in vacuo to yield 374 mg 8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine.
Reaction SMILES: C(OC(=N[O:7][CH2:8][CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2[CH3:27])[C@H:14]([OH:28])[C@@H:13]1[OH:29])C)C.CNC[C@H]1[O:38][C@@H:37](N2C3N=CN=C(N)C=3N=C2C)[C@H:36](O)[C@@H]1O.ClCC(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[C:8]([CH2:9][N:10]([CH3:30])[CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[C:18]2[CH3:27])[C@H:14]([OH:28])[C@@H:13]1[OH:29])([O:38][CH2:37][CH3:36])=[O:7]
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCOC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 35 was prepared by the same procedure as described for the preparation of 6a using 4a (415 mg, 1.41 mm), ethyl chloroacetate (207 mg, 0.18 ml, 1.68 mm), DIEA (91 mg, 0.12 ml, 0.70 mm), and DMF (5 ml): yield 204 mg (38%), MS: m/z 381 (M+H)+; 1HNMR (DMSO-d6) δ 8.06 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.73 (d, 1H, H-1′, J1′,2′=5.4 Hz), 5.33 (bd, 1H, OH-2′, J2′-2′OH=4.7 Hz), 5.19 (bd, 1H, OH-3′, J3′-3′OH=4.9 Hz), 5.03 (ddd, 1H, H-2′, J1′,2′=5.4 Hz, J2′,3′=5.7 Hz, J2′-2′OH=4.7 Hz), 4.17 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.4 Hz, J3′-3′OH=4.9 Hz), 4.02 (q, 2H, CH3—CH2), 3.92-3.99 (m, 1H, H-4′), 3.27 (bs, 2H, NCH3—CH2), 2.83-2.90 (m, 1H, 5′-CH2), 2.70-2.79 (m, 1H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.31 (s, 3H, N—CH3), 1.13 (t, 3H, OCH2—CH3); UV λmax, nm, pH 1, 258.9 (∈ 16,100), pH 7, 260 (∈ 15,900), pH 13, 260.1 (∈ 16,200).
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH3:2][C:1](=[O:5])[CH2:3][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)(C)OO
Solvent: C=CCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(C)=O
Reaction time: 4 h

Procedure:
3 cc of 80% tert-butyl hydroperoxide (23 mmoles), 1 cc of 1-octene (6.5 mmoles), 2 cc of toluene, and 25.4 mg of PPA (0.1 mmole) prepared according to Example 1, are introduced into a heat-insulated glass reactor. An argon atmosphere is applied and stirring is performed at a temperature of 50° C. After 4 hours, it is found that 55% of 1-octene is converted and that 2-octanone is formed with a molar selectivity of 76% with respect to the converted 1-octene.
Reaction SMILES: [P:1]([O:19][C:20]1([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][N:37]=[C:36]([S:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[C:35]3=[O:52])=[CH:30][C:29]=2[O:53][CH3:54])[CH2:23][C:22]([F:25])([F:24])[CH2:21]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].C(=O)(O)[O-].[Na+:59]>C(O)(C(F)(F)F)=O.C(#N)C.O>[P:1]([O-:11])([O-:3])([O:19][C:20]1([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][N:37]=[C:36]([S:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:45][CH:46]=4)[C:35]3=[O:52])=[CH:30][C:29]=2[O:53][CH3:54])[CH2:23][C:22]([F:25])([F:24])[CH2:21]1)=[O:2].[Na+:59].[Na+:59]
Reactant: COc1cc(-n2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)ccc1OCC1(OP(=O)(OCc2ccccc2)OCc2ccccc2)CC(F)(F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1cc(-n2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)ccc1OCC1(OP(=O)([O-])[O-])CC(F)(F)C1
Yield: 103.3 %

Procedure:
To a solution of dibenzyl 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate (79 mg, 0.100 mmol) in TFA (2 mL) was stirred at RT for 3.5 hours. The mixture was concentrated. The crude product was purified by prep-HPLC (Phenomenex, Luna 5 micron 25×250 mm, flow rate 30 ml/min., gradient=20% A to 100% B in 10 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA). Yield 46 mg, 0.075 mmol. as yellow gum. The yellow gum in ACN (2 ml) was added 0.5 N aqueous sodium bicarbonate (302 μl, 0.151 mmol.), the mixture was diluted with water (5 ml). The solution was then lypholized. Yield sodium 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate (51.08 mg, 0.078 mmol, 78% yield) as off-white powder. MS (M+H-611). 1H NMR (400 MHz, MeOD) δ ppm 7.54-7.63 (2 H, m), 7.19-7.33 (3H, m), 7.02-7.17 (3H, m), 6.91 (1H, dd, 3=8.44, 2.39 Hz), 4.28 (2H, s), 3.80 (3H, s), 3.13-3.32 (2H, m), 2.75-2.90 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12]C=2)[N:5]=[C:4]([C:16]2C(Cl)=[CH:18][C:19]([Cl:23])=[C:20]([OH:22])[CH:21]=2)[N:3]=1.Cl[CH2:26][Cl:27].ClC1C=CC=C(C(OO)=[O:36])C=1>CO>[NH2:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[CH:15][CH:14]=[C:13]([OH:36])[CH:12]=2)[N:5]=[C:4]([C:16]2[C:26]([Cl:27])=[CH:18][C:19]([Cl:23])=[C:20]([OH:22])[CH:21]=2)[N:3]=1
Reactant: Nc1nc(SCc2ccccc2)nc(-c2cc(O)c(Cl)cc2Cl)n1
Reactant: ClCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: Nc1nc(Sc2cccc(O)c2)nc(-c2cc(O)c(Cl)cc2Cl)n1

Procedure:
5-(4-Amino-6-benzylsulfanyl-[1,3,5]triazin-2-yl)-2,4-dichlorophenol (150 mg) obtained in Step 2 above was placed in a reaction vessel, and then dichloromethane (10 ml) and methanol (2 ml) were added thereto. The mixture was stirred. m-Chloroperbenzoic acid (210 mg) was added to the resulting suspension at room temperature, and stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure. To this, N,N-dimethylformamide (4.5 ml), triethylamine (0.19 ml), and 3-mercaptophenol (0.12 ml) were added and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, and then sequentially washed with a saturated aqueous sodium bicarbonate solution and water. The ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane and ethyl acetate) to yield 5-[4-amino-6-(3-hydroxyphenylsulfanyl)-[1,3,5]triazin-2-yl]-2,4-dichlorophenol (54 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CC=CC=1>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Yield: 83.6 %

Procedure:
At room temperature, 6.0 g of N-[2,6-dimethyl-4-{1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl}phenyl]3-aminobenzamide, 2.5 g of benzoyl chloride and 1.8 g of pyridine were introduced to 50 ml of tetrahydrofuran. After the loss of the starting material was confirmed through TLC, the reaction solution was filtered, and thus obtained filtrate was concentrated under reduce pressure. Thus obtained residue was purified by silica gel chromatography (eluent:hexane:ethyl acetate=3:1) to give 6.3 g (yield 85%) of the title compound as a powder form.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH:29]2[CH2:31][CH2:30]2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH:29]2[CH2:30][CH2:31]2)[C:10](=[O:12])[CH2:9][O:8][C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:26][CH2:27]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CN2CCC(NC3CC3)CC2)cc1
Reactant: CCOC(=O)COc1ccc(Cl)nn1
Product: O=C(COc1ccc(Cl)nn1)N(C1CC1)C1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was synthesized from ethyl 2-(6-chloropyridazine-3-yloxy)acetate and 1-benzyl N-cyclopropylpiperidine-4-amine in the same manner as in Example 104.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH2:13][NH:12]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([N:12]1[CH2:13][C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CNN1C1C2CC3CC(C2)CC1C3
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)N1C1C2CC3CC(C2)CC1C3
Reaction time: 24 h
Yield: 51.3 %

Procedure:
Under an argon atmosphere, a solution of 2-(adamantan-2-yl)-1,2-diazetidin-3-one (10.2 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL), potassium carbonate (28.0 mg, 0.100 mmol) and benzyl bromide (35.0 mg, 0.100 mmol) were added at room temperature, and the resultant was stirred at the same temperature for 24 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (7.60 mg, 48.6%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[NH2:26][C@@H:27]([C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Br:50])[CH:44]=1)[CH2:28][N:29]([CH3:42])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:26][C@@H:27]([C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Br:50])[CH:44]=3)[CH2:28][NH:29][CH3:42])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: CN(C[C@@H](N)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (156 mg, 0.403 mmol) in DMF (1.28 mL) was added (S)—N-(2-amino-2-(3-bromo-5-fluorophenyl)ethyl)-N-methyl-2-nitrobenzenesulfonamide (180 mg, 0.384 mmol), HOAt (105 mg, 0.768 mmol), DIEA (402 μl, 2.8 mmol), and EDC.HCl (147 mg, 0.768 mmol). The reaction mixture was stirred at room temperature for 15 h, LCMS indicated the product. The mixture was diluted with EtOAc and washed with water and once with saturated Na2CO3 and the organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo providing 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide. The crude product was purified by ISCO column chromatography (0-100% EtOAc in heptane) leading to 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (99%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[C:11](=[O:20])[NH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=2)=[C:4]([F:21])[CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[C:11](=[O:20])[N:12]([CH3:22])[C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][N:15]=2)=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 48 h
Yield: 54.2 %

Procedure:
First, 3.61 g of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1008) was dissolved in 16 ml of N,N-dimethylformamide, to which 2.35 g of potassium carbonate and 1.39 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 2 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=5:1), which afforded 2.04 g (yield, 55%) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-144; m.p., 108.7° C.).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28][NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CCCCC3)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Cyclohexyl amine (0.3 ml, 2.7 mmol) was added to a solution of Example 133 (0.4 g, 0.9 mmol) in DMF (10 mL). The reaction mixture was stirred at 80° C. for 3 h, concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.365 g (80%); 1H NMR (CDCl3): δ 1.21 (q, 2H, CH2), 1.25 (q, 2H, CH2), 1.63 (bs, 2H, CH2), 1.73 (bs, 2H, CH2), 1.88 (bs, 2H, CH2), 2.44 (m, 1H, CH), 2.77 (s, 3H, CH3), 3.4 (s, 2H, CH2), 3.9 (s., 3H, OCH3), 4.7 (s, 2H, CH2), 7.57 (d, 1H, Ar), 7.83 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.4 (s, 1H, Ar), 9.72 (s, 1H, NH); MS m/e (ES+) 507 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([CH:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][O:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH3:11]>[Pd].C(N(CC)CC)C>[CH3:22][CH2:21][CH2:20][CH2:19][CH:12]([CH2:13][O:14][C:15](/[CH:16]=[CH:17]/[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)=[O:18])[CH2:10][CH3:11]
Reactant: COc1ccc(I)cc1
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)/C=C/c1ccc(OC)cc1
Temperature: 142.5 °C
Reaction time: 3 h

Procedure:
Charge 6.8 gallons of molten 4-iodoanisole from step 1, 11.4 gallons 2-ethylhexylacrylate (83.8 pounds), 7.3 gallons triethylamine (44 pounds), and 0.6 pounds of 5% palladium on carbon catalyst (dry) to a 50 gallon tank. With good agitation, begin heating. Heat to 100° -105° C. to reflux. The reflux temperature will gradually increase to about 140-145° C. The total time of reaction above 100° C. will be about 2-4 hours. After the reaction is complete, as determined by gas chromatography, cool the reaction mixture to 25° -30° C. Filter to collect the palladium catalyst and the resulting triethylamine hydroiodide salt. Wash the filtered product with 20 gallons of water to remove any soluble salt. Allow the phases to separate. The top organic product phase is ready for distillation. Its volume is about 15 gallons containing about 119 pounds of product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[C:26]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: Clc1nccnc1Cl
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1

Procedure:
EXAMPLE 89 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2,3-dichloropyrazine (refluxing 2-butanol):
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([S:10][CH3:11])[CH3:9])=[CH:4][N:3]=1.[N:12]#[C:13][NH2:14].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([S:10]([CH3:11])=[N:14][C:13]#[N:12])[CH3:9])=[CH:6][N:7]=1
Reactant: N#CN
Reactant: CSC(C)c1cnc(Cl)nc1
Agent: CC(c1cnc(Cl)nc1)/S(C)=N/C#N
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(c1cnc(Cl)nc1)S(C)=NC#N
Temperature: 25 °C

Procedure:
A solution of 2-chloro-5-[1-(methylthio)ethyl]pyrimidine (0.49 g, 2.61 mmol) and cyanamide (120 mg, 2.86 mmol) in 20 mL of CH2Cl2 was cooled to 0° C. and treated with iodobenzene diacetate (860 mg, 2.59 mmol). The mixture was allowed to warm to room temperature over an hour, the solvent was removed under reduced pressure and the residue was partitioned between hexanes and acetonitrile. The acetonitrile was removed under reduced pressure and the residue was further purified by flash column chromatography on silica gel using a 50% mixture of acetone and petroleum ether as the eluant. The solvents were removed under reduced pressure to yield 0.44 g (74%) of (1E)-[1-(2-chloropyrimidin-5-yl)ethyl](methyl)-λ4-sulfanylidenecyanamide (C) as a pale orange syrup. This material was a 2:1 mixture of diastereomers. The physical properties of the major diastereomer were: 1H NMR (CDCl3) δ 8.68 (s, 2H), 4.38 (q, J=8.3 Hz, 1H), 2.68 (s, 3H), 1.92 (d, J=8.3 Hz, 3H); LC-MS (ESI) m/z 229 (M+H).