Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:43][C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[O:35])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccc(F)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-fluorophenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (44.5 mg, 0.15 mmol) and 1-fluoro-4-isocyanatobenzene (20.4 mg, 0.15 mmol) according to General Procedure G to give 46 mg (70.8%) of pale yellow solid. Anal. Calcd. for C25H30FN5O m/z 435.2, found: 436.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (s, 1H), 7.41 (m, 4H), 7.06 (t, J=8.9 Hz, 2H), 6.93 (d, J=9.1 Hz, 2H), 6.05 (d, J=7.8 Hz, 1H), 3.88 (d, J=11.6 Hz, 1H), 3.76 (d, J=12.7 Hz, 1H), 3.26 (m, 1H), 2.79 (m, 1H), 2.59 (m, 1H), 2.42 (m, 1H), 1.89 (m, 1H), 1.68 (m, 3H), 1.60 (m, 1H), 1.46 (m, 1H), 1.22 (m, 4H), 1.11 (m, 1H).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][CH:14]([S:17][C:18]1[CH:23]=[CH:22]C(O)=[CH:20][CH:19]=1)[CH2:15][CH3:16].O>CN(C=O)C>[CH3:13][CH:14]([S:17][C:18]1[CH:23]=[CH:22][C:1]([O:2][CH2:3][CH2:4][OH:5])=[CH:20][CH:19]=1)[CH2:15][CH3:16]
Reactant: CCC(C)Sc1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Sc1ccc(OCCO)cc1

Procedure:
A mixture of ethylene carbonate (41.08 g, 460.0 mmol) and potassium carbonate (63.57 g, 460.0 mmol) in 100 ml of DMF is heated to 110° and 4-(1-methylpropylthio)phenol (40.19 g, 230.0 mmol) in 100 ml DMF is slowly added dropwise with stirring. The mixture is stirred at 100° for 8 hours. Water is added to the cooled reaction mixture and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% NaOH, with water and with brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenoxy]ethanol.
Reaction SMILES: [OH:1]S(O)(=O)=O.ON=[CH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH3:20])[CH3:19])=[O:10]>O>[CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:9](=[O:10])[C:8]2=[O:1])([CH3:20])[CH3:19]
Reactant: CC(C)c1ccccc1NC(=O)C=NO
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(C)c1cccc2c1NC(=O)C2=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a stirred solution of concentrated H2SO4 (210 ml) and H2O (50 ml), was added over 20 min (26.7 g, 0.13 mol) of 2-(hydroxyimino)-N-(2-isopropylphenyl)acetamide. The mixture was stirred at 75° C. for 2 hr, cooled and poured onto cracked ice. After standing for 15 min, it was extracted with EtOAc, washed with water, dried over MgSO4, and concentrated. Air drying afforded (23.8 g, 97%) of crude product). 1H NMR (300 MHz, CDCl3) δ 8.15 (b, NH), 7.49 (d, 2H), 7.11 (t, 1H), 2.87 (m, 1H), 1.30 (d, 6H); ESI (+) MS m/e=190 (MH+), ESI (−) MS m/e=188 (MH−).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]([OH:11])[C:3]=1[CH3:12].[Na].C([Li])CCC.O1[C:21]([CH3:38])([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:20]1.Cl>O1CCCC1>[CH3:12][C:3]1[C:4]([OH:11])=[C:5]([CH3:10])[C:6]2[CH2:9][CH2:35][C@:33]([CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:24][CH2:23][CH2:22][CH:21]([CH3:38])[CH3:20])[CH3:37])[CH3:36])([CH3:34])[O:8][C:7]=2[C:2]=1[CH3:1]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC1(C)CO1
Reactant: Cc1c(C)c(O)c(C)c(C)c1O
Agent: Cl
Agent: [Li]CCCC
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 1 h
Yield: 78.1 %

Procedure:
10 g (66.7 mmol) of tetramethylhydroquinone are dissolved in 100 ml of dry tetrahydrofuran, 4 g (139 mmol) of sodium hydridge (80% in mineral oil) was added thereto at room temperature, 45 ml of butyllithium (1.6 molar in hexane) are subsequently added dropwise and the mixture is stirred for 1 hour. 10 g (44.3 mmol) of 1,2-epoxy-2,6,10,14-tetramethylpentadecane are now added dropwise; the mixture is left to react for 12 hours while stirring. 100 ml of 1N methanolic hydrochloric acid area added and the mixture is stirred at 50° C. for 2 hours. The mixture is subsequently concentrated at 50° C. and the residue is chromatographed on silica gel with toluene, whereby where are obtained 14.9 g (75%) of α-tocopherol.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].C(OCC)C>C(O)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: Nc1ccc(S)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(N)cc2)s1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
The product of Example 430A (1.0 g, 4.244 mmol), 4-aminothiophenol (0.797 g, 6.366 mmol), and anhydrous sodium acetate (1.74 g, 21.22 mmol) were heated in anhydrous ethanol (40 mL) under a nitrogen atmosphere at reflux for 30 minutes. The reaction was cooled to room temperature, partitioned with ethyl acetate (100 mL) and water (50 mL), separated layers, and washed organic phase with water (2×50 mL) and brine (50 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Trituration of the resulting solid with ethyl ether (2×30 mL) afforded the title compound as a bright yellow solid (1.167 g, 3.598 mmol, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.24 (t, J=7.17 Hz, 3 H) 4.24 (q, J=7.23 Hz, 2 H) 5.94 (s, 2 H) 6.71 (d, J=8.82 Hz, 2 H) 7.35 (d, J=8.46 Hz, 2 H) 8.08 (s, 1 H); MS (ESI+) m/z 325 (M+H)+, MS (ESI−) m/z 323 (M−H)−.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH:18]=[C:17]([CH3:27])[CH:16]=2)=[CH:11][CH:10]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][CH:30]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH:17]([CH3:27])[CH2:16]2)=[CH:13][CH:14]=1)([F:1])[CH3:3]
Reactant: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)=C1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: CC1CC(c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)C2=NS(=O)(=O)CCN2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of NaH (60%, 96 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.101 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3-(1,1-difluoroethyl)phenoxy)phenyl)-5-methylpyridin-2-amine (164 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (30 mg) was added to a solution of the prepared 9-{4-[3-(1,1-difluoroethyl)phenoxy]phenyl}-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide in THF (dry) (15 mL) and MeOH (15 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (47.6 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH:8](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:9].[CH3:23][N:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][C:27](=[O:34])[N:26]([C:35]2[CH:40]=[C:39]([NH2:41])[C:38]([Cl:42])=[CH:37][C:36]=2[F:43])[C:25]1=[O:44].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH:8]([NH:41][C:39]1[CH:40]=[C:35]([N:26]2[C:27](=[O:34])[CH:28]=[C:29]([C:30]([F:32])([F:33])[F:31])[N:24]([CH3:23])[C:25]2=[O:44])[C:36]([F:43])=[CH:37][C:38]=1[Cl:42])[CH3:9]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Reactant: COC(=O)CCNC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCNC(=O)C(C)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 38.7 %

Procedure:
3-[2-(Toluene-4-sulfonyloxy)-propionylamino]propionic acid methyl ester (307 mg) was dissolved in acetonitrile (5 mL). After addition of 1-methyl-3-(5-amino-4-chloro-2-fluorophenyl)-6-trifluoromethyl-1H-pyrimidin-2,4-dione (300 mg) and potassium carbonate (135 mg), the reaction mixture was heated for 6 hours under reflux without cooling. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). Thus obtained organic layer was dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (170 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][O:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1.[CH:27]([N:30](CC)C(C)C)(C)C.N#CBr>C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:27]#[N:30])[CH2:21][CH2:20]2)=[CH:25][CH:26]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Brc1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1
Agent: N#CBr
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N#CN1CCC([C@H]2C[C@H]2COCc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step B (1.00 g, 3.08 mmol) and N,N-diisopropylethylamine (1.61 mL, 9.25 mmol) were dissolved in acetonitrile (20 mL). Cyanogen bromide (5M in acetonitrile, 0.746 mL, 3.7 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned between CH2Cl2 and water. The organic layer was saved and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and evaporated to yield a crude material, which was purified by silica gel column chromatography (gradient elution 0% to 100% EtOAc in hexanes) to yield the title compound as a viscous oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C[S-:11].[Na+]>CN1CCCC1=O>[SH:11][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ncccc1S
Temperature: 140 °C
Yield: 42.7 %

Procedure:
A mixture of 3-chloro-2-cyanopyridine (2.50 g, 18.05 mmol), and sodium thiomethoxide (3.60 g, 51.40 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at 140° C. overnight. The reaction mixture was cooled to 0° C. and quenched with 50% aqueous HCl. A light brown precipitate formed and the reaction was cooled for 1 h while stirring. The light brown solid was collected by vacuum filtration and dried under reduced pressure overnight to provide 3-mercaptopicolinonitrile (1.05 g). The crude product was used carried forward without further purification. MW=136 confirmed by LC-MS, tr=1.85 min (Method E) MH+=137.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([CH:23]([OH:25])[CH3:24])=[CH:18][C:17]=3[Cl:26])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>CN(C=O)C.[Cu](I)I.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>[Cl:26][C:17]1[CH:18]=[C:19]([CH:23]([OH:25])[CH3:24])[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([C:40]#[C:39][C:37]([OH:41])([CH3:38])[CH3:36])[CH:28]=[CH:27][C:5]=2[N:6]=1
Reactant: CC(O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: C#CC(C)(C)O
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)c1cc(Cl)c(Nc2nc3ccc(C#CC(C)(C)O)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 65 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (292 mg, 0.61 mmol) in DMF (3 mL) were added triethylamine (0.255 mL, 1.83 mmol), copper iodide (23 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium (0) (70 mg, 0.06 mmol), and 2-methyl-3-butyn-2-ol (0.179 mL, 1.83 mmol). The solution was degassed by bubbling nitrogen gas and heated to 65° C. for 14 hr. The solution was diluted with EtOAc and washed with water, dried with Na2SO4, filtered, and concentrated under reduced pressure. Purification with column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) provided 5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}-9-(3-hydroxy-3-methylbut-1-yn-1-yl)benzo[c]-2,6-naphthyridin-1(2H)-one as a mixture of enantiomers. The enantiomers were separated on Chiral Technology AD 2×25 cm column at 12 mL/min using 1:1 iPrOH/Heptane in a 25 min run. First enantiomer has a retention time of 7.57 min and the second enantiomer has a retention time of 15.74 min. For both enantiomers: 1H NMR (500 MHz, CD3OD) δ 9.80 (d, 1H), 7.60 (d, 1H), 7.50-7.40 (m, 3H), 7.34 (d, 1H), 3.90 (m, 1H), 1.48 (s, 3H), 1.47 (s, 3H), 1.12 (d, 3 H). LRMS (ESI) calc'd for C25H22Cl2N3O3 [M+H]+, 482.1; found 482.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:15]O>C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH3:15])=[O:9])=[N:6][CH:7]=1
Reactant: Nc1cnc(C(=O)O)nc1
Reactant: CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncc(N)cn1
Yield: 68 %

Procedure:
A suspension of 5-aminopyrimidine-2-carboxylic acid (Goldenbridge Pharma, Inc.; 5.70 g, 41.0 mmol) in MeOH (120 mL) was cooled in an ice-water bath and treated dropwise with thionyl chloride (8.97 mL, 123 mmol). The resulting suspension was heated at reflux for 20 h and then concentrated to give a yellow solid. The solid was dissolved in saturated aqueous NaHCO3 (60 mL) and extracted into EtOAc using a Gregar Extractor. The extract was concentrated to give methyl 5-aminopyrimidine-2-carboxylate (4.26 g, 68% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 2H), 4.35 (br s, 2H), 4.02 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([S:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH:15]=1
Reactant: COC(=O)CSc1ccc(N)cc1
Reactant: O=Cc1cccnc1
Product: COC(=O)CSc1ccc(NCc2cccnc2)cc1

Procedure:
Following the procedure described in Example 9, (4-aminothiophenoxy)-acetic acid, methyl ester (Preparation 8) is reacted with 3-pyridinecarboxaldehyde (B-5A wherein m is 1) to yield the titled product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:42])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.Cl>C(OCC)(=O)C.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:42])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(CN)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Temperature: 25 °C
Reaction time: 3 h
Yield: 201.3 %

Procedure:
A suspension of (S)-9-chloro-5-[p-tert-butoxycarbonylaminomethyl-o-(ethoxycarbonylmethoxy) phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg) in ethyl acetate (4 mL) was added 4N hydrogen chloride in 1,4-dioxane (2 mL). The mixture was stirred for 3 h at room temperature, and concentrated in vacuo to give 135 mg of the title compound.
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[CH3:12][O:13][CH:14]1[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[CH:16][S:15]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:12][O:13][C:14]1([O:9][CH3:8])[C:19](=[O:20])[NH:18][C:17]([CH3:21])=[CH:16][S:15]1
Reactant: COC1SC=C(C)NC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC1(OC)SC=C(C)NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.6 %

Procedure:
m-Chloroperbenzoic acid (25.6 g) was added dropwise to a stirred solution of 2-methoxy-5-methyl-2H-1,4-thiazin-3(4H)-one (16 g) in methanol (500 ml) under ice-cooling and the mixture was stirred at room temperature for 4 hours. Then, the reaction mixture was made alkaline by addition of anhydrous potassium carbonate and evaporated to dryness. The residue was extracted twice with chloroform and the combined extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with ethyl ether to give 2,2-dimethoxy-5-methyl-2H-1,4-thiazin-3(4H)-one (10 g, yield 53%) as pale yellow plates.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][S:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][S:52][CH2:51][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: C1CSCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCSCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), thiomorpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>C(Cl)Cl.CO>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:8]
Reactant: COC(=O)c1cncc(NC(=O)C(C)CSC(C)=O)c1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cncc(NC(=O)C(C)CS)c1

Procedure:
Following the procedure of Example 2, but substituting an equivalent amount of methyl 5-(2-acetylthiomethyl-propionamido)-nicotinate, obtained as disclosed in Example 12, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate and using a mixture of methylene chloride/methanol 99:1 as eluent for the chromatographic column, methyl 5-(2-mercaptomethyl-propionamido)-nicotinate is obtained: m.p. 96°-97° C., from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:25]([OH:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[C:37](Cl)(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C(Cl)Cl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]4[O:27][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3hydroxy-1H-isoindol-1-one (1.4 g, 3.5 mmol) in DCM (30 ml) was added Et3N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0 C. under nitrogen. After stirring for 1 h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g (83%) of the desired product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccccc1CCN
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1CCNC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Forty (40) grams of 4-bromobenzoic acid was dissolved in 200 ml of dry dimethylformamide. While the solution was cooled with ice with stirring, 23 g of triethylamine and 22 g of ethyl chloroformate were added. After a lapse of 30 minutes, 28 g of 1-amino-2-(2-methylphenyl)ethane was added dropwise. The mixture was stirred at room temperature for 1 hour and then at 50° to 60° C. for 1 hour, and poured into ice water. The crystals precipitated were washed in water, dried, and recrystallized from cyclohexane to afford 49 g of 1-(4-bromobenzoylamino)-2-(2-methylphenyl)ethane as colorless needles having a melting point of 101.5° to 103.0° C.