Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.[CH3:40][C:41]([CH3:56])([S:43]([NH:46][C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([NH2:55])[CH:50]=1)=[O:48])(=[O:45])=[O:44])[CH3:42]>CN(C)C=O>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:55][C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([C:47]([NH:46][S:43]([C:41]([CH3:56])([CH3:40])[CH3:42])(=[O:45])=[O:44])=[O:48])[CH:50]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: CCN(CC)CC
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CC(C)(C)S(=O)(=O)NC(=O)c1cccc(N)c1
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)Nc2cccc(C(=O)NS(=O)(=O)C(C)(C)C)c2)(C2CCCCC2)N=Cc2ccccc21

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 4, using 5-cyclohexyl-1,3-dihydro-1-methyl- 3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.3 g, 0.69 mmol), triethylamine (96 μl, 0.69 mmol), dimethylformamide (6 ml) and 1-(1,1-dimethylethylsulphonylaminocarbonyl)-3-aminobenzene (0.19 g, 0.76 mmol). The product (176 mg, 46%) was afforded as a colourless solid after recrystallisation from ethanol. mp 180° C. (dec.). 1H NMR (360 MHz, D6-DMSO) δ 0.84-0.98 (1H, m), 1.38 (9H, s), 1.08-1.65 (7H, m), 1.71-1.81 (1H, m), 1.86-1.94 (1H, m), 2.88-2.98 (1H, m), 3.32 (3H, s), 5.08 (1H, d, J=8.3 Hz), 7.29-7.42 (4H, m), 7.54 (1H, s), 7.56 (1H, s), 7.64 (1H, t, J=7.7 Hz), 7.75 (1H, d, J= 7.9 Hz), 7.84 (1H, s), 9.19 (1H, s), 11.51 (1H, brs).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](N)[N:11]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][N:11]4[N:15]=[C:16]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=5)[N:17]=[C:10]4[CH:9]=3)=[CH:4][CH:3]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Nc1cc(-c2ccc(Cl)nc2)cc2nc(-c3ccccn3)nn12
Reactant: C1COCCN1
Product: c1ccc(-c2nc3cc(-c4ccc(N5CCOCC5)nc4)ccn3n2)nc1
Yield: 62 %

Procedure:
A solution of 0.10 g (0.0003 mol) 7-(6-chloro-pyridin-3-yl)-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 15 ml morpholine were stirred at 130° C. for 4 hours. Removal of the amine and chromatography on silicagel with dichloromethane/methanol 9/1 gave 0.07 g (62%) 7-(6-morpholin-4-yl-pyridin-3-yl)-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin beige solid, MS m/e (%):374 (M+H+,100).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23](CC(OC)=O)=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](O)(=O)C1C=CC=CC=1.[CH2:40]([O:42][C:43](=[O:51])C1C=CC(I)=CC=1)[CH3:41]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:43]([O:42][CH2:40][CH3:41])=[O:51])=[CH:22][CH:21]=3)=[CH:16][C:17]=2[CH3:31])[CH2:10][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (23.0 mg, 0.12 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 68.0 mg (54%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[N-:12]=[C:13]=[O:14].[C:15]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])N)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([C@@H:21]([NH:12][C:13](=[O:14])[NH:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:27])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: [N-]=C=O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 28 g (179 mmol) of methyl 1-aminocyclohexane-1-carboxylate was added to a solution of 38 g (179 mmol) of L-leucine tert-butyl ester isocyanate (prepared analogously to J. S. Nowick et al., J. Org. Chem. 1996, 61, 3929) in 300 ml of absolute DMF. After stirring at room temperature for 2 hours, the reaction mixture was allowed to stand overnight. The solvent was removed in vacuo, the residue was treated with heptane and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered off with suction and washed with heptane. Yield: 45.94 g (69%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(OCc2ccc(Cl)c(Cl)c2)ccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
4-Hydroxy-2-methoxybenzaldehyde (408 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10 (v/v)), whereby the objective title compound was obtained as a white solid (801 mg, yield: 96%).
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[N:9]1([CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH:13]=[CH:12][N:11]=[CH:10]1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:5]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)([CH3:20])[CH3:19])=[CH:22][CH:23]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(O)cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Oc1ccc(C(C)(C)NCCCn2ccnc2)cc1

Procedure:
In a similar manner to Example 71, a solution of butanesulphonyl chloride (0.45 g) in dichloromethane (5 ml) was added in portions over 5 minutes to a solution of 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenol (0.75 g) and triethylamine (0.29 g) in dicloloromethane (5 ml) at 0° C. with stirring, to give 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl 1-butanesulphonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>O>[Cl:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(Cl)cc(Cl)c2o1
Temperature: 50 °C
Yield: 72.2 %

Procedure:
To a 2 L round bottom flask fitted with a mechanical stirrer and condenser was added 3,5-dichlorosalicylaldehyde (200 g, 1.05 mol, 1 equiv.), acetic anhydride (356 g, 3.49 mol) and triethylamine (95.0 g , 0.94 mol. 0.90 equiv.). The reaction solution was heated at reflux overnight. The dark brown reaction mixture was cooled to 50° C. and water (1 L) added with stirring. After one hour the mixture was filtered and the filtrate combined with EtOH (1 L). This mixture was heated to 45° C. for one hour, cooled to room temperature, filtered and the solid (fraction A) washed with EtOH (0.5 L). The combined EtOH solutions were concentrated by rotary evaporation to an oil (fraction B). The solid from fraction A was dissolved in methylene chloride (1.5 L) and the resulting solution passed through a pad of silica gel (1300 mL volume). The resulting dark brown solution was concentrated to an oil that was triturated with hexanes (1.3 L) to give a solid that was isolated by filtration and washed (hexanes) to give substantially pure 6,8-dichlorocoumarin (163 g). A further 31 g of product was obtained by treating the oil, fraction B, in a similar fashion; the oil was dissolved in methylene chloride (0.5 L) passed through a silica pad (0.5 L volume) and triturated with hexanes. The total isolated yield was 194 g or 86% yield of the brown solid.
Reaction SMILES: C(NC(C)C)(C)C.CN(C)CCN(C)C.C([Li])CCC.CN(C)[C:23](=[O:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][C:36]=1[CH3:37]>C1COCC1>[CH:32]1[C:31]2[NH:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23](=[O:38])[CH2:37][C:36]=2[CH:35]=[CH:34][N:33]=1
Reactant: Cc1ccncc1Nc1ccccc1C(=O)N(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1Cc2ccncc2Nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (7.61 mL, 53.89 mmol) and tetramethylethylenediamine (8.13 mL, 53.89 mmol) in THF (50 mL) was added n-butyllithium (1.6 M, 34.2 mL, 54.77 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min., then 0° C. for 10 min. This solution was transferred into a solution of N,N-dimethyl-2-((4-methylpyridin-3-yl)amino)benzamide in THF (100 mL) at 0° C. The resulting solution was stirred overnight and quenched by adding saturated ammonium chloride solution (20 mL). The solvent was then removed under reduced pressure and the residue dissolved in dichloromethane (100 mL), washed with water (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, 50% hexane in ethyl acetate) to afford the pure desired product, 5H-benzo[b]pyrido[4,3-f]azepin-6(11H)-one (2.2 g) as a yellow solid. 400 MHz 1H NMR (DMSO-d6) δ 9.68 1H), 8.53 (s, 1H), 8.27 (d, J=4.4 Hz, 1H), 7.79 (m, 1H), 7.53-7.49 (m, 1H), 7.38-6.89 (m, 2H), 6.93-6.89 (m, 1H), 3.78 (s, 2H); LCMS (M+H)=211.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26](O)[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:3][CH:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[CH2:23][O:22][C:21]2[CH:32]=[CH:33][C:18]([O:17][CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([Cl:5])=[CH:7][CH:8]=4)[N:13]=3)=[CH:19][C:20]1=2
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Clc1ccc2ccc(COc3ccc4c(c3)C(Cl)c3ccccc3CO4)nc2c1

Procedure:
While stirring under ice cooling, 0.34 ml of thionyl chloride was added to 1.88 g of 2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine dissolved in 21 ml of methylene chloride and the mixture was stirred at the same temperature for 30 minutes to produce 11-chloro-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine. After the solvent was removed from the reaction mixture, the residue was dissolved in 20 ml of methylene chloride, 1.25 ml of triethylamine and 1.69 ml of methyl thioglycolate were added to the solution while stirring under ice cooling and the mixture was stirred at room temperature for 7 hours. After the solvent was removed from the reaction mixture, 60 ml of ethanol and 45 ml of a 1N-sodium hydroxide aqueous solution were added to the residue and the mixture was stirred at room temperature for 1 hour. After the solvent was removed, 150 ml of ice water was added to the residue, the mixture was adjusted to about pH 2 with 1N-hydrochloric acid and then the aqueous layer was extracted with 150 ml of methylene chloride. After the organic layer was washed with water, the residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 0.54 g of the title compound as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C[C:21](N(C)C)=[O:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.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>[O:10]1[C:11]2[CH:16]=[CH:15][C:14]([C:2]3[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=3)=[CH:13][C:12]=2[O:22][CH2:21][CH2:9]1
Reactant: Nc1ccnc(Cl)n1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccnc(-c2ccc3c(c2)OCCO3)n1
Temperature: 150 °C

Procedure:
2-Chloro-pyrimidin-4-ylamine (1 g, 7.7 mmol), 4-methoxybenzeneboronic acid (1.41 g, 9.26 mmol) and dimethylacetamide (12 mL) were added to a microwave tube containing a stirrer bar, potassium phosphate (3.28 g, 15.44 mmol) was dissolved in water (4 mL) and added to the vial. The tetrakis(triphenylphosphine)palladium (0.44 g, 0.386 mmol) was added and the reaction was heated to 150° C. for 10 min. The reaction was filtered through silica and washed through with methanol and concentrated. Yield: 1.10 g, 71%; LCMS method: 1, RT: 3.43 min, MI: 241 [M+1].
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O=O.[K+].O=O.C1(C)C=CC(S(Cl)(=O)=[O:40])=CC=1>CO>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:40]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=O
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mmol) is dissolved with stirring in methanol (40 ml). The resulting solution is cooled in an icewater bath while solid potassium superoxide (2.20 g, 31 mmol) is added slowly (with evolution of oxygen). After stirring for a further 15 minutes, a solution of p-toluenesulphonyl chloride (2.38 g, 12.5 mmol) in 30 ml methanol is added dropwise over 20-30 minutes. The reaction mixture is stirred for a further 30 min. After this time the mixture is filtered under vacuum. The residue is washed with methanol and the combined filtrate evaporated under reduced pressure. The resulting solid is slurried with water, filtered, and washed with water and ether, to give (tolyl)diphenylsulphoxonium hexafluorophosphate (0.6 g, 54 %) identical with authentic material.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][NH:22][CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[S:19][C:20]2[CH2:21][N:22]([S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[CH2:23][CH2:24][C:25]=2[N:26]=1)=[O:17]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCc3nc(C(=O)Nc4ccccc4N)sc3C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethyl amine (1.0 eq) was added to solution of N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained in step VIII of example I (1.0 mmol) in 10 mL THF. The solution was cooled to 0° C. 4-Methyl-benzenesulfonyl chloride (1.0 mmol) was added slowly with continuous stirring. Reaction mixture was brought to room temperature and stirred for 2 h Reaction mixture was concentrated, diluted with water, extracted dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].C[OH:36]>C1COCC1>[CH2:27]([O:26][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:32](=[O:33])[CH2:31][O:30][CH3:29])[C:7]2=[O:36])[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH3:28]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: COCC(=O)Cl
Reactant: CO
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)COC)c3C2=O)ccc1OC
Yield: 32 %

Procedure:
A solution of (1S)-7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (0.5 g, 1.2 mmol) and 2-methoxyacetyl chloride (0.3 mL, 3.2 mmol) in THF (6 mL) was heated to reflux for 17 hours. To the mixture was added methanol (5 mL). The solvent was removed in vacuo to give a solid, which was purified with Prep HPLC to give (1S)—N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-2-methoxy-acetamide as an off-white solid (180 mg, 32% yield): mp 151-153° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7 Hz, 3H, CH3), 2.84 (s, 3H, CH3), 3.56 (s, 3H, CH3), 3.77 (dd, J=5, 14 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.08 (s, 2H, CH2), 4.12 (q, J=7 Hz, 2H, CH2), 4.53 (dd, J=10, 15 Hz, 1H, CHH), 5.87 (dd, J=5, 10 Hz, 1H, NCH), 6.81-6.82 (m, 1H, Ar), 7.10-7.13 (m, 2H, Ar), 7.51 (d, J=7 HZ, 1H, Ar), 7.67 (t, J=8 Hz, 1H, Ar), 8.81 (d, J=8 Hz, 1H, Ar), 10.42 (s, 1H, NH); 13C NMR (CDCl3) δ 14.69, 41.59, 48.80, 54.81, 55.96, 59.74, 64.55, 72.18, 111.49, 112.53, 116.06, 118.59, 120.49, 125.09, 129.39, 131.33, 136.02, 136.59, 148.62, 149.77, 167.57, 168.89, 169.16. Analy. calculated for C23H26N2O8S: C, 56.32; H, 5.34, N, 5.71. Found: C, 56.23; H, 5.30; N, 5.56.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:34])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([CH2:27][CH2:28]C(OCC)=O)=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8].[CH3:39][Mg]Br.CC[O:44][CH2:45][CH3:46]>>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([F:34])=[C:13]([NH:15][C:16]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:45]([OH:44])([CH3:46])[CH3:39])=[CH:26][C:21]3=[N:20][CH:19]=2)=[O:17])[CH:14]=1)=[O:8]
Reactant: C[Mg]Br
Reactant: CCOCC
Reactant: CCOC(=O)CCc1ccn2c(C(=O)Nc3cc(C(=O)NCc4ccc(F)c(F)c4)ccc3F)cnc2c1
Product: CC(C)(O)CCc1ccn2c(C(=O)Nc3cc(C(=O)NCc4ccc(F)c(F)c4)ccc3F)cnc2c1
Temperature: 0 °C

Procedure:
Ethyl 3-(3-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)propanoate (step 1) (50 mg, 0.095 mmol) was suspended in dry ether and cooled to 0° C. Methylmagnesium bromide (0.318 ml, 3.0M in ether, 0.953 mmol) was added and the mixture was stirred and allowed to warm to RT over 16 hrs. The mixture was partitioned between 10% aq. Citric acid and EtOAc. The organics were separated, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the title product;
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:26]=[CH:25][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][SH:24])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1>C(Cl)Cl>[ClH:10].[ClH:10].[C:1]1([NH:7][C:8](=[SH:24][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]3[CH:25]=[CH:26][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:17][CH2:18]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cl
Product: OC(Nc1ccccc1)=[SH]CCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 128.2 %

Procedure:
The procedure described in Example 35 was followed, using 1.3 g of phenyl isocyanate, 3.0 g of 2-[4-(4-chlorobenzyl)piperazin-1-yl]ethanethiol and 100 ml of methylene chloride, to give 2.2 g (43% of theory) of N-phenyl-S-{2-[4-(4-chlorobenzyl)piperazin-1-yl]ethyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 232°-236° C. (dec.).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.[O:9]1[C:22]([CH3:24])([CH3:23])[CH:10]1[CH2:11][C:12]1[C:13]([OH:21])=[CH:14][C:15]([O:19][CH3:20])=[C:16]([CH:18]=1)[OH:17].C(=O)([O-])O.[K+]>CO>[OH:9][C:22]([CH:10]1[CH2:11][C:12]2[CH:18]=[C:16]([OH:17])[C:15]([O:19][CH3:20])=[CH:14][C:13]=2[O:21]1)([CH3:24])[CH3:23]
Reactant: COc1cc(O)c(CC2OC2(C)C)cc1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)CC(C(C)(C)O)O2
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.1 %

Procedure:
To a solution of 5-(2,3-epoxy-3-methylbutyl)-2-methoxyhydroquinone diacetate (1.848 g) in methanol (36 ml) was added potassium hydrogencarbonate (1.50 g) in one portion. The mixture was stirred for 21 hours at ambient temperature and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate (30 ml) and saturated sodium chloride solution (30 ml). The separated organic layer was washed with saturated sodium chloride solution, dried, and evaporated to dryness. The oily residue was crystallized from isopropyl ether to yield 2,3-dihydro-2-(1-hydroxy-1-methylethyl)-6-methoxy-5-benzofuranol (964 mg) as a white solid.