Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Tl+].[Cl:9][CH2:10][CH2:11][S:12](Cl)=[O:13]>CCOCC>[Cl:9][CH2:10][CH2:11][S:12]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: [O-]c1ccccc1
Reactant: O=S(Cl)CCCl
Agent: [Tl+]
Solvent: CCOCC
Product: O=S(CCCl)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of thallium (I) phenoxide (28.6 w) in dry ether (100 v) was rapidly treated with 2-chloroethanesulfinyl chloride, prepared as in Example I. The slurry was vigorously stirred for 1 hour at ambient temperature with exclusion of moisture. Removal of thallium(I) chloride by filtration and evaporation of the etheral filtrate solution gave an oil. The oil was then subjected to molecular distillation in a wiped-film apparatus at 70-75° (1 ×10-4 torr) to give phenyl 2-chloroethanesulfinate (122 w) as a mobile liquid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[N:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:7][CH2:6][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Propargyl bromide (356.9 mg, 3 mmol) was slowly added to a mixture of tert-butyl 1-piperazinecarboxylate obtained in step 2(i) above (558.8 mg, 3 mmole) and diisopropylethylamine (407.1 mg, 3.15 mmol) in CHCl3 (25 ml) at 0° C. The mixture was stirred for 24 h at room temperature. 50 ml of CHCl3 was then added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene-hexane (1:1) to give tert-butyl 4-propargylpiperazine-1-carboxylate (D6) (crude 337 mg, 86%). H1 NMR (250 MHz, CDCl3): 1.42 (s, 9H), 2.22(s, 1H), 2.46 (s, 4H), 3,26 (s, 2H), 3.41 (s, 4H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][C:10]1[CH:22]=[CH:21][C:13]2[N:14]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[S:16][C:12]=2[CH:11]=1>C(#N)C>[CH3:6][N:4]([CH3:5])[CH:3]=[N:20][S:17]([C:15]1[S:16][C:12]2[CH:11]=[C:10]([OH:9])[CH:22]=[CH:21][C:13]=2[N:14]=1)(=[O:18])=[O:19]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1nc2ccc(O)cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide dimethyl acetal (1.5 mL, 11.3 mmol) was added to a partial suspension of 6-hydroxybenzothiazole-2-sulfonamide (2.3 gm, 10 mmol) in acetonitrile (20 mL) to give an immediate solution. After stirring at room temperature for 1 hour, the reaction mixture was cooled and the crystalline product which formed (1.95 gm) was collected m.p. 195°-198° C. Evaporation of the reaction solvent and dissolution of the residue in ethyl acetate/acetonitrile which was washed with water, dried (Na2SO4) and evaporated yielded an additional 0.6 gm from methylene chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([C@H:4]([N:7]([C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[NH2:8])[CH2:5][CH3:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:35]=[C:34]([B:36]2[O:40]C(C)(C)C(C)(C)[O:37]2)[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl.O>[CH3:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([CH3:16])[CH:13]=1)[C:9]([N:7]([C@H:4]([CH2:5][CH3:6])[C:2]([CH3:1])([CH3:3])[CH3:19])[NH:8][C:29]([C:28]1[CH:32]=[CH:33][C:34]([B:36]([OH:40])[OH:37])=[CH:35][C:27]=1[F:26])=[O:30])=[O:18]
Reactant: CC[C@@H](N(N)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](N(NC(=O)c1ccc(B(O)O)cc1F)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
In a 25 mL round bottom flask equipped with a magnetic stir bar were added (R)—N-(2,2-dimethylpentan-3-yl)-3,5-dimethylbenzohydrazide (1.317 g, 5.02 mmol) in 7 mL CH2Cl2 and a solution of potassium carbonate (1.388 g, 10.04 mmol) in distilled water (4 mL) were cooled in an ice bath at 0-4° C. and stirred for 10 min. The 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (1.714 g, 6.02 mmol) was added as a solution in 3.5 mL dichloromethane. The reaction was stirred at 0-4° C. for 30 min., the ice bath was removed and the mixture was stirred for 16 h at room temperature. The reaction was analyzed by LCMS and shows the reaction was complete. The organic layer was separated using a Biotage phase separator column and was transferred to a 40 g Redisep SiO2 column on the ISCO HPLC system. The compound was eluted with 0-100% EtOAc—hexanes and then with 10% MeOH—CH2Cl2. The desired fractions were combined and concentrated on a rotary evaporator to give the desired compound as an off-white foam (1.518 g, 59% yield). MS (ESI) calcd for C29H40BFN2O4 ([M+H]+) 511. found 511.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([CH:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[OH:19])=[N:17][C:4]=2[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([C:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])=[N:17][C:4]=2[CH:3]=1
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)c3ncccc3F)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(C(=O)c3ncccc3F)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of {6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanol (807 mg, 1.61 mmol) in dichloromethane (15 mL) was added Dess-Martin periodinane (2.7 g, 6.45 mmol.) at 0° C. Then reaction was gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (15 mL), quenched with aqueous saturated NaHCO3 solution (40 mL), and extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 100% EtOAc/hexanes) afforded {6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanone. MS APCI calcd. for C25H22Cl2FN5O [M+H]+ 498. found 498.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH2:26]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38](=O)[C:39]([O:41][CH3:42])=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1COCC1>[CH2:26]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1/[C:38](=[CH:2]\[O:3][CH3:4])/[C:39]([O:41][CH3:42])=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1sccc1Cc1ccccc1
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C(/C(=O)OC)c1sccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride and sodamide (0.4 g of a 1:1 molar mixture) in dry THF was added a solution of methyl 2-(3-benzyl-2-thienyl)-2-oxoacetate (220 mg, 0.8 mmol) in dry THF (5 ml). The reaction mixture was stirred at room temperature for 30 minutes. More (methoxymethyl)triphenylphosphonium chloride and sodamide (0.2 g of a 1:1 molar mixture) were added and stirring was continued for a further one hour. The reaction mixture was poured into water and then extracted with ether. The combined ether layers were washed with water and brine and then dried. Filtration through a pad of silica gel to remove triphenylphosphine oxide, followed by HPLC (eluent dichloromethane) afforded (Z)-methyl 2-(3-benzyl-2-thienyl)-3-methoxypropenoate, an oil (100mg), 1H nmr : delta 3.64 (3H, s), 3.78 (6H,s), 6.75 (1H,d), 7.0-7.4 (6H,m), 7.60 (1H,s) ppm; and (E)-methyl 2-(3-benzyl-2-thienyl)-3-methoxypropenoate, an oil (30 mg), 1H nmr : delta 3.64 (3H,s), 3.80 (3H,s), 3.82 (3H,s), 6.56 (1H,s), 6.75 (1H,d}, 7.0-7.3 (6H,m}ppm.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[S:36][C:16]2=[CH:17][CH:18]=[C:19]3[C:24]([N:23]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:27]=4)[N:21]=[CH:20]3)=[C:15]2[CH:14]=1)=[O:12])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl.O.C(O)(C(F)(F)F)=O>>[NH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[S:36][C:16]2=[CH:17][CH:18]=[C:19]3[C:24]([N:23]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([S:32](=[O:34])(=[O:35])[NH2:33])[CH:27]=4)[N:21]=[CH:20]3)=[C:15]2[CH:14]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCCNC(=O)c1cc2c(ccc3cnc(Nc4cccc(S(N)(=O)=O)c4)nc32)s1
Reaction time: 8 h
Yield: 95 %

Procedure:
(2-{[2-(3-Sulfamoyl-phenylamino)-thieno[2,3-h]quinazoline-8-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester (138.1 mg, 0.25 mmol) was placed in a 50 mL florentine and cooled in an ice-bath. Premixed TFA/dichloromethane/water (1:4:0.1, 0.5 mL TFA) was added in one portion and the resultant suspension was stirred at 0° C. for 35 minutes. After a further 1.75 hours at room temperature the solution was concentrated under reduced pressure to give a yellow solid. This solid was azeotroped with dichloromethane (3×10 mL), triturated with diethyl ether and isolated by filtration. The solid collected was washed with diethyl ether (3×5 mL) and pentane (3×5 mL) and placed in a drying pistol at 40° C. overnight giving a yellow powder (145.5 mg, 95% yield containing ˜1.5 eq. TFA). MS (ES+) 442. δH (d6 DMSO) 3.0-3.1 (2H, m), 3.5-3.7 (2H, m), 7.3-7.4 (2H, br s), 7.5 (1H, m), 7.6 (1H, m), 7.8-8.1 (5H, m), 8.2-8.3 (1H, m), 8.7-8.9 (3H, m), 9.4 (1H, s), 10.5 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(O)c(OCc2ccccc2)c1
Yield: 45 %

Procedure:
To a solution of 5.79 g of 3,4-dihydroxylphenyl acetic acid ethyl ester dissolved in dry acetone were added 4.48 g of potassium carbonate and 4.15 ml of benzyl bromide. The mixture was heated to reflux until the starting materials were exhausted; and then the solvent was distilled off under reduced pressure. To the residues thus obtained was added 50 ml of water; and the mixture was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to obtain residues, which were purified by chromatography to provide 3.80 g (yield 45%) of 3-benzyloxy-4-hydroxyphenylacetic acid ethyl ester, having the characteristics of: NMR(CDCl3, 200 MHz) δ1.24(t, J=7 Hz, 3H, CH3), 3.45(s, 2H, CH2CO), 4.12(q, J=7 Hz, 2H, OCH2), 5.05(s, 2H, CH2Ph), 6.77-7.35(m, 6H, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.C[O:11][C:12]([CH:14]1[C:18](=O)[CH2:17][CH2:16][CH2:15]1)=O>COCCO>[CH3:8][C:7]1[C:2]2=[N:1][C:15]3[CH2:16][CH2:17][CH2:18][C:14]=3[C:12](=[O:11])[N:3]2[CH:4]=[CH:5][C:6]=1[CH3:9]
Reactant: Cc1ccnc(N)c1C
Reactant: COC(=O)C1CCCC1=O
Solvent: COCCO
Product: Cc1ccn2c(=O)c3c(nc2c1C)CCC3

Procedure:
A solution of 24.4 g. of 2-amino-3,4-dimethylpyridine, 62.4 g. of methyl cyclopentanone-2-carboxylate and 250 ml of ethylene glycol monomethyl ether is stirred and heated under reflux for 40 hours. Workup as in Example 3 gives 28.3 g. of the named product as colorless plates after recrystallization from cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:13][C:7]=3[C:6]=2[CH:19]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([Cl:27])=[O:26])=[CH:23][CH:22]=1>>[ClH:27].[CH2:15]([N:14]([CH2:17][CH3:18])[CH:12]1[CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=4)=[CH:19][C:6]=3[C:7]=2[CH2:13]1)[CH3:16]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN(CC)C1CCc2oc3ccc(N)cc3c2C1
Product: CCN(CC)C1CCc2oc3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Product: Cl
Yield: 70.4 %

Procedure:
Beginning with 0.100 gm (0.30 mMol) 8-amino-1,2,3,4-tetrahydro-2-diethylaminodibenzofuran and 0.052 gm (0.33 mMol) 4-fluorobenzoyl chloride, 0.088 gm (70%) of the title compound were recovered as an off-white solid by the procedure described in Example 17.
Reaction SMILES: [NH2:1][CH2:2]C1C=NC=CC=1.C[C:10]1([CH2:15]N)[CH2:14][S:13][CH:12]=[N:11]1.[F:17][C:18]1([F:37])[CH2:20][CH:19]1[CH2:21][N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33]([OH:35])=O)=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36]>>[F:37][C:18]1([F:17])[CH2:20][CH:19]1[CH2:21][N:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:1][CH2:2][C:12]3[S:13][CH:14]=[C:10]([CH3:15])[N:11]=3)=[O:35])=[C:30]([CH3:32])[N:31]=2)[C:23]1=[O:36]
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Reactant: CC1(CN)CSC=N1
Reactant: NCc1cccnc1
Product: Cc1csc(CNC(=O)c2sc(N3CCN(CC4CC4(F)F)C3=O)nc2C)n1
Yield: 77 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 3-(aminomethyl)pyridine with 1-(4-methyl-1,3-thiazole-4-yl)methylamine to react with 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colourless solid in 77% yield: mp 157-159° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.42 (t, J=6.0 Hz, 1H), 7.11 (s, 1H), 4.36 (d, J=6.0 Hz, 1H), 4.02-3.96 (m, 2H), 3.64-3.47 (m, 3H), 3.20-3.12 (m, 1H), 2.59 (s, 3H), 2.44 (s, 3H), 2.04-1.89 (m, 1H), 1.68-1.55 (m, 1H), 1.37-1.26 (m, 1H); MS (ES+) m/z 428.9 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.ClC[C:11]([N:13](CCCCCCCC)CCCCCCCC)=[O:12].C(N(C(C)C)CC)(C)C.C(COC)[O:40]C>CCCCCCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[C:3]=1[C:2]([NH2:1])=[O:40]
Reactant: NCc1ccccn1
Reactant: COCCOC
Reactant: CCCCCCCCN(CCCCCCCC)C(=O)CCl
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccnc1C(N)=O

Procedure:
Pyridine diamide 5 was prepared according to the general procedure described in Example 8 using 2-(aminomethyl)pyridine (0.019 mol), 2-chloro-N,N-dioctylacetamide (0.056 mol), diisopropylethylamine (0.056 mol) and dimethoxyethane (30 mL). The product was isolated from the heptane extraction of the acidic aqueous layer. The product was made basic by extraction with aqueous NaOH. The organic solution was concentrated, and the residue was distilled (150°-200° C., 0.10 mm).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1(C)[C:13]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[H-].[Na+].[CH3:25]OCCOC>>[C:16]1([CH3:25])[CH:17]=[CH:12][C:13]([S:18]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:19])=[O:20])=[CH:14][CH:15]=1
Reactant: COCCOC
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1

Procedure:
The 2-benzyloxyalkyl p-toluenesulfonate used in step (a) may be prepared by conventional techniques from commercially available material. For example, a solution of 2-benzyloxyethanol and toluene sulfonyl chloride may be added to a slurry of sodium hydride in ethylene glycol dimethyl ether cooled (e.g. using an ice bath) under a nitrogen atmosphere. After the addition, the mixture is warmed and allowed to react at room temperature. Crude 2-benzyloxyethyl p-toluenesulfonate may be obtained from the reaction mixture by diluting the mixture with diethyl ether, filtering the diluted mixture through anhydrous magnesium sulfate, and concentrating the filtered product under vacuum.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[N:19]1([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:29]/[NH:28][C:26](=[O:27])[CH2:25][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: NNC(=O)CN1CCOCC1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)CN2CCOCC2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2-morpholin-4-ylacetohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.92 (t, 3H), 1.26 (s, 1H), 1.36 to 1.39 (m, 5H), 1.64-1.72 (m, 4H), 2.61 (d, 4H), 3.29 (s, 2H), 3.84-3.87 (m, 8H), 6.41 (d, 1H), 6.60 (dd, 1H), 7.75 (d, 2H), 13.86 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl[CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>O>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:17]1[N:16]([CH2:15][CH2:14][CH2:13][O:18]1)[C:4]2=[O:6]
Reactant: O=C=NCCCCl
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: O
Product: O=c1c2cccc(Cl)c2nc2n1CCCO2
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
A 250 mL round bottom flask is charged with 2-amino-3-chlorobenzoic acid (5.00 g, 29.1 mmol) and 40 mL of 10% aqueous KHCO3. The slurry is cooled to 0° C., and 3-chloropropylisocyanate (5.25 mL, 51.2 mmol) is added. The reaction mixture is allowed to warm to room temperature over 3 h, warmed to reflux for 2 h, then stirred at room temperature for 16 h. It is then diluted with 40 mL H2O and cooled to 0° C. The product is collected by filtration to provide 5.68 g of a yellow solid. This material is purified by recrystallization: it is dissolved in a minimal volume of warm CH2Cl2 (ca. 10 mL), cooled to 0° C., and IPE (ca. 20 mL) added to the point of cloudiness; crystallization is allowed to proceed at that temperature for 1 h. The resulting yellow solid is collected and dried to provide 3.87 g (16.3 mmol, 56% yield) of light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1[N:3]([S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(C)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1C
Yield: 37 %

Procedure:
Using ethyl 2,4-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate (3.0 g), sodium hydride (60% in oil, 596 mg) and benzenesulfonyl chloride (1.92 mL), a procedure as in Reference Example 4 was performed to give the title compound as a brown oil (yield 506 mg, 37%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[C:17]1([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[OH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH:23]([O:24][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: Cc1ccccc1C(O)c1ccccc1
Product: Cc1ccccc1C(OC(=O)O[C@H]1CN2CCC1CC2)c1ccccc1

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with phenyl-o-tolyl-methanol.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[CH3:10][N:11]([CH3:42])[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C@H:22]([C:27]([NH:29][C:30](=O)[C@H:31](CCC2C=CC=CC=2)[NH2:32])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[C:43]([C:46]#N)([CH3:45])=O.O>CN(C=O)C>[C:31]([C@@H:30]([NH:29][C:27](=[O:28])[C@@H:22]([NH:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([N:11]([CH3:10])[CH3:42])=[CH:17][CH:16]=1)(=[O:20])=[O:19])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:45][CH2:43][C:46]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)#[N:32]
Reactant: CC(=O)C#N
Reactant: CC(C)C[C@H](NS(=O)(=O)c1ccc(N(C)C)cc1)C(=O)NC(=O)[C@@H](N)CCc1ccccc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(N(C)C)cc1)C(=O)N[C@H](C#N)CCc1ccccc1
Yield: 57 %

Procedure:
Cyanuric chloride (33 mg, 0.18 mmol) was added to a solution of N-[N-((4-dimethylaminophenyl)sulfonyl)-L-leucinyl]-L-homophenylalaninamide (80 mg, 0.18 mmol) in DMF (2 mL) at 0° C. After stirring for 2h, the reaction was quenched by addition of satd. NaHCO3, filtered, diluted with EtOAc, washed sequentially with H2O (×5), brine, dried over Na2SO4, and concentrated giving a yellow foam. The crude residue was fractionated by preparative HPLC (65% AcCN/H2O/0.1% TFA) giving the title compound (47 mg, 57%) as a white solid, m.p. 46-48° C. 1H NMR (400 MHz, CDCl3): δ: 7.74(2H, d, J=9), 7.37-7.34 (2H, m), 7.30-7.26 (2H, m), 7.23-7.21 (3H, m), 6.79 (1H, d, J=8.5), 4.91 (1H, bs), 4.70 (1H, ddd, J=8, 8, 8), 3.68-3.73 (1H, m), 3.06 (3H, s), 2.84-2.76 (2H, m), 2.16-2.09(2H, m), 1.63-1.56 (2H, m), 1.42-1.37 (1H, m), 0.88 (3H, d, J=6), 0.71 (3H, d, J=6).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:34]([NH:41]O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.NO>CN(C)C=O.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:41][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: ONCc1ccccc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: Cl
Agent: NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(ONCc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.344 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (83.5 mg, 0.515 mmol) in N,N-dimethylformamide (1.4 mL) was stirred for 1 hour. In a separate flask was placed N-benzylhydroxylamine hydrochloride (82.2 mg, 0.515 mmol), triethylamine (71.7 μL, 0.515 mmol), and N,N-dimethylformamide (2 mL). This solution was stirred for 20 minutes. The hydroxylamine solution was added to the acylimidazole solution and the resulting solution was stirred for 1 hour at 70° C. The solution was cooled to room temperature and water (10 mL) was added. The insoluble material was filtered and dried to give the title compound (110 mg, 81% yield, m.p. 169-179° C. dec.).