Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=2)=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C(N(CC)CC)C.C1COCC1>[C:7]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:20])=[CH:17][N:16]=2)=[CH:9][CH:8]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a solution of N,N-dimethylethylenediamine (160 mg) in acetonitrile (5 ml)/THF (10 ml) were added 6-(4-biphenylylmethoxy)nicotinic acid (450 mg), WSC (340 mg), HOBt (230 mg), and triethylamine (0.7 ml) at room temperature. After stirring at room temperature for 12 hr, the reaction mixture was diluted with 10% aqueous potassium carbonates and extracted with ethyl acetate/THF. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent; THF) and recrystallized from ethyl acetate/diisopropyl ether to obtain the titled compound (400 mg).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17]O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:17][C:5]1[C:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Temperature: 5 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 30 g (105.58 mmol) of [5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl]-methanol in 210 mL of dichloromethane is added 41.96 g (158 mmol) of triphenylphosphine. The resulting mixture is cooled in an ice bath (about 0-10° C.) and added in portions to carbon tetrabromide (53 g, 158.37 mmol). The reaction is stirred at room temperature for 2 h. The solvent is evaporated to obtain an orange oil which is purified on silica gel column chromatography using Hexanes to hex/EtOAc 8:2 as eluent, to obtain 33 g of the title compound as a white solid (90%). MS (m/e): 346 (M+1).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19]C(C=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O.Cl.[CH2:32]1[CH2:36]O[CH2:34][CH2:33]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH:32]([CH:36]1[CH2:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]#[C:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:23])=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)=[CH:33][CH3:34]
Reactant: Cc1ccc(C#Cc2ccc(C3CCC(C=O)CC3)cc2)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Product: CC=CC1CCC(c2ccc(C#Cc3ccc(C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.03 g of 4-(4-p-tolylethynylphenyl)cyclohexanecarbaldehyde were dissolved in 100 ml of THF, and 15.22 g of ethyltriphenylphosphonium bromide were added quickly under a nitrogen atmosphere. 4.6 g of potassium tert-butoxide were then added in portions. The suspension was stirred overnight at RT, then poured into water and neutralized using 2 N hydrochloric acid solution. Conventional work-up gave 1-propenyl-4-(4-p-tolylethynylphenyl)cyclohexane as an E/Z isomer mixture.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:43])[C:14]=3[CH:44]=2)=[N:7][CH:8]=1)#[N:2].[OH-].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=4)[CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:15]([CH3:43])[C:14]=3[CH:44]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Oc4ccc(C#N)cn4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(Oc3ccc(C#N)cn3)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Ethyl 3-{[(4-{[{5-[(5-cyanopyridin-2-yl)oxy]-3-methyl-1-benzofuran-2-yl}(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (300 mg) obtained in Example A201 was dissolved in tetrahydrofuran (4.0 mL), and 1N aqueous sodium hydroxide solution (1.1 mL) was added to the solution, and the mixture was stirred at 50° C. for 1 hr. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.1 mL) under ice-cooling and stirred at 0° C. for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (271 mg, 87%) as a colorless amorphous form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]/[C:10](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11]/[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9]/[C:10](/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)/C=C(/CCc1ccc(Cl)cc1)c1ccccc1
Yield: 73.5 %

Procedure:
A solution of (Z)-ethyl 5-(4-chlorophenyl)-3-phenylpent-2-enoate (139 mg) and 4M NaOH (1.1 ml) in EtOH (10 ml) was stirred at rt for 4 h. The mixture was poured into water (30 ml), acidified to pH 2 with 10% HCl and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated to afford a crude, which was purified by crystallisation from hexane/ethylacetate to afford (Z)-5-(4-chlorophenyl)-3-phenylpent-2-enoic acid (93 mg) as colourless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>C1(C)C=CC=CC=1.[Cu]I>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2
Reactant: Ic1ccccc1
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A 234 mg portion of ethyl 2,3-dimethyl-1H-indole-5-carboxylate was dissolved in 1 ml of toluene, and 0.145 ml of iodobenzene and 10 mg of copper(I) iodide and 480 mg of tripotassium phosphate and 26 ml of trans-1,2-cyclohexanediamine were added at room temperature, followed by stirring at 100° C. for 24 hours. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate:hexane=1:4) to obtain 79 mg of ethyl 2,3-dimethyl-1-phenyl-1H-indole-5-carboxylate as a colorless oily material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.Cl>O1CCCC1.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[OH:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(O)c2ccccn2)C1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
2-Bromopyridine (6.50 g, 40 mmol) was added to isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 20 mL, 40 mmol) at room temperature. The mixture was stirred for 10 minutes then warmed to 30° C. and stirred for 105 minutes. The mixture was cooled to −10° C. and a solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (5.5 g, 10 mmol) in tetrahydrofuran (9 mL) was added dropwise. The reaction mixture was stirred for 15 minutes at −10° C. followed by stirring at room temperature for 1 hour. The reaction mixture was cooled and treated with water (20 mL) followed by aqueous hydrochloric acid (1.0 M, 40 mL). The mixture was stirred for 10 minutes then extracted with dichloromethane (×2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (gradient: 20-80% ethyl acetate in cyclohexane) to afford the diastereoisomeric (2:1) mixture (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol as an off-white foam (3.25 g). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J=4.8 Hz, 1 H); 8.00 (d, J=8.2 Hz, 2 H); 7.84-7.86 (m, 3 H); 7.44-7.46 (m, 1 H); 7.29-7.30 (m, 1.5 H); 7.09-7.10 (m, 3.5 H); 6.95-6.97 (m, 2.5 H); 6.41 (s, 0.5 H); 6.18 (s, 1 H); 5.11 (s, 0.5 H); 5.04 (s, 1 H); 4.87 (s, 1 H); 4.50 (d, J=11.8 Hz, 1 H); 4.10 (d, J=13.3 Hz, 2.5 H); 3.80 (d, J=12.1 Hz, 0.5 H); 3.69 (s, 0.5 H); 3.24 (d, J=16.6 Hz, 1 H); 3.09-3.13 (m, 1.5 H); 2.54-2.58 (m, 2.5 H); 2.25-2.27 (m, 1 H); 2.11 (d, J=16.6 Hz, 1 H); 1.43 (s, 0.5 H).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([S:10][C:11]#N)=[CH:8][N:9]=1)[C:2]([CH3:4])=[O:3].SC[C@H]([C@@H](CS)O)O.BrC[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CO.CN(C=O)C.O>[CH3:27][C:26]([O:25][C:23](=[O:24])[CH2:11][S:10][C:7]1[S:6][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[N:9][CH:8]=1)([CH3:29])[CH3:28]
Reactant: CC(=O)Nc1ncc(SC#N)s1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(SCC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a mixture of 2-acetamino-5-thiocyanatothiazole (5.97 g, 30 mmol) in MeOH (360 mL) under argon was added dithiothreitol (9.26 g, 60 mmol) at rt. The mixture was stirred at rt for 2 h and it was concentrated to afford a reduced solid product. This solid product was dissolved in DMF (30 mL) and to this solution were added tert-butyl bromoacetate (5.85 g, 30 mmol) and potassium carbonate (5.0 g, 36 mmol). The mixture was stirred at rt for 2 h and water (200 mL) was added to the mixture. The precipitates were collected, washed with water and dried. The solid was dissolved in methylene chloride (100 mL) and MeOH (10 mL) and filtered through a silica gel pad. The filtrate solution was concentrated to afford the desired product (7.5 g, 87%) as a solid, mp 162-163° C.
Reaction SMILES: C([O-])=O.[NH4+].[NH2:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][C:7]=1[N+:16]([O-])=O>CO.O.[Pd]>[NH2:16][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:6]=1[NH2:5])[O:10][CH2:11][CH2:12][OH:13]
Reactant: Nc1ccc(OCCO)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(OCCO)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 113.3 %

Procedure:
A degassed solution of ammonium formate (1.4 g) in MeOH/water (10/1) was added to 2-(4-amino-3-nitrophenoxy)ethan-1-ol (234 mg), followed by Pd/C (10%). The flask was closed and the reaction mixture was stirred at RT for 20 h. The reaction mixture was filtered off and Pd/C was further washed with MeOH/water. The filtrate was lyophilized to afford 225 mg of black solid. 1H-NMR (DMSO): 8.19 (s, 1H); 6.41 (d, 1H, 8.3 Hz); 6.17 (d, 1H, 2.7 Hz); 5.98 (dd, 1H, 2.8 Hz and 8.3 Hz); 4.98 (br s, NH2); 3.77 (t, 2H, 5.2 Hz); 3.63 (t, 2H, 5 Hz).
Reaction SMILES: S1CC(=O)NC1=S.C(C(CC)(CC)C([O-])([O-])[O-])C.C(OC(=O)C)(=O)C.C([O:28][C:29](=[C:31]1[S:35][C:34](=[S:36])[N:33]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:32]1=[O:44])[CH3:30])C>>[F:43][C:40]1[CH:39]=[CH:38][C:37]([N:33]2[C:32](=[O:44])[C:31](=[C:29]([OH:28])[CH3:30])[S:35][C:34]2=[S:36])=[CH:42][CH:41]=1
Reactant: CCOC(C)=C1SC(=S)N(c2ccc(F)cc2)C1=O
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: O=C1CSC(=S)N1
Solvent: CC(=O)OC(C)=O
Product: CC(O)=C1SC(=S)N(c2ccc(F)cc2)C1=O

Procedure:
Similar reaction of this rhodanine (0.2 m.) with 140 g. (0.86 m.) of triethylorthoacetate in 350 ml. of acetic anhydride followed by alkaline hydrolysis of the intermediate 5-(1'-ethoxyethylidene)-3-(4'-fluorophenyl)-rhodanine gives the corresponding 3-(4'-fluorophenyl)-5-(1'-hydroxyethylidene)-rhodanine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>[OH-].[Na+].O1CCOCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH:2]2[C:10]([OH:12])=[O:11])=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1Cc2ccccc2N1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of (D,L) indoline-2-carboxylic acid (548 mg, 3.36 mmol) in 1N aq. NaOH (8 mL), a solution of 4-chlorophenylisocyanate (728 mg, 4.74 mmol) in dioxane (8 mL) was added. The mixture was stirred at room temperature overnight. It was then washed with Et2O (2×). The aqueous layer was separated, acidified with 4N HCl to pH 1 to 2. The product was extracted with EtOAc. The EtOAc solution was dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give the desired product as a powder (325 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.C([C:34]1([OH:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:35]1[C:36](Cl)=[O:37])(=O)C.[OH-].[Na+].Cl>C(Cl)Cl>[OH:43][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5])=[O:37]
Reactant: Nc1ccccc1C(=O)NCCCCCC(=O)O
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(=O)c1ccccc1NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 0.30 g (1.20 mmol) of 6-(2-aminobenzoylamino)hexanoic acid in 5 ml of dry methylene chloride, add 0.23 g (2.10 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 0.15 g (1.53 mmol) of triethylamine and a solution of 0.20 g (2.05 mmol) of 2-acetylsalicyloyl chloride dissolved in 5 ml of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 10 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Purify the reaction product by recrystallization (EtOH/H2O). This yields 0.24 g (62%) of 6-[2-(2-hydroxybenzoylamino)benzoylamino]hexanoic as a white solid.
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]([OH:18])([CH3:17])[C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[C:21]([C@:23]1([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29])#[CH:22]>>[OH:18][C:8]1([CH3:17])[CH2:7][O:6][C:5]2[CH:19]=[CH:20][C:2]([C:22]#[C:21][C@:23]3([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=[C:9]12
Reactant: CC1(O)COc2ccc(I)cc2-n2nc(C(N)=O)cc21
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2C(C)(O)CO3)C1=O

Procedure:
Similar to as described in General Procedure G, racemic 9-iodo-4-hydroxy-4-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a diasteromeric mixture of the titled compound after purification by prep HPLC.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[C:19]([OH:26])[C:18]([NH:27][C:28]2[C:31](=O)[C:30](=[O:33])[C:29]=2[O:34]CC)=[CH:17][CH:16]=1>CO>[Cl:14][C:15]1[C:20]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[C:19]([OH:26])[C:18]([NH:27][C:28]2[C:29](=[O:34])[C:30](=[O:33])[C:31]=2[NH:13][C@@H:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:17][CH:16]=1
Reactant: CCOc1c(Nc2ccc(Cl)c(C(=O)N(C)C)c2O)c(=O)c1=O
Reactant: Cc1ccc([C@H](N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc([C@H](Nc2c(Nc3ccc(Cl)c(C(=O)N(C)C)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
A mixture of 412 mg (2.27 mmol, 1.1 eq) of C—(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine (prepared in EXAMPLE 50, steps 1 to 4) and 700 mg (2.07 mmol, 1 eq) of 6-chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide in 45 ml of methanol was stirred at ambient temperature for 3 days. The methanol was evaporated off and the residue was taken up with ethyl acetate and washed with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue (0.90 g) was chromatographed on silica gel (80 g prepacked column, eluent dichloromethane/methanol, from 0 to 10% of methanol). 520 mg of 6-chloro-2-hydroxy-N,N-dimethyl-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamide were obtained in the form of an ochre solid. Yield=53%. Mp=165-167° C.
Reaction SMILES: [C:1]1([S:7]([CH:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])CCCCC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)CCCCCCC/C=C\CCCCCCCC.C1(S([O-])=O)C=CC=CC=1.[Na+].O>CN(C)C=O>[CH2:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC/C=C\CCCCCCCC(CCCCC)S(=O)(=O)c1ccccc1
Agent: CCCCCCCC/C=C\CCCCCCCCBr
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
The initial oleylphenylsulfone may be prepared in the following manner: a mixture of 16.5 g (5.10-2 mole) oleyl bromide and 8.2 g (5.10-2 mole) sodium phenyl sulphinate in 100 cm3 dimethylformamide is stirred for 15 hours at 25° C. The reaction mixture is then poured into 800 cm3 iced water and the organic phase is extracted five times with ether. The combined ethereal extracts are washed with a saturated aqueous solution of sodium chloride then dried over magnesium sulphate and concentrated. The residue obtained is purified by being passed over a silica column (elution solvent: cyclohexane). By concentration of the eluate, 15 g (yield: 77%) oleylphenylsulfone are obtained in the form of a colourless oil identified by NMR and infrared spectrography.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([O:14]C)[CH:11]=[C:10]([O:16]C)[CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl.C(=O)=O.CC(C)=O>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([OH:16])[CH:11]=[C:12]([OH:14])[CH:13]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(OC)cc(C(=O)C2CCCC2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(c1cc(O)cc(O)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of cyclopentyl-(3,5-dimethoxy-phenyl)-methanone (234 mg) in anhydrous dichloromethane (5 mL) cooled in dry ice/acetone bath was added dropwise a solution of boron tribromide (4 mL of 1 M solution in dichloromethane). After the addition was completed, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Unreacted boron tribromide was quenched with methanol. Then the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 200 mg of the title compound (97% yield). Note: the title compound decomposes on air. HRMS calcd for C12H14O3 [M+H]+ 207.1016, observed 207.1016.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1CC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](CCC(=O)N)NC(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)(C)C>[C:1]([O:5][C:6](=[O:43])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
0.55 g (0.93 mmol) of N-[[N-[N-(benzyloxycarbonyl)-L-glutaminyl]-L-phenylalanyl]methyl]-L-proline tert.butyl ester, prepared as described in Example 6, was reduced in 15 ml of isopropanol in the presence of 90 mg of sodium borohydride as described in Example 7. After working-up, the product was chromatographed on silica gel using 2% methanol in chloroform for the elution. There were obtained 60 mg of isomer 1 of N-[3(S)-[[N-(benzyloxycarbonyl)-L-glutaminyl]amino]-2(R or S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester in the form of a solid; Rf (System B): 0.37; MS: m/e 597 [M+H]+, and 65 mg of isomer 2 in the form of a solid; Rf (System B): 0.25; MS: m/e 597 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:7]=[C:8]([CH3:43])[C:9]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]4[O:40][CH2:39][CH2:38][C@H:21]5[S:22](=[O:37])(=[O:36])[C:23]([CH3:35])([CH3:34])[C:24]([NH:26]C(=O)OC(C)(C)C)=[N:25][C@:20]5([CH3:41])[C:19]=4[CH:42]=3)=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:26][C:24]1[C:23]([CH3:35])([CH3:34])[S:22](=[O:36])(=[O:37])[C@@H:21]2[CH2:38][CH2:39][O:40][C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:9]4[C:8]([CH3:43])=[N:7][C:6]([O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:11][N:10]=4)=[O:13])=[CH:42][C:19]=3[C@@:20]2([CH3:41])[N:25]=1
Reactant: Cc1nc(OCC2CC2)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(NC(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(OCC2CC2)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]1CCO2
Temperature: 85 °C
Yield: 68.9 %

Procedure:
To a reaction mixture of tert-butyl ((4aR,11bR)-10-(5-(cyclopropylmethoxy)-3-methylpyrazine-2-carboxamido)-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (40 mg, 0.065 mmol) in DMF 1 ml was added K2CO3 (40 mg, 0.29 mmol). It was heated to 85° C. for 3 h. It was cooled to RT, diluted with water, and extracted with EtOAc. The organic phase obtained was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 15% to 25% to 40% EtOAc/MeOH/Et3N in (40% EtOAc in Heptane) to yield 23 mg of desired product. MS m/z: 514.2 [M+H].