Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1C=CC(C=NO)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)=[CH:14][CH:13]=1.C([N-]C(C)C)(C)C.[Li+].ClCCCI>C1COCC1.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:22]3[C:23](=[O:27])[CH:24]([CH2:4][CH2:3][CH2:2][Cl:1])[CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: O=C1CCCc2onc(-c3ccc(Cl)cc3)c21
Agent: CC(C)[N-]C(C)C
Agent: ClCCCI
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2c(-c3ccc(Cl)cc3)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In a similar manner to that of Examples 7a-d starting with 4-chlorobenzaldehyde oxime, the starting ketone is prepared. In 220 ml anhydrous THF was dissolved 8.1 g 3-(4-chlorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 32.8 ml lithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise. The resulting solution was stirred for fifteen minutes at -78° C. and 4.6 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and the layers were separated. The aqueous phase was extracted twice with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (start with 5% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) gave 5.2 g of 3-(4-chlorophenyl)-5-(3-chloropropyl)-6,7-dihydro-1,2-benzisoxazol-4 (5H)-one.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1.[C:24]([C:32](O)=[O:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)CCl>C(Cl)Cl>[O:31]=[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]([N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=1)[C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)=[O:33]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: FC(F)(F)c1ccc(CCNc2ccc(C(F)(F)F)nc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of [2-(4-trifluoromethyl-phenyl)-ethyl]-(6-trifluoromethyl-pyridin-3-yl)-amine (50 mg) in CH2Cl2 (3 mL) was added under a nitrogen atmosphere at 0° C. benzoyl formic acid (1.1 eq., commercially available) and EDC (1.1 eq). After stirring for 12 h a ambient temperature, the mixture was washed with aqueous Na2CO3 (saturated, 2.5 mL) and water (2.5 mL), the combined aqueous layers were extracted with CH2Cl2 (3×2.5 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (46 mg, 66%) as a light yellow solid. MS m/e: 467.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH2:14][CH:15]=[CH2:16])C=C.C(Cl)Cl>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[N+:10]([C:6]1[C:5]2[O:13][CH2:14][CH:15]=[CH:16][CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: C=CCOc1c(CC=C)cccc1[N+](=O)[O-]
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1OCC=CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-allyl-2-allyloxy-3-nitrobenzene (100 mg, 0.0004 mol) in methylene chloride (6 mL, 0.09 mol) at room temperature was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (20 mg, 0.00002 mol). The reaction mixture was stirred at room temperature overnight. The reaction solvent was removed in vacuo leaving a dark solid which was purified by ISCO column chromatography on silica gel using hexane-methyl-t-butyl ether (3:1). The fractions corresponding to product were combined and concentrated in vacuo to give 9-nitro-2,5-dihydrobenzo[b]oxepine as a dark solid which was further purified to give product as an off-white solid (80 mg, 90%). 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, 1H, J=8.09 Hz), 7.33 (d, 1H, J=7.32 Hz), 7.11 (dd, 1H, J=7.58, 8.09 Hz), 5.86 (m, 1H), 5.54 (d, 1H, J=11 Hz), 4.79 (s, 2H), 3.54 (s, 2H);
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([C:33]2[C:34](F)=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:32])[CH:25]=1)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=O)(C)(C)C.Cl.Cl.[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([CH2:51][NH2:52])=[C:45]2[CH:44]=[CH:43]1>>[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([CH2:51][NH:52][C:34]3[N:35]=[CH:36][CH:37]=[CH:38][C:33]=3[C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([C:15]([O:14][CH2:13][C@@H:9]4[CH2:10][CH2:11][CH2:12][NH:8]4)([C:16]([F:18])([F:19])[F:17])[C:20]([F:22])([F:23])[F:21])[CH:25]=3)=[O:32])=[C:45]2[CH:44]=[CH:43]1
Reactant: NCc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COC(c1cccc(NC(=O)c2cccnc2F)c1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Product: O=C(Nc1cccc(C(OC[C@@H]2CCCN2)(C(F)(F)F)C(F)(F)F)c1)c1cccnc1NCc1ccnc2[nH]ccc12

Procedure:
The titled compound was prepared from (S)-2-(2,2,2-trifluoro-1-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-phenyl}-1-trifluoromethyl-ethoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Example 1. MS (ES+): 593 (M+H). Calc'd. for C28H26F6N6O2—592.54.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[N+]([C:13]1[CH:14]=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18])([O-])=O.[C:23](=O)([O-])[O-:24].[K+].[K+]>CN(C)C=O>[CH3:23][O:24][C:13]1[C:14]([O:9][C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[C:15]([C:21]#[N:22])[C:16](=[CH:19][CH:20]=1)[C:17]#[N:18]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(C#N)c1Oc1ccccc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture is prepared by adding 136.4 grams (1.1 moles) of p-methoxyphenol, 173 grams (1 mole) of 4-nitrophthalonitrile, and 207 grams of potassium carbonate in 1667 ml of dimethylformamide. The mixture is heated to 70° C. and mechanically stirred. Samples are taken of this reaction mixture periodically and analyzed by GLC. After five hours, the reaction is complete. The p-methoxyphenoxyphthalonitrile is isolated by quenching the crude reaction mixture in ice water. The product is further purified by washing the crude precipitate with dilute sodium carbonate and then water. Finally the p-methoxyphenoxyphthalonitrile is vacuum dried at 60° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][N:22]=1>C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH3:19])=[O:17])=[N:22][CH:23]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(Br)cn1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Diisopropylamine (0.45 ml, 3.17 mmol) was dissolved in THF (10 ml) under a nitrogen atmosphere and cooled to −10° C. n-BuLi (2.64 ml, 3.17 mmol, 1.2M solution in THF) was added dropwise over 5 minutes. The reaction mixture was stirred at −10° C. for 30 minutes, after which time the reaction mixture was cooled to −78° C. Methyl isobutyrate (0.36 ml, 3.17 mmol) was added dropwise over 5 minutes. Stirring was continued at −78° C. for 45 minutes. 2,5-Dibromopyridine (0.5 g, 2.11 mmol) in THF (10 ml) was added and the mixture allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride solution, extracted into DCM (3×20 ml), the combined organics dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC on silica gel [19:1 heptane/EtOAc as eluent] to provide the title compound as colourless oil (195 mg, 36%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH:33]([C:37]#[N:38])[C:34]([NH2:36])=[O:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:36][C:34](=[O:35])[CH:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:37]#[N:38]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: N#CC(N)C(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CC(NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)C(N)=O
Reaction time: 1 h
Yield: 28.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-2-cyanoacetamide (4.59 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.4 min) to provide N-(2-amino-1-cyano-2-oxoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.013 mmol, 28.6% yield) as a mixture of diastereomers. LCMS=513.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.28 (2 H, m), 7.50-7.80 (7 H, m), 5.40-5.63 (1 H, m), 5.27 (1 H, s); HPLC peak RT=9.2 min (Method A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[C:12]1([C:10]2[N:11]=[C:7]([C:3]3[CH:2]=[N+:1]([O-:26])[CH:6]=[CH:5][CH:4]=3)[S:8][CH:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(-c2csc(-c3cccnc3)n2)cc1
Solvent: ClCCl
Product: [O-][n+]1cccc(-c2nc(-c3ccccc3)cs2)c1
Reaction time: 2 h
Yield: 28.7 %

Procedure:
In 50 ml of dichloromethane was dissolved 1 g of 2-(pyridin-3-yl)-4-phenylthiazole. Thereto was added 900 mg of m-chloroperbenzoic acid at room temperature. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with an aqueous sodium hydrogencarbonate solution and dried The solvent was removed by distillation. The residue was recrystallized from ethyl acetate to obtain 306 mg of 3-(4-phenylthiazol-2-yl) pyridine-N-oxide as a brown powder.
Reaction SMILES: F[C:2](F)([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH:3]=[C:4](I)[CH2:5][OH:6].[OH2:16].Cl.[NH2:18]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:13][C:8]([F:14])([C:2]1[O:16][N:18]=[C:4]([CH2:5][OH:6])[CH:3]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: O
Reactant: OCC(I)=CC(F)(F)C(F)(F)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCc1cc(C(F)(F)C(F)(F)F)on1

Procedure:
8.9 g of 4,4,5,5,6,6,6-heptafluoro-2-iodo-2-hexene-1-ol was dissolved in 90 ml of ethanol, and 40 ml of water, 4.17 g of hydroxylamine hydrochloride and 20.70 g of potassium carbonate were then added. The mixture was stirred and heated under reflux for 20 hours. The reaction mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.78 g of (5-pentafluoroethyl-isoxazol-3-yl)methanol.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:21].[NH3:22]>C(O)C>[ClH:21].[F:1][C:2]([F:19])([F:20])[CH:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([NH2:22])=[NH:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(Oc1ccc(C#N)cc1)C(F)(F)F
Reactant: N
Agent: Cl
Solvent: CCO
Product: CCCCCCC(Oc1ccc(C(=N)N)cc1)C(F)(F)F

Procedure:
Into 20 ml of dry ethanol containing 3.76 g of oa p-(1-trifluoromethyl-heptyloxy)-benzonitrile, about 1 g of dry hydrogen chloride was introduced under stirring at a temperature below 10° C. After stirring at room temperature for 3 days, solvent was distilled off to obtain any oily product. To this, were added slowly 20 ml of dry ethanol containing about 2 g of ammonia under cooling with ice, followed by stirring at room temperature for 3 days. Ethanol and ammonia were removed to obtain 3.40 g of oily oa p-(1-trifluoromethyl-heptyloxy)-benzamidine hydrochloride. This oily hydrochloride was solidified by trituration in hexane to use the following reaction.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>C1COCC1>[OH:8][CH2:7][C@@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH:3]([CH3:4])[CH2:5][CH3:6]
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CCC(C)[C@@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a solution of L-(+)-isoleucinol (2.0 g, 17.1 mmol) in THF (30 mL) was slowly added 1,3-propanesultone (1.94 g, 16.3 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 70% water/EtOH (240 mL). Dowex Marathon C ion exchange resin (strongly acidic, 15 g) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (60 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (1.70 g, 44%). 1H NMR (D2O, 500 MHz) δ ppm 3.78 (d, 1H, J=13.1 Hz), 3.64 (m, 1H), 3.14 (m, 3H), 2.03 (m, 2H), 1.75 (m, 1H), 1.32 (m, 1H), 1.17 (m, 1H), 0.79 (m, 6H). 13C (D2O, 125 MHz) δ ppm 63.42, 57.38, 48.27, 44.77, 33.64, 25.91, 21.52, 13.31, 10.94. [α]D=+20.4° (c=0.00212 in water), ES-MS 240 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:25][CH2:26][CH:27]1[O:29][CH2:28]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[CH2:28][CH:27]([CH2:26][Cl:25])[O:29][C:7]3([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: ClCC1CO1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN1C(=O)CN2CC(CCl)OC2(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 8 h

Procedure:
A mixture of 10g. (35 mmole) of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 10 g. of aluminum chloride, and 200 ml. of dried benzene was treated with 30 ml. of 1-chloro-2,3-epoxypropane in 100 ml. of benzene. The reaction mixture was stirred overnight. Work-up as in Method A, Example 5, above gave 32 g. of a crude oil. The oil was dissolved in benzene, filtered over Florisil, evaporated to dryness and crystallized from ether-petroleum ether to give the above-titled product as colorless needles, m.p. 140°-142°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH:6]([N:20](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([F:19])[CH:8]=1)[CH3:2]>CCO.CC(O)=O.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH:6]([NH2:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([F:19])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccc(-c2ccccc2)c(F)c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC(N)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 12 h

Procedure:
A solution of the dibenzylamine 13-3 (5.65 gm, 11.75 mmol) in EtOH/HOAc (90/10 mL) was purged with argon and treated with Pd(OH)2 (3 g) and placed under 1 atm of H2 gas for 12 h. Additional portions (2.5 g) or Pd(OH)2 were added after 24 h, 48 h and 144 h. The reaction mixture was purged with argon, filtered through Celite, and the filtrate dissolved in aq HCl (pH=1) The aqueous solution was washed with EtOAc, neutralized with satd aq NaHCO3, and extracted with EtOAc (3×30 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product 13-4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.[Li+].C[Si]([N-:32][Si](C)(C)C)(C)C>>[NH2:32][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Agent: [Li+]
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N)cc3c2C)c1
Yield: 18.7 %

Procedure:
The intermediate ethyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate was prepared from ethyl 3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (Intermediate 18) (45 mg, 0.1 mmol) and LiHMDS (1M in THF, 120 μL, 0.12 mmol) according to General Procedure 4, described in Example 45, using a modified reaction time and reaction temperature (100° C., 1500 s, microwave reactor) yielding 7.3 mg of ethyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]-amino}benzoate.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].CN(C=O)C.CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>CO>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:16]([S:13]([C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[C:3]3=[O:22])=[CH:8][CH:9]=2)(=[O:14])=[O:15])[C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
Synthesized according to General Procedure 8. To a stirred solution of (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (5.0 g, 14.8 mmol) and DMF (25 mL), under N2, at 5° C. (ice bath) was added DIEA (2.5 mL, 14.8 mmol). To this solution was added 4-fluorobenzenesulfonyl chloride (2.9 g, 14.8 mmol) portionwise over 10 minutes. The solution was stirred at ambient temperature for 20 minutes. To this solution was added MeOH (75 mL). The mixture was cooled to 5° C. via an ice bath and stirred for 30 minutes. The precipitate was filtered, washed with MeOH (20 mL), and vacuum dried to give [(R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl]-N-(thiazol-2-yl)benzenesulfonamide as a white solid (6.5 g, 13.1 mmol, 89% yield). 1H-NMR (400 MHz, DMSO) δ 8.03-7.96 (m, 2H), 7.83-7.80 (m, 2H), 7.72 (d, J=5.1 Hz, 1H), 7.61 (dd, J=1.8, 7.1 Hz, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 7.37 (dd, J=2.0, 15.6 Hz, 1H), 7.02 (d, J=5.1 Hz, 1H), 5.88 (d, J=5.9 Hz, 1H), 4.38-4.32 (m, 1H), 3.83-3.78 (m, 1H), 3.71 (td, J=9.5, 5.4 Hz, 1H), 2.52-2.42 (m, 1H), 1.87 (td, J=9.4, 4.1 Hz, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=498.3; tR=1.32 min.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][N:15]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH2:19][O:18][C:17]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:16]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.CCOCC>C(O)C>[ClH:31].[Cl:31][C:29]1[CH:28]=[CH:27][C:17]2[O:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:15]([CH2:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:16]=2[CH:30]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCN2c3ccccc3OCOc3ccc(Cl)cc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)[C@@H]1CCCN(CCCN2c3ccccc3OCOc3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 135.2 %

Procedure:
The above ester (0.77 g, 1.73 mmol) was dissolved in ethanol (7.5 ml) and 2 N sodium hydroxide (2.86 ml, 5.71 mmol) was added. The mixture was stirred at room temperature for 16 h. The ethanol was evaporated in vacuo and the remainder was diluted with water (25 ml). pH was adjusted to 6 by addition of 6 N hydrochloric acid and the aqueous solution was extracted with dichloromethane (3×15 ml). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The remainder was dissolved in tetrahydrofuran (15 ml) and 2.5 N hydrogen chloride in ether (0.59 ml, 1.47 mmol) was added dropwise. Ether (30 ml) was added and the mixture was stirred for 3 h, the precipitate was filtered off and dried, to afford 0.53 g (68%) of the title compound as a powder.
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.ClC(OCC1C=CC=CC=1)=O>C1COCC1.ClCCl.[Pd]>[N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1=CCCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A solution of 1-benzyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (890 mg, 2.93 mmol) and 5% Pd/C (90 mg) in THF (70 ml) were stirred under a hydrogen atmosphere for 12 hours. The mixture was then filtered over celite and concentrated giving colourless oil. This was dissolved in dichloromethane (10 ml), cooled to 0° C. and DIPEA (1.02 ml, 5.86 mmol) followed by benzyl chloroformate (0.45 ml, 3.22 mmol) were added. On complete addition the reaction was raised to room temperature and stirred for a further 1 hour. The mixture was then diluted with dichloromethane (40 ml) and washed with water (2×20 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 99:1 to 90:10 dichloromethane/MeOH) to give the title product as colourless oil (521 mg, 59%).