Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17].[F-].[K+]>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH:16]=[CH2:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])c1Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)OC)c(Cl)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A solution of methyl 2-chloro-5-iodo-3-nitrobenzoate (3 g, 8.8 mmol) and vinyl tributyltin (3.6 g, 11.4 mmol) in DMF (50 mL) was degassed with argon. PdCl2/(PPh3)2 (308 mg, 0.44 mmol) was added, the reaction vessel was sealed under argon and the reaction mixture was stirred at 90° C. for 16 h. The reaction mixture was cooled to RT and treated with aqueous KF (1.5 g in 20 mL water) for 2 h30. The mixture was diluted with water and EtOAc filtered on cellite. The organic layer was separated, washed with aq LiCl (×3), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (120 g silica gel, 0 to 20% EtOAc in hexane) to give methyl 2-chloro-3-nitro-5-vinylbenzoate as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=2 Hz, 1H), 7.83 (d, J=2 Hz, 1H), 6.69 (dd, J=17.4 Hz, 10.8 Hz, 1H), 5.89 (d, J=17.4 Hz, 1H), 5.52 (d, J=10.8 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:14]1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(O)cc1

Procedure:
A solution of 5.8 g of tert-butyl 3-{2-[2-(2-acetylaminoethyl)-5-fluorophenoxy]ethoxy}-4-(4-benzyloxyphenyl)piperidine-1-carboxylate in 200 ml of ethyl acetate is hydrogenated at room temperature in the presence of 2.03 g of 10% Pd/C over 15 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.29 (EtOAc); Rt=4.30.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:18]([N:20]([CH2:23][CH2:24]Cl)[CH2:21][CH3:22])[CH3:19]>>[ClH:16].[CH2:18]([N:20]([CH2:23][CH3:24])[CH:21]([C:14]1[C:13]([Cl:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH3:22])[CH3:19]
Reactant: CCN(CC)CCCl
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: Cl
Product: CCN(CC)C(C)c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12
Yield: 140.1 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-chloroindazole (4.57 g) and diethylaminoethyl chloride hydrochloride (5.16 g) were treated to obtain 5.1 g of 1-diethylaminoethyl-3-phenyl-5-chloroindazole hydrochloride (m.p. 185°-186° C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[OH:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]2[N:24]=[CH:25][NH:26][C:22]=2[CH:21]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]([NH:8][C:6]2[N:7]=[C:2]([N:26]3[C:22]4[CH:21]=[C:20]([CH2:19][OH:18])[CH:28]=[CH:27][C:23]=4[N:24]=[CH:25]3)[CH:3]=[N:4][CH:5]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CC(Nc1cncc(Cl)n1)c1ccc(F)cc1
Reactant: OCc1ccc2nc[nH]c2c1
Product: CC(Nc1cncc(-n2cnc3ccc(CO)cc32)n1)c1ccc(F)cc1
Yield: 8.1 %

Procedure:
In a procedure analogous to Example 3, reaction of 6-chloro-N-[1-(4-fluorophenyl)ethyl]pyrazin-2-amine (1.80 g, 7.15 mmol) and 5-hydroxymethyl benzimidazole (1.26 g, 8.5 mmol) furnished the two products which were separated by column chromatography using dichloromethane-methanol (98:2-92:8) as eluant. From the less polar fractions was obtained [1-(6-{[1-(4-fluorophenyl)ethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-yl]methanol as a pale yellow solid (210 mg).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([NH:38][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopentylamine (20 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with a 3:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 54 mg of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]3[NH:10][C:9](=[O:17])[C:8](=[O:18])[NH:7][C:6]=3[C:5]=2[CH2:4]1)[CH3:2].[N+:19]([O-])([O-:21])=[O:20].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH2:1]([N:3]1[CH2:16][CH2:15][C:14]2[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:11]3[NH:10][C:9](=[O:17])[C:8](=[O:18])[NH:7][C:6]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: CCN1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of 9-ethyl-1,4,7,8,9,10-hexahydro-pyrido[3,4-f]quinoxaline-2,3-dione (0.61 g, 2.16 mmol) in 20 mL of concentrated sulfuric acid was treated with a solution of potassium nitrate (0.25 g, 2.47 mmol) in 2 mL concentrated sulfuric acid. After stirring for 3 hours at room temperature, the reaction mixture was poured onto ice and cooled in an isopropyl alcohol/dry ice bath. Ammonium hydroxide was added to adjust the pH to 8.9, and the yellow solid was collected by filtration (0.59 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC.Cl.[CH3:31][NH:32][O:33][CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([N:32]([O:33][CH3:34])[CH3:31])=[O:10])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a stirred solution of 6-chloropyridazine-3-carboxylic acid (12.5 g, 0.078 mol) in CH2Cl2 (80 mL) at 0° C. were added triphosgene (11.6 g, 0.039 mol), Et3N (55 mL, 0.4 mol), and N,O-dimethylhydroxylamine hydrochloride (7.6 g, 0.078 mol). The reaction mixture was stirred at room temperature for 2 h. The salt was filtered, after removal of the solvent in vacuo, the residue was purified by column chromatography to afford 6-chloro-N-methoxy-N-methylpyridazine-3-carboxamide (13.5 g, 86%). 1H NMR (DMSO-d6, 400 MHz): δ 8.08 (d, J=9.2 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 3.33 (s, 3H), 8.06 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[Br:12]Br.[K+].[Br-]>O>[Br:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: BrBr
Reactant: O=C1Cc2cccc(F)c2N1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C1Cc2cc(Br)cc(F)c2N1
Reaction time: 0.33 h
Yield: 75 %

Procedure:
7-Fluoroindolin-2-one (800 mg, 5293 μmol) was taken up in 30 mL of boiling water. Br2 (273 μL, 5293 μmol) and KBr (1260 mg, 10586 μmol) were added dropwise in 5 mL of water over 10 minutes. A white precipitate began to form as the solution was added. The mixture was stirred for 20 minutes. The mixture was then chilled in an ice bath for 30 minutes, washed with 30 mL of a saturated NaHCO3 solution and extracted twice with 50 mL of EtOAc. The organic layers were concentrated and purified with silica gel column chromatography, eluting with 0-35% EtOAc/hexane to give 5-bromo-7-fluoroindolin-2-one (913 mg, 75% yield). MS m/z: 230 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 3.58 (s, 2H), 7.20 (dd, J=10.07, 0.88 Hz, 2H), 7.63 (s, 1H).
Reaction SMILES: COC1[C:4](C=O)=[CH:5][C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2C=1.[C:15]([O:18][C:19](=[O:21])[CH3:20])(=O)[CH3:16]>N1C=CC=CC=1>[C:19]([O:18][C:15]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1)(=[O:21])[CH3:20]
Reactant: COc1cc2c(cc1C=O)OCCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.5 %

Procedure:
To a solution of 6-methoxy-3,4-dihydrobenzopyran-7-carboxaldehyde (5.00 g, 28.1 mmol) in pyridine (15.0 mL) was added acetic anhydride (3.5 mL, 31.1 mmol) and the mixture allowed to stir at room temperature for 4 hours then poured into ice water (300 mL). The product which precipitated was collected by filtration, washed with water (75 mL) and air dried to afford 6-acetoxy-3,4-dihydrobenzopyran, (5.86 gm, 94.5%), m.p. 76°-77°.
Reaction SMILES: C(O)(C)C.FC(F)(F)C([NH:9][CH:10]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12])=O.[OH-].[K+]>C(O)C>[NH2:9][CH:10]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: CC(C)(O)C(NC(=O)C(F)(F)F)c1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: CC(C)(O)C(N)c1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
After 170 mL of isopropanol and 170 mL of ethanol were added to 36.0 g of the 1-(trifluoroacetylamino)-1-(2-naphthyl)-2-methyl-2-propanol obtained, 56 g of an aqueous solution of 22% by weight of potassium hydroxide was added dropwise thereto over 30 minutes at room temperature. Then, the inner temperature of the mixture was raised to 50° C. and at the same temperature, the mixture was stirred for 2 hours to effect reaction. The reaction mixture was concentrated, and 320 mL of chloroform and 160 mL of water were added to the resulting concentrated residue to carry out extraction treatment. The organic layer obtained was washed with 80 mL of water and the organic layer obtained was dried over dehydrated sodium sulfate and then concentrated. The resulting concentrated residue was dried at an inner temperature of 30° C. under reduced pressure to obtain 24.3 g of a brown solid of 1-amino-1-(2-naphthyl)-2-methyl-2-propanol (yield: 97%).
Reaction SMILES: C[O:2][C:3]1C=C(C=C[C:10]=1OCC1C=CC(OC)=CC=1)C=O.C[O-].[Na+].Cl.[NH:25]([CH:32]=[C:33]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[C:39]([O:53][CH3:54])[CH:38]=1)[C:34]#[N:35])[C:26]1C=CC=C[CH:27]=1>CS(C)=O.ClCCl.O>[CH3:54][O:53][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][C:40]=1[O:43][CH2:44][C:45]1[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=1)[CH2:36][C:33](=[CH:32][N:25]1[CH2:26][CH2:27][O:2][CH2:3][CH2:10]1)[C:34]#[N:35]
Reactant: COc1ccc(COc2ccc(CC(C#N)=CNc3ccccc3)cc2OC)cc1
Reactant: COc1ccc(COc2ccc(C=O)cc2OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COc2ccc(CC(C#N)=CN3CCOCC3)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Methoxy-4-[(4-methoxybenzyl)oxy]benzaldehyde (20.0 g, 73.4 mmol) and 3-morpholinopropronitrile (Lancaster, 11.0 g, 77.1 mmol) were stirred in DMSO (15 mL) at 65 C until the mixture was homogeneous. The solution was cooled to 40 C and sodium methoxide (0.79 g, 14.7 mmol) was added. The mixture was stirred at 75 C for 15 minutes, then cooled to room temperature and diluted with dichloromethane (150 mL) and water (200 mL). 1N HCl (25 mL) was added and the two layers were seperated. The organics were combined and dried (magnesium sulfate), filtered and concentrated to a red oil (29.5 g, 73 mmol) that was used directly in the synthesis of 3-anilino-2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}prop-2-enenitrile. 1H NMR (300 MHz, d6-DMSO): δ 7.38 (d, 2H), 7.03-6.95 (m,3H), 6.84 (t, J=13.5 Hz, 2H), 6.73 (d, J=8.2 Hz, 1H), 4.98 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.66-3.60 (m, 2H), 3.55-3.50 (m, 3H), 3.46-3.43 (m, 2H), 3.36 (s, 1H), 3.33-3.29 (m, 2H). MS (ES+, m/z)=395 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][NH2:10])=[O:8])=[CH:3][CH:2]=1.CN1CCCC1=O.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:7]([NH:9][NH:10][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:8])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NNC(=O)c1ccccc1)c1ccccc1

Procedure:
After 10 g (73 mmol) of benzohydrazine was put into a 300 mL three-neck flask, 25 mL of N-methyl-2-pyrrolidone was added thereto, and the mixture was stirred, a mixed solution of 10 mL of N-methyl-2-pyrrolidone and 10 mL (88 mmol) of benzoyl chloride was dripped into the mixture through a 50 mL dropping funnel. The mixture was stirred at 80° C. for 3 hours, and the contents of the flask were reacted together. After the reaction, the reaction solution was added to approximately 500 mL of water and the mixture was stirred, so that a solid was precipitated out. The precipitated solid was collected by suction filtration. The collected solid was washed with water, methanol was added to the obtained solid, and the mixture was washed, so that 10 g of a powdery white solid, which was the object of the synthesis, was obtained at a yield of 57%.
Reaction SMILES: C(O)(=O)CC[C:4](O)=[O:5].[NH2:9][C@H:10]([C@@H:18]([OH:36])[CH2:19][C@@H:20]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C([N+]([O-])=O)=CC=C(OC(OCC2SC=NC=2)=O)C=1.Cl.C(=O)(O)[O-].[Na+].[OH-].[Na+].Cl>CCCCCCC.C1COCC1.O.C(OCC)(=O)C>[C:32]([O:31][C:29]([NH:28][C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:19][C@@H:18]1[O:36][C:4](=[O:5])[NH:9][C@H:10]1[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:30])([CH3:33])([CH3:35])[CH3:34]
Reactant: O=C(O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2S,3S,5S)-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane succinate salt (30 g, 63 mmol; U.S. Pat. No. 5,654,466), ((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate hydrochloride (22.2 g; U.S. Pat. No. 5,597,926) and sodium bicarbonate (16.2 g) were mixed with 300 mL of water and 300 mL of ethyl acetate and the mixture was stirred at room temperature for about 30 minutes. The organic layer was then separated and heated at about 60° C. for 12 hours, and then stirred at 20-25° C. for 6 hours. 3 mL of ammonium hydroxide (29% ammonia in water) was added and the mixture stirred for 1.5 hours. The resulting mixture was washed with 4×200 mL of 10% aqueous potassium carbonate and the organic layer was separated and evaporated under vacuum to provide an oil. The oil was suspended in about 250 mL of heptane. The heptane was evaporated under vacuum to provide a yellow solid. The yellow solid was dissolved in 300 mL of THF and 25 mL of 10% aqueous sodium hydroxide was added. After stirring for about 3 hours, the mixture was adjusted to pH 7 by addition of 4N HCl (about 16 mL). The THF was evaporated under vacuum to leave an aqueous residue, to which was added 300 mL of distilled water. After stirring this mixture, a fine suspension of solids resulted. The solid was collected by filtration and the filtered solid was washed with water (1400 mL) in several portions, resulting in the desired product.
Reaction SMILES: C(O)(=O)C.[C:5]([C:8]1[CH:39]=[CH:38][C:11]([C:12]([NH:14][C:15](=[O:37])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:25]([O:27]C(C)(C)C)=[O:26])=[CH:19][CH:18]=2)=[O:13])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15](=[O:37])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:13])=[CH:38][CH:39]=1)(=[NH:6])[NH2:7]
Reactant: CCOCCC(Cc1ccc(NC(=O)NC(=O)c2ccc(C(=N)N)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCOCCC(Cc1ccc(NC(=O)NC(=O)c2ccc(C(=N)N)cc2)cc1)C(=O)O

Procedure:
In a similar manner to Example 3, t-butyl 3-(4-[3-(4-amidinobenzoyl)ureido]phenyl)-2-(2-ethoxyethyl)propionate, acetate salt (82 mg), and trifluoroacetic acid (5 ml) were reacted to give the title compound (64 mg) as an off-white solid: NMR Spectrum (DMSO-d6) 1.08 (3H, t), 1.70 (2H, m), 2.73 (3H, m), 3.35 (4H, m), 7.19 (2H, d), 7.48 (2H, d), 7.92 (2H, d), 8.18 (21H, d), 9.35 (4H, br s), 10.64 (1H, s), 11.25 (1H, br s), 12.05 (1H, br s); Mass Spectrum m/Z 427 (M+H)+ ; Elemental Analysis: calculated for C22H26N4O5. 1.4 CF3CO2H: C, 50.8%; H, 4.7%; N, 9.6%; found: C, 50.6%; H, 4.8%; N, 9.8%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](/[N:9]=[N:10]/[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]=O.[C:23]1(=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[CH2:24]1>>[Cl:1][C:2]1[N:3]=[C:4](/[N:9]=[N:10]/[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH:7]=[C:24]1[C:23](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:32]
Reactant: O=C1CC(=O)c2ccccc21
Reactant: CCN(CCO)c1ccc(/N=N/c2nc(Cl)c(C=O)s2)cc1
Product: CCN(CCO)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3.5 g (10.33 mmol) 4-chloro-2-((E)-{4-[ethyl(2-hydroxyethyl)amino]phenyl}-diazenyl)-1,3-thiazole-5-carbaldehyde and 2.33 g (15.50 mmol) 1H-indene-1,3(2H)-dione were dissolved in 90 ml ethanole and stirred under reflux. After 6 hours the mixture was allowed to cool to room temperature. The formed precipitate was filtered, washed with ethanol and dried in vacuum at 40° C. to obtain a dark powder.
Reaction SMILES: CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50][C:51]([CH3:68])([CH3:67])[C@H:52]([NH:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C:53](O)=[O:54].[NH4+].[Cl-]>CN(C=O)C>[CH3:67][C:51]1([CH3:68])[S:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[NH:43][C:53](=[O:54])[C@H:52]1[NH:56][C:57](=[O:58])[O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CC(C)(Sc1ccccc1N)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Sc2ccccc2NC(=O)[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
DIEA (4.14 g, 5.6 mL, 32.0 mmol, Eq: 2) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 12.5 g, 24.0 mmol, Eq: 1.5) were added to (R)-3-(2-aminophenylthio)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (6 g, 16.0 mmol, Eq: 1.00) in DMF (200 mL). The mixture was stirred at RT overnight then heated to 80° C. for 3 h. The mixture was poured onto sat. NH4Cl and extracted with EtOAc. The combined extracts were washed with H2O, concentrated and the residue was purified by silica gel chromatography to give (R)-benzyl 2,2-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-ylcarbamate (3 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[F:14])[CH:5]=[CH:4][C:3]=1[OH:15].C(N(C(C)C)CC)(C)C.CS(O[C@H:30]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:31]1=[O:43])(=O)=O.CO.ClCCl>C(#N)C.C(=O)(O)[O-].[Na+]>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][N:32]2[CH2:33][CH2:34][CH:30]([N:11]3[CH2:12][CH2:13][C@@H:8]([C:6]4[CH:5]=[CH:4][C:3]([OH:15])=[C:2]([F:1])[CH:7]=4)[C@H:9]([F:14])[CH2:10]3)[C:31]2=[O:43])=[CH:41][CH:40]=1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(Cl)cc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C1C(N2CC[C@@H](c3ccc(O)c(F)c3)[C@H](F)C2)CCN1Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 38 %

Procedure:
To a solution of 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (1.0 g, 4.7 mmol, from example 114, step E) in acetonitrile (25 mL) was added diisopropylethylamine (2.5 mL, 14 mmol) and it was heated to 60° C. for 30 min. To this preheated mixture was then added (S)-1-(4-chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (1.710 g, 5.63 mmol, from step C) in acetonitrile (15 mL). The reaction mixture was heated at 90° C. for 16 h. The reaction was diluted with sat. aqueous sodium bicarbonate and extracted with EtOAc. The organic layers were combined and concentrated to a black oil. The oil was purified using silica gel column chromatography (20-100% EtOAc/hexanes then 0-20% MeOH/dichloromethane) to afford 1-(4-chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (752 mg, 38% yield). Chiral HPLC analysis revealed that the final product was a (3:1) mixture of diasteromers, due to partial epimerization. The diastereomeric mixture (750 mg) was separated by preparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=35% methanol in CO2, 150 bar; temp=35° C.; flow rate=40 mL/min; injection volumn=0.75 mL (˜42 mg/mL in MeOH) stacked intervals; λ=220 nM; Peak 1=5.5 min, Peak 2=7.9 min) to afford the titled compound (482 mg) of Example 116 (the second peak to elute). Data for Example 116: LC-MS m/z 421 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.17-7.03 (m, 1H), 6.88 (s, 2H), 4.78-4.46 (m, 1H), 4.38 (d, J=11.5 Hz, 2H), 3.70-3.48 (m, 1H), 3.45-3.37 (m, 1H), 3.28-3.03 (m, 2H), 2.82-2.63 (m, 2H), 2.61-2.53 (m, 1H), 2.40-2.21 (m, 1H), 2.18-2.02 (m, 1H), 1.98-1.84 (m, 1H), 1.82-1.50 (m, 2H).