Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:21])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.[C:42]([NH:45][CH:46]([CH:61]([CH3:63])[CH3:62])[C:47]([CH:49]1[N:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[S:51][N:50]1C(O)=O)=[O:48])(=[O:44])[CH3:43].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([N:50]2[CH:49]([C:47](=[O:48])[CH:46]([NH:45][C:42](=[O:44])[CH3:43])[CH:61]([CH3:63])[CH3:62])[N:53]=[C:52]([C:54]([CH3:56])([CH3:55])[CH3:57])[S:51]2)=[O:21])[CH2:11][C:10](=[O:12])[O:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: CC(=O)NC(C(=O)C1N=C(C(C)(C)C)SN1C(=O)O)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)NC(C(=O)C1N=C(C(C)(C)C)SN1C(=O)NC1CC(=O)OC1OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of (2-benzyloxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (40) (0.385 g, 1.32 mmol) in DMF (2 ml) and CH2Cl2 (2 ml) was added DMBA (0.456 g, 2.92 mmol) and Pd(PPh3)4 (0.136 g, 0.12 mmol) and the solution was stirred at room temperature for 15 min. A solution of (39) in CH2Cl2 (4.5 ml) and DMF (0.5 ml) was added, followed by HOBT (0.168 g, 1.24 mmol) and EDC (0.256 g, 1.33 mmol). The reaction was stirred at room temperature for 18 hours under N2. The solvent was evaporated. The crude material was dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give a yellow solid. Purification by flash column chromatography gave the title compound (41) as a mixture of diastereomers (374 mg, 88% yield) 1H-NMR (500 MHz, CDCl3) δ 0.75-1.05 (m, 6H), 1.19-1.34 (m, 9H), 1.93-2.08 (m, 3H), 2.19-2.50 (m, 2H), 2.80-3.03 (m, 1H), 4.56-4.93 (m, 3H), 5.02-5.20 (m, 1H), 5.46-5.56 (m, 1H), 5.95-6.16 (m, 2H), 6.86-6.95 (m, 1H), 7.20-7.43 (m, 5H). Analytical HPLC (C18 column), (mixture of diastereomers) 8.58 min. LC-MS (ES+) m/e=519.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]1[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(Cl)c1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A stirred mixture of 20.0 g (0.12 mole) of 2-chloro-4-nitroaniline and 17.9 g (0.14 mole) of 2,5-dimethoxytetrahydrofuran in 30 ml of glacial acetic acid was heated at reflux for three hours. The mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether. The extract was washed with a saturated aqueous potassium carbonate solution then dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to leave a solid. The solid was purified by recrystallization from methylcyclohexane to yield 22.5 g of 1-(2-chloro-4-nitrophenyl)pyrrole (mp 54°-55° C.).
Reaction SMILES: N[C:2]1([NH:35][CH:36]([CH3:38])[CH3:37])[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]1[NH:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C.[Cl:46][CH2:47][C:48](Cl)=[O:49].O>C(Cl)(Cl)Cl>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:16][C:17]([C:19]2[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:2]([N:35]([C:48](=[O:49])[CH2:47][Cl:46])[CH:36]([CH3:38])[CH3:37])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)NC1(N)C=C(OCc2ccccc2)C=CC1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)CCl)c1cc(OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-4-benzyloxy-2-isopropylaminophenyl)amide (140 mg) and triethylamine (42 mg) in chloroform was added chloroacetyl chloride (48 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After addition of water to the reaction solution, it is extracted with chloroform. The extract was dried over sodium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 4′-trifluoromethylbiphenyl-2-carboxylic acid {4-benzyloxy-2-[(2-chloroacetyl)isopropylamino]phenyl}amide (140 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: ClCc1cccnc1
Agent: Cl
Product: Cc1c(C)c2c(c(C)c1OCc1cccnc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 76 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 3-chloromethylpyridine hydrochloride, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:7]=1.[CH3:17][NH2:18].C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:8]([NH:18][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: CN
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(c1ccccc1)c1cc(Br)ccc1O

Procedure:
(5-Bromo-2-hydroxy-phenyl)-phenyl-methanone (1.00 g, 3.536 mmol), 4 Å molecular sieves (1 g), and DCM are mixed then methylamine in THF (8.84 mL, 2M, 17.682 mmol) is added to followed by p-toluenesulfonic acid in acetic acid (0.474 mL, 12%, 0.354 mmol). Sodium triacetoxyborohydride (4.20 g, 19.80 mmol) is added in three separate portions. The mixture is quenched with saturated Na2CO3 solution and extracted with EtOAc. The organic phase is dried over Na2SO4 and the solvent removed on a rotary evaporator. This provides the desired compound which is used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].Cl.[C:4]([C:8]([C:11]([O:14][CH:15]([C:17]([O:20][CH2:21][C:22]([C:25]([OH:27])=[O:26])([F:24])[F:23])([F:19])[F:18])[F:16])([F:13])[F:12])([F:10])[F:9])([F:7])([F:6])[F:5].[NH3:28]>>[C:4]([C:8]([C:11]([O:14][CH:15]([C:17]([O:20][CH2:21][C:22]([C:25]([O-:27])=[O:26])([F:24])[F:23])([F:19])[F:18])[F:16])([F:13])[F:12])([F:10])[F:9])([F:7])([F:6])[F:5].[NH4+:28]
Reactant: N
Reactant: O=C(O)C(F)(F)COC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C(F)(F)COC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F
Product: [NH4+]

Procedure:
The HOCH2CF2COOEt (30 g) obtained by the method described in Synthesis Example 1, tert-BuOK (1.5 g), tert-BuOH (10 g) and a stirrer bar were placed in a 300-ml four-necked flask equipped with a dropping funnel, cold finger and thermometer. After several repetitions of replacement of the flask inside atmosphere with nitrogen, CF3CF2CF2OCF═CF2 (51.8 g) was added dropwise at 20-25° C. over 5 hours while the flask contents were stirred with the magnetic stirrer. Then, after overnight stirring, the flask contents were washed with several portions of a 10% (by weight) aqueous solution of HCl and several portions of a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate and filtered, and the filtrate was distilled under reduced pressure to give 62.1 g of a mixture of CF3CF2CF2OCHFCF2OCH2CF2COOEt and CF3CF2CF2OCHFCF2OCH2CF2COOH. The structures of these compounds were identified by 1H-NMR, 19F-NMR and 13C-NMR. This mixture was subjected to hydrolysis with a 6 N aqueous solution of sodium hydroxide, the hydrolysis product was lyophilized and then neutralized with 12 N hydrochloric acid, and the thus-obtained CF3CF2CF2OCHFCF2OCH2CF2COOH was neutralized with aqueous ammonia and the neutralization product was lyophilized to give 47.3 g of CF3CF2CF2OCHFCF2OCH2CF2COONH4.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:23])[C:18](=[N:21][CH3:22])SC)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.CCO.O.[NH2:30][NH2:31].[Cl-:32]>>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:23])[C:18]([NH:30][NH2:31])=[N:21][CH3:22])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32]
Reactant: [Cl-]
Reactant: NN
Reactant: CN=C(SC)N(C)C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: I
Solvent: O
Solvent: CCO
Product: CN=C(NN)N(C)C1CCC(NC(=O)OCc2ccccc2)CC1
Product: Cl

Procedure:
0.84 g of [4-(1,2,3-trimethyl-isothioureido)-cyclohexyl]carbamic acid benzylester in the form of a hydroiodide are stirred with 10 ml of of a strong basic ion exchanger in chloride form. A suspension obtained is filtered and the filtrate obtained is lyophilized. The lyophilisate is treated with 15 ml of EtOH and with 0.08 ml of hydrazine monohydrate. The mixture obtained is refluxed for 2.5 hours and from the mixture obtained solvent is evaporated. [4-(3-Amino-1,2-dimethyl-guanidino)-cyclohexyl]-carbamic acid benzylester in the form of a hydrochloride is obtained.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:9]2[C@H:10]3[C@H:11]([CH2:20][CH2:21][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH2:19]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 74.5 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (100.03 g, 0.28001 mol) and potassium t-butoxide (31.42 g, 0.2800 mol) in anh. dimethylsulfoxide (DMSO, 320 mL) under argon was stirred in an oil bath (68-81° C.) 1 h, after which estrone (15.14 g, 55.99 mmol) in anh. DMSO (320 mL) was added via syringe. See FIG. 17. Stirring was continued 1 h and the reaction allowed to cool. The mixture was poured into 800 mL of ice-1N hydrochloric acid and then extracted three times with 400 mL aliquots of ether. The combined organic extracts were washed with 350 mL of saturated sodium bicarbonate+400 mL of brine, dried over sodium sulfate, and flash filtered through a 58mm high×84 mm dia. column of silica gel (200-40 mesh). Product continued eluting with additional ether. Concentration of appropriate fractions under reduced pressure and three-fold recrystallization from aqueous ethanol gave very fine white needles (11.47 g, 42.73 mmol, 76%), m.p. 134-136° C., homogeneous to TLC (20% ethyl acetate/hexanes on silica gel, Rf 0.45). (NA-1994A-242B)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[N:3]=[C:2]2[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1nc(N2CCNCC2)c2cc(F)ccc2n1
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirring solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (500 mg, 1.82 mmol) in CH2Cl2 (20 mL) at 0° C., under an N2 atmosphere was rapidly added a solution of piperazine (0.263 g, 7.28 mmol) and triethylamine (0.35 mL, 2.55 mmol) in CH2Cl2. The mixture was stirred for 1 h and then quenched with H2O, extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-5% MeOH in CH2Cl2 gave 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (400 mg, 68%). LC/MS: m/z 325.5 (M+H)+ at 2.12 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (m, 1H), 7.97 (m, 1H), 7.78 (m, 2H), 7.39 (m, 1H), 6.95 (m, 2H), 3.83 (t, J=4.9 Hz, 4H), 2.92 (t, J=4.9 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+:22]>O>[OH2:16].[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O-:20])=[O:19].[Na+:22]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 3.5 g. (0.0125 mole) of 2-amino-3-(p-chlorobenzoyl)phenylacetic acid in a water solution containing 0.5 g. of sodium hydroxide (0.125 mole) was refluxed 45 minutes, cooled and filtered. The filtrate was concentrated to an oily consistency and poured into a large volume of acetone. A yellow precipitate separated which was collected and identified by nuclear magnetic resonance spectrum as the desired product. The product (2.6 g.) (67%) melted at 265° C. (dec.) after crystallization from ethanol-ethyl ether.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:48]([C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[N:52][CH:51]=1)=[CH2:49]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH:49]=[CH:48][C:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH:53]=[N:52][CH:51]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: C=Cc1cncc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4cncc5ccccc45)cc3CC[C@@H]12
Reaction time: 20 h

Procedure:
A 508 mg portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, 4 mg of palladium acetate, 20 mg of tri-o-tolylphosphine, 0.34 mL of triethylamine and 5 mL of dimethylformamide were combined in a sealable tube with a stir bar, and the mixture was warmed to 50° under argon. An 0.26 g portion of 4-ethenylisoquinoline was added. Then the vessel was blanketed with argon and sealed and the mixture was heated with stirring at 120° for 20 hours. It was then cooled, and concentrated under vacuum and the residue was purified by chromatography on silica gel, eluting with 5% isopropanol in chloroform. An 0.29 g portion of an oil was obtained, which was recrystallized from ethyl acetate/hexane to obtain the desired product in crystalline form. mp 183°-185°; FDMS 382 M+.
Reaction SMILES: [CH:1]1([C:7]2[S:8][C:9]3[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([O:18]C)[C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Ce+4].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[CH:1]1([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH:14]=[CH:13][C:12](=[O:18])[C:10]=3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(OC)c2sc(C3CCCCC3)nc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1C=CC(=O)c2sc(C3CCCCC3)nc21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
1 g (3.61 mmol) of 2-cyclohexyl-4,7-dimethoxy-1,3-benzothiazole is put into suspension in an acetonitrile/water mixture (3/1) at 0° C. then 4.36 g (7.96 mmol; 2.2 eq.) of cerium (IV) and ammonium nitrate are added to the suspension. The reaction mixture is maintained for 1.5 hours under stirring at ambient temperature, then 0.78 g (yield=88%) of 2-cyclohexyl-1,3-benzothiazole-4,7-dione is obtained after filtration, washing with cold water and drying under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=1)[C:2]1C=CC=C[CH:3]=1.[H][H].C([OH:25])C>[Pd]>[CH2:19]([NH:18][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C@@H:2]2[CH2:3][O:25]2)=[CH:10][CH:11]=1)=[O:17])[CH3:20]
Reactant: CCNC(=O)Nc1ccc(OCc2ccccc2)cc1
Reactant: CCO
Reactant: [H][H]
Agent: [Pd]
Product: CCNC(=O)Nc1ccc(OC[C@@H]2CO2)cc1

Procedure:
N-[4-(Benzyloxy)phenyl]-N′-ethylurea (6.3 g, 23.30 mmol) was dissolved in ethanol (150 mL). 10% Palladium on carbon (0.6 g) was added and the mixture shaken overnight under 50 psi hydrogen on a Parr apparatus. The solution was filtered through a Celite pad, the residue washed with ethanol and the solvent removed in vacuo to yield the title compound (3.84 g, 21.2 mmol).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH2:22][C:23](N(OC)C)=[O:24])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([CH3:13])=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H](N(CC(=O)C(C)=C)C(=O)OC(C)(C)C)C=C)([C:32](C)([CH3:34])[CH3:33])(C)C.C([Mg]Br)=CC(=C)C>>[Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH2:22][C:23](=[O:24])[C:32]([CH3:34])=[CH2:33])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C:11]([CH3:13])=[CH2:12])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C)C(=O)OC(C)(C)C
Agent: C=C(C)C=C[Mg]Br
Product: C=C(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C(=C)C
Yield: 92 %

Procedure:
The title compound was prepared from (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-methylbut-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 188, 4.24 g, 10.18 mmol) following the procedure described for Intermediate 6 substituting the relevant isoprenyl magnesium bromide (0.5 M in THF) (204 mL, 101.77 mmol). Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product as a light yellow oil (3.72 g, 92%).
Reaction SMILES: C1(C[CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:35](O)=[O:36])[CH:32]=3)[CH2:27]2)=[O:25])=[CH:19][CH:18]=1)=[O:16])[CH2:12][CH3:13].C1C2C(=CC=CC=2)CN1[C:47](NC1C=CC(C(O)=O)=CC=1)=[O:48]>>[CH3:47][O:48][CH2:8][CH2:9][NH:10][C:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([NH:14][CH2:11][CH2:12][CH3:13])=[O:16])=[CH:18][CH:19]=1)=[O:25])[CH2:34]2)=[O:36]
Reactant: NCCCc1ccccc1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(=O)NCCOC)cc3C2)cc1

Procedure:
The title compound was prepared as described in Example 1C, substituting 2-methoxyethanamine for 3-phenylpropan-1-amine and 2-{[4-(propylcarbamoyl)phenyl]carbamoyl}isoindoline-5-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.26 (t, J=5.7 Hz, 1H), 7.79-7.85 (m, 2H), 7.73-7.80 (m, 2H), 7.63-7.67 (m, 2H), 7.45 (d, J=7.8 Hz, 1H), 4.81-4.83 (bs, 4H), 3.39-3.51 (m, 4H), 3.27 (s, 3H), 3.03-3.22 (m, 2H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:52]([O:56][C:57]([NH:59][CH2:60][C:61](O)=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][N:27]([C:61](=[O:62])[CH2:60][NH:59][C:57](=[O:58])[O:56][C:52]([CH3:53])([CH3:54])[CH3:55])[CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCNCC3)ns2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 74 %

Procedure:
A solution of N-1,2-benzisoxazol-3-yl-4-(3-piperazin-1-yl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide (100 mg, 0.241 mmol), 1-hydroxybenzotriazole (32.5 mg, 0.241 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92.5 mg, 0.482 mmol) and N-(tert-butoxycarbonyl)glycine (42.3 mg, 0.241 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured to water, and a solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to give 102 mg (73.9%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)Cl>[C:1]([NH:5][C:15](=[O:16])[CH2:14][Cl:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a cooled (0° C.) solution of tert-butyl amine (5.25 mL, 50 mmol) in DCM (40 mL) was added triethylamine (14 mL, 101 mmol) followed by chloro acetylchloride (3.98 mL, 50.3 mmol). The reaction was warmed to RT and stirred for 2 h. The reaction mixture was concentrated, redissolved in EtOAc (20 mL) and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 5.39 g of crude product which was further purified by flash column chromatography using 7:3 Pet. Ether: EtOAc as the eluant. Pure N-tert-butyl-2-chloroacetamide (3.65 g) was isolated.