Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1c(Cl)cccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1c(Cl)cccc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 3-chloro-N1-phenylbenzene-1,2-diamine (1.72 g, 7.87 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.64 g, 8.65 mmol), HOAt (1.18 g, 8.65 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.66 g, 8.65 mmol) in DCM (40 mL) cooled to 0° C. under a nitrogen atmosphere was added Et3N (3.3 mL, 0.0236 mol). The reaction mixture was stirred at 0° C. for 5 min, then slowly warmed to RT and stirring was continued for 16 h. The resulting mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) affording [(S)-1-(2-Chloro-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an off-white solid (1.60 g, 52% over three steps). LCMS: RT 3.75 min [M+H]+ 390.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:21][C:22]([C@@H:24]1[CH2:28][O:27]C(C)(C)[O:25]1)=O.O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([C@@H:24]([OH:25])[CH2:28][OH:27])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Reactant: CC1(C)OC[C@@H](C(=O)CCl)O1
Solvent: O
Solvent: CCO
Product: OC[C@H](O)c1csc(Nc2ncc(Br)cc2Oc2ccc(F)cc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
To 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (0.5 g, 1.5 mmol) in ethanol (50 mL) was added (S)-2-chloro-1-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanone (0.34 g, 1.9 mmol) and the reaction stirred at 80° C. for 1 hr. The reaction was poured into water (250 mL) and then filtered. The solid was triturated with ethyl acetate and methanol. The solid was suspended in ethyl acetate (500 mL) and washed with 1 N NaOH (500 mL). The organics were concentrated and the crude material was purified by chromatography using 3 to 10% MeOH/CH2Cl2 as eluent to give (R)-1-(2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)ethane-1,2-diol (0.043 g, 0.10 mmol, 7%) (ABCI POS 426, 428 M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6]1)=[O:4].[CH3:19]I.[H-].[Na+].Cl>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:19])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
16.2 g (62.95 mmol) of trans-4-tert-butoxy carbonylamino-cyclohexanecarboxylic acid methyl ester and 5.87 mL (94.43 mmol, 1.5 eq) of methyl iodide in 100 ml DMF were treated under stirring and ice-cooling with 3.57 g (81.84 mmol, 1.3 eq) of NaH (55% in oil). The solution was stirred at RT for 20 h and then treated under ice-cooling with 1M HCl. The reaction mixture was dissolved in ether and washed 4 times with water. The ether-phases were concentrated under reduced pressure to yield 17.5 g (quantitative) of trans-4-(tert-butoxycarbonyl-methyl-amino)-cyclohexanecarboxylic acid methyl ester, MS: 201 (M−OC4H9).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][C:15]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:13]=3)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>O1CCCC1>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][CH:13]=4)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2[nH]c3ccc(C(=O)CCCCl)cc3c2c1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCN1CCCCC1)c1ccc2[nH]c3ccc(C(=O)CCCN4CCCCC4)cc3c2c1

Procedure:
A solution of 15.0 g (0.04 mole) of 3,6-bis(4-chlorobutyryl)carbazole, 85.0 g (1.0 mole) of piperidine and 2.0 g of potassium iodide in 15 ml of tetrahydrofuran was heated at 110°C in a reaction bomb for 24 hours with stirring. Upon cooling the reaction mixture was filtered and diluted with 700 ml of ice water. The resulting solid was washed with water, dried over magnesium sulfate and recrystallized from chloroformpetroleum ether (75°-90°C) and then from acetone to give the desired product. M.P. 171°-173°C, λmaxEtOH 259, E1cm1% 894.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OCC)C.O1CCCC1>[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:23])[CH2:3][CH:2]=[CH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CCCCCCCCCCOc1ccccc1
Reactant: C=CC[Mg]Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)CCCCCCCCCOc1ccccc1
Temperature: 0 °C
Yield: 42 %

Procedure:
To 85 ml of a 1M solution of allyl magnesium bromide in diethyl ether cooled in ice bath was added dropwise, under nitrogen, a solution of 20 g of 10-phenoxydecanal in 200 ml of dry tetrahydrofuran. The mixture was poured into 400 ml of ice and 30 ml of 9M sulfuric acid was added. Upon standing the mixture formed aqueous and organic layers. The organic layer was stirred for 15 min with solid sodium bicarbonate and concentrated. The aqueous layer was extracted with diethyl ether (2×200 ml) and the extracts were combined with the concentrated organic layer. The combined organics were washed with 300 ml of water and 300 ml of a half-saturated aqueous solution of sodium chloride, filtered, and concentrated. The residue was flash chromatographed utilizing as successive eluents 5% diethyl ether/hexane, 10% diethyl ether/hexane, and 25% diethyl ether/hexane to give 18.51 g (42%) of 13-phenoxy-1-tridecen-4-ol as a solid, m.p. 50°-52°.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH:39]2[CH2:42][CH2:41][CH2:40]2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O.[NH4+].[Cl-]>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH:39]3[CH2:40][CH2:41][CH2:42]3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1(C2CCC2)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C2CCC2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.5 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 1.13 mL, 2.82 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (437 μL, 2.82 mmol) in THF (5 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 3-cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 283 mg, 0.94 mmol) in THF (3 mL) was added and stirred for 30 min at 100° C. in a sealed vial. Saturated aqueous NH4Cl solution (10 mL) was added, extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (40 mL), brine (40 mL), dried (Na2SO4) and evaporated. The reaction mixture was then purified by automated flash chromatography (SiO2, 20→70% EtOAc/hexanes). Selected fractions were combined and concentrated under reduced pressure. The obtained product was further purified twice by preparative HPLC (5→90% gradient of MeCN—H2O with 0.1% TFA) to obtain the desired product 3-cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (7 mg, 1.5% yield). LC-MS: Rt (retention time): 3.17 min, MS: (ES) m/z 499.1 (M+H+). 1H NMR (400 MHz, CDCl3) δ8.08 (s, 3H), 7.63 (s, 1H), 7.12-7.16 (m, 1H), 7.04-7.09 (m, 2H), 4.18 (d, 1H, J=8.5 Hz), 3.58 (d, 1H, J=8.5 Hz), 3.18 (d, 1H, J=17 Hz), 2.8 (d, 1H, J=17 Hz), 2.2 (s, 3H), 2.17 (s, 3H), 1.85-2.0 (m, 2H), 0.68-0.8 (m, 1H), 0.5-0.62 (m, 2H), 0.15-0.2 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[O:18][CH2:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][CH3:28])[CH:22]=1)[CH2:2][CH2:3][CH3:4].[CH2:29]([N:37]=[C:38]=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[O:18][CH2:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:28])[C:38]([NH:37][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\OCC)C(=O)OC)ccc1-c1cccc(NC)c1
Reactant: O=C=NCCc1ccccc1
Product: CCCCOc1cc(/C=C(\OCC)C(=O)OC)ccc1-c1cccc(N(C)C(=O)NCCc2ccccc2)c1
Yield: 75.4 %

Procedure:
40 mg (0.1 mmol) of methyl (Z)-3-(2-butoxy-3′-methylaminobiphenyl-4-yl)-2-ethoxyacrylate and 16 mg (0.11 mmol) phenethyl isocyanate are heated at 85° C. by microwave in an Emrys Optimizer machine for 20 minutes. The residue obtained is purified by chromatography on a column of silica eluted with a 95/5 and then 90/10 heptane/ethyl acetate mixture. 40 mg (72%) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]-2-ethoxyacrylate are obtained.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24][CH3:25])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].[H-].[Na+].I[CH2:29][CH3:30]>O1CCCC1>[CH2:29]([O:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24][CH3:25])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH3:30]
Reactant: CCI
Reactant: COc1ccc(OC)c2c(OC)c(C(O)CCC(C)C)cc(OC)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(CCC(C)C)c1cc(OC)c2c(OC)ccc(OC)c2c1OC
Temperature: 0 °C
Yield: 84.9 %

Procedure:
850 mg (2.44 mmole) of 2-(1-hydroxy-4-methylpentyl)-1,4,5,8-tetramethoxynaphthalene and 510 mg (12.2 mmole) of sodium hydride (55% dispersion in oil) were dissolved in 10 ml of dry tetrahydrofuran and 1.9 g (12.2 mmole) of iodo-ethane was added thereto under nitrogen gas and then the mixture was refluxed for 3 hours. After adding 20 ml of ice water, the reaction mixture was extracted twice with dichloromethane, dried over anhydrous magnesium sulfate and filtered through a filter paper. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel 2.5×15 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 10:1 to 1:1, to obtain 780 mg of the title compound as a pale yellow oil.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][C:20]=2[O:19][CH2:18]1>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:8]([N:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:24]2[CH:23]=[CH:22][C:21]3[O:17][CH2:18][O:19][C:20]=3[CH:25]=2)[CH2:28][CH2:29]1)=[O:16]
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: O=C(Nc1ccccn1)Oc1ccccc1
Product: O=C(Nc1ccccn1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
The title compound was prepared from pyridin-2-yl-carbamic acid phenyl ester and 1-benzo[1,3]dioxol-5-ylmethyl-piperazine. NMR (400 MHz, CDCl3): 8.18 (d, J=3.9 Hz, 1H), 7.67-7.64 (m, 1H), 6.66-6.64 (m, 2H), 6.54-6.51 (m, 3H), 5.94 (s, 2H), 3.80 (s, 2H), 3.53 (t, J=4.9 Hz, 4H), 2.36 (t, J=4.8 Hz, 4H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:28][C:29](O)=[O:30])[CH:21]=[CH:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:28][C:29]([NH:15][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:14])=[O:30])[CH:21]=[CH:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Reactant: CC(N)c1ccccc1N1CCCCC1
Product: COC(=O)c1ccc(CC(=O)NC(C)c2ccccc2N2CCCCC2)cc1OC

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-ethylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:15]=[CH:16][S:17][CH:18]=3)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][CH:3]=[C:2]3[Cl:1])([C:14]2[N:15]=[CH:16][S:17][CH:18]=2)[OH:13])=[CH:22][CH:21]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C(c1ccc2nccc(Cl)c2c1)c1cscn1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc2nccc(Cl)c2c1)c1cscn1
Reaction time: 2 h

Procedure:
To a solution of (4-chloroquinolin-6-yl)(thiazol-4-yl)methanone (52 mg, 0.189 mmol) in THF (2 mL) was slowly added (4-chlorophenyl)magnesium bromide (0.246 mL, 0.246 mmol, 1M in THF) and the resulting solution was kept at 0° C. for 2 hr. The reaction was quenched with saturated NH4Cl at 0° C. and the aqueous mixture was extracted with EtOAc twice. The combined organics were concentrated and purified by silica column (40% EtOAc/hexanes) chromatography to yield (4-chlorophenyl)(4-chloroquinolin-6-yl)(thiazol-4-yl)methanol. (ES, m/z) [M+H]+ 387, 389.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][C:9]([C:16]([OH:18])=[O:17])=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([OH:22])=[O:21].C(=O)(O)[O-].[K+:27]>O>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][C:9]([C:16]([O-:18])=[O:17])=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([O-:22])=[O:21].[K+:27].[K+:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccc(C(=O)O)cc1C2=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: O=C([O-])c1ccc2c(c1)C(=O)c1ccc(C(=O)[O-])cc1C2=O

Procedure:
Anthraquinone-2,6-dicarboxylic acid (1.00g) was dissolved in the minimum quantity of water (20 ml) containing one equivalent of potassium bicarbonate (0.68g) at the boil. The solution was filtered whilst hot and allowed to crystallise. The product which separated was filtered off, dried at 100°C, and analysed for the dihydrate. Analysis: Required Carbon 47.06, Hydrogen 2.47%; Found Carbon 47.09, Hydrogen 2.48%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:30]2[NH:31][CH:32]=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:35])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Br)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.8 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (79 mg, 61%).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[N+:13]([O-:15])=[O:14])[CH:4]1[OH:24].CO.C([BH3-])#N.[Li+].[CH3:31][C:32]([CH3:34])=O>O>[ClH:1].[CH2:17]([O:16][C:8]1[C:9]([N+:13]([O-:15])=[O:14])=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]([OH:24])[CH:3]([NH:2][CH:32]([CH3:34])[CH3:31])[CH2:12][CH2:11]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)=O
Reactant: NC1CCc2c(ccc(OCc3ccccc3)c2[N+](=O)[O-])C1O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CC(C)NC1CCc2c(ccc(OCc3ccccc3)c2[N+](=O)[O-])C1O

Procedure:
To a solution of 5.0 g. of 2-amino-6-benzyloxy-1-hydroxy-5-nitro-1,2,3,4-tetrahydronaphthalene hydrochloride in 50 ml. of methanol are added 5.0 g. of lithium cyanoborohydride and 150 ml. of acetone, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is added in water and the resulting crystals are recovered by filtration, rinsed with water, dried and dissolved in alcoholic hydrochloric acid. After treatment with activated carbon, ethyl ether is added, whereupon 4.7 g. of 6-benzyloxy-2-isopropylamino-5-nitro-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride is obtained as colorless needles melting at 268°-270° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cc1F
Temperature: 55 °C
Yield: 102.4 %

Procedure:
To an oven dried round bottom flask with stir bar was added 4-bromo-2-fluorobenzaldehyde (5 g, 24.6 mmol), (R)-2-methylpropane-2-sulfinamide (3.28 g, 27.1 mmol) and DCE (49 mL). To this mixture was then added copper (II) sulfate (5.90 g, 36.9 mmol). Reaction mixture was heated in a preheated oil bath to 55° C. for 18 hours. Reaction mixture was filtered through a pad celite, washing the solids with CH2Cl2. The filtrate was concentrated to afford a viscous yellow oil of (R,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.73 g, 25.2 mmol, 103% yield). 1H NMR (400 MHz, CDCL3) δ 1.27 (s, 9H) 7.31-7.42 (m, 2H) 7.87 (t, J=7.87 Hz, 1H) 8.83 (s, 1H). LCMS m/z 307.9 (M+H)+, Rt 1.01 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].N1C=CN=C1.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1>CO.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[C:21]1[CH2:20][C:19](=[O:25])[CH2:24][CH2:23][CH:22]=1
Reactant: O=C1C=CCCC1
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C(O)C2=CCCC(=O)C2)c(Cl)n1
Yield: 87 %

Procedure:
The clear solution of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 87% yield (2.56 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[C:69]([C:70]2[CH:75]=[CH:74][C:73]([NH2:76])=[CH:72][CH:71]=2)=[N:68][N:67]=[N:66]1>C(Cl)Cl>[NH:68]1[C:69]([C:70]2[CH:75]=[CH:74][C:73]([NH:76][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]3)=[O:30])=[CH:72][CH:71]=2)=[N:65][N:66]=[N:67]1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 130 mg, 0.344 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-(1H-tetrazol-5-yl)-phenylamine (Alfa, 55 mg, 0.344 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (24 g column, eluent, 30% EtOAc/methylene chloride) to give a yellow solid. 21 mg.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]12[O:11][CH:10]1[CH2:9][O:8][CH2:7][CH2:6]2.[Cl-].[NH4+]>CO.O>[N:1]([C@@H:5]1[CH2:6][CH2:7][O:8][CH2:9][C@H:10]1[OH:11])=[N+:2]=[N-:3]
Reactant: C1CC2OC2CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@@H]1CCOC[C@H]1O
Temperature: 65 °C
Yield: 40.6 %

Procedure:
Sodium azide (50.4 g, 775 mmol) is added to a stirring solution of 4,7-dioxabicyclo[4.1.0]heptane (9.7 g, 96.9 mmol) and ammonium chloride (23.0 g, 426 mmol) in methanol (484 mL) and water (97 mL), and heated to 65° C. under nitrogen for 18 h. The mixture is cooled to room temperature and water (200 mL) is added. The methanol is removed in vacuo and the remaining aqueous layer is extracted with EtOAc (3×). The organic portions are combined, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound as a tan oil (5.63 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ 5.40-5.33 (m, 1H), 3.78-3.74 (m, 2H), 3.40-3.32 (m, 3H), 2.97-2.90 (m, 1H), 1.82-1.77 (m, 1H), 1.46-1.41 (m, 1H).
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][S:5]1)#[N:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13]Cl>>[C:1]([N:3]=[C:4]1[N:8]([CH2:13][C:12]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:10]([Cl:9])[CH:11]=2)[CH2:7][CH2:6][S:5]1)#[N:2]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#CN=C1NCCS1
Product: N#CN=C1SCCN1Cc1ccc(Cl)c(Cl)c1
Yield: 79.2 %

Procedure:
3.82 g (30 mmoles) of 2-cyanimino-thiazolidine are reacted with 6 g (31 mmoles) of 3,4-dichlorobenzyl chloride as described in the previous Example, and the evaporation residue is recrystallized from 50 ml of ethanol to yield 6.8 g of 2-cyanimino-3-(3,4-dichlorobenzyl)-thiazolidine, melting at 130° to 132° C.