Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[N:6].[CH2:7](Cl)[C:8]1[CH:16]=[CH:15][C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=1>C(#N)C>[O:13]1[C:14]2[CH:15]=[CH:16][C:8]([CH2:7][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH2:6])=[CH:9][C:10]=2[O:11][CH2:12]1
Reactant: CNCCC#N
Reactant: ClCc1ccc2c(c1)OCO2
Solvent: CC#N
Product: CN(CCCN)Cc1ccc2c(c1)OCO2
Reaction time: 18 h

Procedure:
To N-methyl-β-alaninenitrile (50 g, mmol in acetonitrile was added piperonyl chloride (50 g, mmol). After stirring for 18 h, the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with aqueous carbonate, dried (MgSO4), and the solvent was removed in vacuo. The residue was dissolved in methanol saturated with ammonia (600 mL) and Raney nickel (10 g) was added. After shaking under an atmosphere of hydrogen at 20 psi for 6 h, the reaction was filtered through celite and the solvent was removed in vacuo to give 65 g of N-(1,3-benzodioxol-5-ylmethyl)-N-methyl-1,3-propanediamine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[CH3:22][C@@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1.CN1C(=O)CCC1>CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@H:23]2[CH3:22])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1ccc(F)cc1
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCOC[C@H]2C)nc(Cl)c1C(=O)NCc1ccc(F)cc1
Temperature: 180 °C
Yield: 19.3 %

Procedure:
A mixture of 6.0 g (19.2 mmol) 2,6-dichloro-N-(4-fluorobenzyl)-4-methyl-pyridine-3-carboxylic amide (synthesized according to the methods described in section a) of example 2), 3.9 g (28.7 mmol) (R)-3-methylmorpholine hydrochloride, 13.0 ml (76.6 mmol) and NMP (18.4 ml) was heated in the MW to 180° C. for 16 h. After cooling to RT the mixture was partiotionated between EtOAc and a 2M aq. NaOH sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 1.4 g (3.7 mmol, 20%) 2-chloro-N-(4-fluorobenzyl)-4-methyl-6-[(3R)-3-methylmorpholino]-pyridine-3-carboxylic amide.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.BrCCC=C>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:21][O:20][C:18]([C:13]1([CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: [Li]CCCC
Reactant: COC(=O)C1CCCC1
Agent: C=CCCBr
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCCC1(C(=O)OC)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (10.5 mL, 75 mmol) in tetrahydrofuran (100 mL) pre-cooled to −75° C. was added a 2.5 M solution of n-butyllithium in hexanes (30 mL, 75 mmol) dropwise. Following addition, the reaction mixture was warmed to 0° C. for 30 min and then re-cooled to −75° C. To the mixture was added a solution of methyl cyclopentane carboxylate (8 g, 62 mmol) in tetrahydrofuran (40 mL) dropwise. After stirring for 30 min, a solution of 4-bromo-1-butene (8.2 mL, 81 mmol) in HMPA (6 mL) was added dropwise. The cooling bath was removed to allow the mixture to warm to 20° C. After 1.5 h, the reaction mixture was poured into ice/H2O (200 mL). The two layers were separated and the aqueous layer was extracted with Et2O (100 mL). The organic solutions were combined and dried over K2CO3, filtered and concentrated to afford the 12.1 g of the title compound as an oil. LC/MS: RT=3.57 min. MS (ESI) m/z=183 (M+H+)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[NH:7][C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9])=[O:5].[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[N:7]1[CH2:12][CH2:11][O:10][C:8]1=[O:9])=[O:5]
Reactant: COCC(=O)N(NC(=O)OCCCl)c1c(C)cccc1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(=O)N(c1c(C)cccc1C)N1CCOC1=O
Reaction time: 0.5 h

Procedure:
11.8 g (0.0375 mol) 2-Chloroethyl 2-(methoxyacetyl)-2-(2,6-dimethylphenyl)-hydrazinecarboxylate are added portion-wise to a suspension of 2.0 g sodium hydride (in form of about 55% by weight in mineral oil) in 100 ml absolute toluene at room temperature under a blanket of nitrogen. The reaction temperature rises gradually during this addition up to 40°. After the addition is complete the mixture is stirred during 30 minutes without cooling and afterwards cooled to 10°. The unreacted sodium hydride is then destroyed with ethanol, the obtained solution washed with water dried with MgSO4 and the solvent removed in vacuo to give the end title compound which is recrystallised from ethanol to yield the title compound as colourless crystals. m.p. 103°-104°.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:15]=[CH:16][CH:17]=1.[N+]([O-])(O)=O.[OH-].[NH4+]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:15]=[CH:16][C:17]=1[N+:6]([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(Cn2ccnc2)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cn2ccnc2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To 184 parts of cold (10° C., ice bath) concentrated sulfuric acid were added portionwise 75 parts of 1-[(3-methoxyphenyl)methyl]-1H-imidazole mononitrate during 1 hour. Upon complete addition, stirring was continued for 30 minutes at 10° C. 15 Parts of concentrated nitric acid were added dropwise during 30 minutes at 15° C. Upon completion, the whole was stirred for 30 minutes at 10° C. The reaction mixture was poured into 1500 parts of crushed ice and the whole was treated with an ammonium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of ethyl acetate, methanol and methanol, saturated with ammonia, (95:2.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was stirred in 45 parts of ethyl acetate. The precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 28.2 parts (40.3%) of 1-[(3-methoxy-4-nitrophenyl)methyl]-1H-imidazole (int. 145).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O>O1CCCC1>[Br:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCc1sc(C(=O)OC)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (600 mg, 2.40 mmol) [prepared according to Example 98] in Tetrahydrofuran (THF) (10 ml) was added N-bromosuccinimide (512 mg, 2.88 mmol). The mixture stirred in a sealed tube at 70° C. for 2 h. The reaction mixture was then concentrated and purified with silica gel using a 0-5% gradient (ethyl acetate/hexane) to afford the title compound as an off-white solid: LC-MS (ES) m/z 330 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:19]=[C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=5)[CH3:27])[CH2:22][CH2:21]4)[CH:17]=[CH:16][C:12]=3[C:13](O)=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N+:41]([C:44]1[CH:45]=[C:46]([S:58]([NH2:61])(=[O:60])=[O:59])[CH:47]=[CH:48][C:49]=1[NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)([O-:43])=[O:42].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:26]([N:23]2[CH2:22][CH2:21][N:20]([C:18]3[CH:17]=[CH:16][C:12]([C:13]([NH:61][S:58]([C:46]4[CH:47]=[CH:48][C:49]([NH:50][CH2:51][CH:52]5[CH2:53][CH2:54][O:55][CH2:56][CH2:57]5)=[C:44]([N+:41]([O-:43])=[O:42])[CH:45]=4)(=[O:59])=[O:60])=[O:14])=[C:11]([O:10][C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[CH:2][NH:1]5)[CH:19]=3)[CH2:25][CH2:24]2)[CH3:27])=[CH:39][CH:38]=1
Reactant: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(c2ccc(C(=O)O)c(Oc3cccc4[nH]ccc34)c2)CC1
Reactant: NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCC4CCOCC4)c([N+](=O)[O-])c3)c(Oc3cccc4[nH]ccc34)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 175E (66 mg), 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide (75 mg) and 4-dimethylaminopyridine (58.4 mg) in dichloromethane (5 mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (45.8 mg). The mixture was stirred at ambient temperature overnight and concentrated. The concentrate was purified by RP HPLC (10-70% acetonitrile in 0.1% trifluoroacetic acid water/70 minutes). The desired fractions were concentrated to remove acetonitrile and the concentrate was diluted with dichloromethane and neutralized with aqueous NaHCO3. The dichloromethane layer was dried over Na2SO4 and concentrated to provide the title compound. 1H NMR (500 MHz, dimethysulfoxide-d6) δ ppm 11.31 (1H, s), 11.25 (1H, s), 8.62 (1H, t), 8.50 (1H, d), 7.68 (1H, dd), 7.53 (2H, d), 7.46 (2H, d), 7.37 (1H, t), 7.24-7.31 (4H, m), 7.17 (1H, d), 7.12 (1H, dd), 7.07 (1H, d), 6.96 (1H, t), 6.69 (1H, dd), 6.42 (1H, d), 6.26 (2H, s), 3.85 (2H, dd), 3.21-3.33 (5H, m), 3.01 (4H, s), 2.29-2.39 (2H, m), 2.15-2.22 (2H, m), 1.83-1.94 (1H, m), 1.57-1.68 (2H, m), 1.22-1.31 (2H, m), 1.17 (3H, d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.I[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu]I.O.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[CH:6]=[CH:5]2
Reactant: Sc1ccc2cc(Br)ccc2c1
Reactant: N#Cc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: OCCO
Product: N#Cc1ccccc1Sc1ccc2cc(Br)ccc2c1

Procedure:
A mixture of 6-bromo-2-naphthyl hydrosulfide (Step 2, 2.08 g, 8.7 mmol), 2-iodobenzonitrile (2 g, 8.56 mmol), copper(I) iodide (83 mg, 0.44 mmol) and potassium carbonate (2.4 g, 17.4 mmol) was degassed then isopropyl alcohol (10 mL) and ethylene glycol (0.97 mL, 17.4 mmol) added. The reaction was heated to 80° overnight. The cooled reaction mixture was poured into water and extracted with dichloromethane (x3). The combined organic layers were washed with ammonium chloride solution, water and brine, filtered, dried over MgSO4 and evaporated in vacuo to give 2-[(6-bromo-2-naphthyl)thio]benzonitrile (2.85 g, containing some 2,2′-dithiobis(6-bromonaphthalene)). 2.19 g of this was treated according to the method of Example 2 Step 4 to give 2-[(6-bromo-2-naphthyl)sulfonyl]benzonitrile (1.33 g, 56%). 1H NMR (500 MHz, CDCl3) δ 8.76 (1H, s), 8.41 (1H, d, J=8.0 Hz), 8.07 (1H, s), 7.94-7.79 (5H, m), 7.72-7.68 (2H, m); m/z (ES+) 372, 374 [MH+].
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:16])([CH3:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH:16][C:3]([CH3:2])([CH3:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1
Reactant: CC(C)(N)Cc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1ccc2ccccc2c1)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 140 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-1-(naphthalen-2-yl)propan-2-amine hydrochloride (5.9 g, 25.0 mmol), 3-chloro-4-fluoro-1-nitrobenzene (5.27 g, 30.0 mmol) and K2CO3 (6.9 g, 50.0 mmol) in DMSO (50 mL) was stirred at 140° C. overnight. The mixture was cooled to rt and poured into 150 mL of water. The mixture was then extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=10:1) to give the title compound as yellow foam (3.78 g, 43%).
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)#[N:3].[H-].[Na+].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=1>CN(C=O)C>[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][O:43][C:44]1[CH:45]=[CH:46][C:47]([CH:48]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:29][CH:28]=2)=[CH:50][CH:51]=1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5.51 g (13.29 mmol) of (4-cyanobenzyl)triphenylphosphonium chloride in 100 ml of dry DMF under positive nitrogen atmosphere is cooled to 0° C. and 0.50 g (20.77 mmol) of an 80% NaH in oil dispersion is added in small portions. The suspension is aged for 15 minutes at 0° C. followed by 45 minutes at room temperature to assure complete anion formation. The flask is cooled back to 0° C. and 3.5 g (13.29 mmol) of 4-(2-quinolinylmethyloxy)benzaldehyde in 20 ml of DMF is dropped in over a period of 15 minutes. The reaction is allowed to equilibrate at room temperature and stirred for 2 hours. The resultant mixture is poured into ice water and filtered. The precipitate is dissolved in CH2Cl2, dried, and concentrated in vacuo. The crude product is recrystallized from ether to give 4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile. (M.P. 116° C.-112° C.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:12][C:13]3[NH:17][CH:16]=[C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14]=3[CH3:23])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:35][O:34][C:32]1[CH:31]=[C:28]([CH:27]=[C:26]([O:25][CH3:24])[CH:33]=1)[CH2:29][O:21][C:20](=[O:22])[CH2:19][CH2:18][C:15]1[C:14]([CH3:23])=[C:13]([CH:12]=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[NH:17][CH:16]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(O)ccc21
Reactant: COc1cc(CCl)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COC(=O)CCc2c[nH]c(C=C3C(=O)Nc4cc(O)ccc43)c2C)cc(OC)c1
Yield: 28.1 %

Procedure:
3-[5-(6-Hydroxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid (100 mg), 56 mg 3,5-dimethoxy-benzylchloride and 207 mg potassium carbonate in 2 mL anhydrous dimethylformamide were heated at 90° C. overnight. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 39 mg of the title compound as a brown solid.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[C:15]([CH3:18])([O-])[CH3:16].[K+].[CH2:20](Cl)[CH:21]=[CH2:22].O>CCCCCC>[CH2:16]([C:12]1([CH2:22][CH:21]=[CH2:20])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:15]=[CH2:18]
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: C=CCCl
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: C=CCC1(CC=C)c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
There were put 10 g of fluorene manufactured by Wako Pure Chemical Industries, Ltd. and 10.1 g of potassium tert-butoxide manufactured by Aldrich Chemical Company in a 200 mL-round bottom flask, and 120 mL of dry N,N-dimethylformaide manufactured by Wako Pure Chemical Industries, Ltd. were added thereto. While stirring the resultant mixture in a nitrogen atmosphere at 50° C., 5.86 mL of allyl chloride manufactured by Kanto Chemical Co., Inc. were added dropwise thereto over 2 hours. The mixture was stirred at 50° C. for 8 hours. Additional 10.1 g of potassium tert-butoxide manufactured by Aldrich Chemical Company were added thereto, and then additional 5.86 mL of allyl chloride manufactured by Kanto Chemical Co., Inc. were added dropwise thereto over 2 hours. The mixture was stirred overnight at 50° C. The obtained reaction mixture was added to 900 mL of water, and then 300 mL of hexane were added thereto. The organic layer thereof was subjected to extraction with ether three times, and the extract was washed with water four times. The washed extract was further washed with diluted hydrochloric acid, and then with water in this order. The further washed extract was dried over anhydrous magnesium sulfate manufactured by Nacalai Tesque, Inc. The dried extract was subjected to removal of the solvent by distillation, and the resultant liquid was distilled in vacuo, thereby obtaining 12.8 g 9,9-diallylfluorene at 90° C. under 4 mmHg as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[O:25]=[C:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C:32](O)=[O:33]>>[ClH:16].[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:32](=[O:33])[CH2:31][N:27]2[CH2:28][CH2:29][CH2:30][C:26]2=[O:25])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: O=C(O)CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Product: Cl
Product: O=C(CN1CCCC1=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate and (2-oxopyrrolidin-1-yl)acetic acid, and by a method similar to that in Example 39, the title compound was obtained.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[NH2:18][OH:19].[OH-].[K+].CO>C1COCC1>[OH:19][NH:18][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: NO
Reactant: COC(=O)C=CC=CCSc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C=CC=CCSc1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a solution of the 6-(4-chlorophenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.44 g, 1.64 mmol) in distilled THF (9.0 mL) containing 50% aqueous hydroxylamine (1.0 ml, 15.2 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 2.6 mL, 2.6 mmol) over a period of 30 minutes. After stirring at 0° C. for 1 h, distilled water (9.0 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.21 g, 48%) as a pale brown powder, mp 120-122° C. (decomp).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[NH:14][N:13]=1>C1COCC1.CCOC(C)=O.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>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: Clc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]nc(Cc2ccc(Cl)cc2)c2ccccc12

Procedure:
A solution of (4-chlorobenzyl)zinc(II) chloride in THF was added to a suspension of 4-chlorophthalazin-1(2H)-one and Pd(PPh3)4 in THF, and subjected to microwave conditions at 180° C. for 20 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated to give crude 4-(4-chlorobenzyl)phthalazin-1(2H)-one. This material was treated with O-(diphenylphosphoryl)hydroxylamine similar to that described in Example 1B to give the title compound. LC/MS (APCI) M/Z 286 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH3:15])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Cl)c(C=O)c2ccccc21
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
A solution of 2-chloro-1H-indole-3-carboxaldehyde (1.0 g, 5.5 mmol) in DMF (30 mL) is treated portionwise over 10 min with 60% sodium hydride (440 mg, 11 mmol). After stirring for 30 min, methyl iodide (685 μL, 11 mmol) is slowly added and the resulting mixture is stirred 3 hr at room temperature. Water (5 mL) is cautiously added and the solvents are removed. The residue is dissolved in ethyl acetate and washed with water, with brine, dried, filtered and concentrated to give 2-chloro-1-methyl-1H-indole-3-carboxaldehyde (1.16 g, 105%), mp 94.5-95.5° C., as a white solid. MS 194 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[SH:14].Cl[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:18].ClC=C(C1C=CC=CC=1)C>CC(C)=O.CCOCC.O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:16]
Reactant: C=C(CCl)c1ccccc1
Reactant: Sc1ccccc1Cl
Agent: CC(=CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=C(CSc1ccccc1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Potassium carbonate (4.6 g, 0.033 mole) is suspended in acetone (100 cc) and the whole is heated to 50°-60° C. An acetone (30 cc) solution of 2-chlorothiophenol (4.3 g, 0.03 mole) and of a mixture (9.1 g, 0.03 mole) containing 1-chloro-2-phenyl-2-propene (50%) and 1-chloro-2-phenyl-1-propene (50%) is added dropwise under nitrogen. After 1 h of stirring at 50°-60° C. the reaction mixture is poured into water and ice (150 g) and is then reextracted with ether (3×100 cc). It is washed with water (2×150 cc) and dried over MgSO4. The crude (11.7 g) is distilled in a ball oven to give 1-[2'-chlorophenylthio]-2-phenyl-2-propene (6.3 g, 80%) Bp0.5 =180° C. nD24 =1.6340.