Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26]3[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=3[CH2:24][O:23][C:22]=2[CH:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[C:27](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26]5[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=5[CH2:24][O:23][C:22]=4[CH:38]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(CCl)ccc21
Reactant: CCCc1nc2c(C)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)OCc1ccccc1C2=CC(=O)OCC
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
4-Methyl-2-propyl-1H-benzimidazole (464 mg) was dissolved in a mixture of 50 ml of DMF and 80 ml of toluene, and 106.4 mg of sodium hydride (60% oily) was added to the solution under ice cooling, followed by stirring for 30 minutes. To the mixture was added 732 mg of Compound 1-c, and the mixture was heated under reflux for 3 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate/triethylamine (20/5/1)] to give 629 mg (61%) of the product.
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[OH:2].[CH3:11][O:12][CH2:13][CH:14]=O.C1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:11][O:12][CH2:13][CH:14]1[O:10][CH2:9][C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:1][O:2]1
Reactant: OCC1(CO)CCCCC1
Reactant: COCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: COCC1OCC2(CCCCC2)CO1
Yield: 97 %

Procedure:
A mixture of 288 g (2 moles) of 1,1-dimethylolcyclohexane, 191 g (2.2 moles) of 85% strength methoxyacetaldehyde and 250 ml of cyclohexane was heated with 2 g of p-toluenesulfonic acid under a water separator until water no longer separated off. The resulting solution was washed with dilute sodium hydroxide solution, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 388 g (97% yield) of 3-methoxymethyl-2,4-dioxaspiro[5.5]undecane of boiling point 95° C./1 mbar were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([O:14]CC)=O)=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[S:5][C:6]=1[CH3:7].[OH-].[Na+].CC(O)=O>CCO>[CH3:1][C:2]1[C:3]2[C:12](=[O:14])[NH:11][C:9](=[S:10])[NH:8][C:4]=2[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1c(NC(N)=S)sc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1sc2[nH]c(=S)[nH]c(=O)c2c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.2 %

Procedure:
To a suspension of ethyl 4,5-dimethyl-2-thioureidothiophene-3-carboxylate (Example 50a) (37 mg, 0.17 mmol) in dry EtOH (10 mL) was added sodium hydroxide (21 mg, 0.52 mmol). The reaction mixture was then stirred at room temperature for 5 minutes and refluxed for 10 minutes. The reaction mixture was cooled to room temperature, neutralized with 10% AcOH and then concentrated to dryness. The residue was purified by chromatography on silica gel (Gradient 0-50% EtOAc in Hexanes) to give the title compound (8 mg) in 24% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 6H), 12.24 (s, 1H), 13.27 (s, 1H). MS 202 (MH+).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].[CH3:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH:17](O)[CH2:18][CH2:19][CH:20](CC)[CH2:21][CH3:22])CC>>[CH2:22]([O:2][S:1]([O-:5])(=[O:4])=[O:3])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8].[Na+:6]
Reactant: CCCCC(CC)CCC(O)CCC(CC)CC
Reactant: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCOS(=O)(=O)[O-]

Procedure:
sodium sulfate of 3,9-diethyltridecanol-6
Reaction SMILES: [CH2:1]([Zn]CC)C.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH:15]=[CH2:16].ICI>ClC(Cl)C>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH:15]1[CH2:1][CH2:16]1
Reactant: CC[Zn]CC
Reactant: C=COc1ccc(F)cc1Br
Solvent: ICI
Solvent: CC(Cl)Cl
Product: Fc1ccc(OC2CC2)c(Br)c1
Reaction time: 72 h
Yield: 8.7 %

Procedure:
Diethyl zinc (1M in toluene, 23 ml, 23 mmol) was added under nitrogen with stirring to a solution of 2-bromo-4-fluoro-1-vinyloxy-benzene (Preparation 88, 1.0 g, 4.61 mmol) in dichloroethane (45 ml) at −10° C. (ice-salt-MeOH), taking care to maintain the temperature below 0° C. Diiodomethane (6.17 g, 23 mmol) in dichloroethane (10 ml) was then added via a syringe to the reaction mixture over 5 minutes ensuring that the reaction mixture remained at a temperature below +5° C. (internal temp). The reaction mixture was stirred at this temperature for twenty minutes and then allowed to attain room temperature and stirring was continued for 72 hours. The reaction was quenched with cold saturated ammonium chloride (aqueous solution) (5 ml) then the lower organic phase was removed, whilst the aqueous was extracted with a further dichloromethane (20 ml). The combined organic layers were dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo. Purification by column chromatography on silica gel eluting with tert-butyldimethyl ether:heptane 1:99 to 1:19 afforded almost pure title compound (93 mg, 9%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)CCC>CC1C=CC(C)=CC=1.[Cl-].[NH4+].CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(-c2nc3cc(OC)cc(-c4ccco4)c3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
7-Bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (300 mg, 0.90 mmol) and dichlorobis(tri-o-tolylphosphine)palladium(II) (71 mg, 0.09 mmol) were dissolved in p-xylene (3 mL) and stirred for 10 min at room temperature under a nitrogen atmosphere. 2-(Tributylstannyl)furan (449 mg, 1.26 mmol) was added and the mixture was refluxed for 4 hours. The mixture was cooled to room temperature, diluted with a saturated solution of ammonium chloride and extracted with EtOAc. The organic extracts were washed with water, then brine and dried over MgSO4 and concentrated. Purification by flash chromatography (20%–30% EtOAc/petroleum ether) gave the title compound as a white solid (99% yield, m.p. 120–121° C.); MS m/e 322 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>C(OCC)C.CO>[OH:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][OH:25])[C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCCNCCO
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)N(CCO)CCO
Temperature: 0 °C

Procedure:
A solution of 2.75 g palmitoyl chloride (10 mmol) in 20 ml anhydrous ethylether is added drop by drop in 30 minutes to a solution of 2.2 g diethanolamine (21 mmol) in 50 ml methanol and 100 ml anhydrous ethyl ether under continuous stirring at 0° C.
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3](=[CH2:5])[CH3:4].[C:7]([CH:10]1[C:15]([CH3:17])([CH3:16])[CH:14]2[CH2:18][CH:11]1[CH:12]=[CH:13]2)(=[O:9])[CH3:8].[Cl-].[NH4+]>C(OCC)C>[CH2:2]([C:7]([CH3:8])([CH:10]1[C:15]([CH3:16])([CH3:17])[CH:14]2[CH2:18][CH:11]1[CH:12]=[CH:13]2)[OH:9])[C:3](=[CH2:5])[CH3:4]
Reactant: C=C(C)CCl
Reactant: CC(=O)C1C2C=CC(C2)C1(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C(C)CC(C)(O)C1C2C=CC(C2)C1(C)C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
Into a 1 liter reaction flask equipped with a reflux condenser, thermometer, stirrer, dropping funnel and nitrogen inlet tube are placed 12 g (0.5 moles) of magnesium turnings and 250 cc anhydrous diethyl ether. Over a 2 hour period, 45.3 g (0.5 moles) of methallyl chloride is added. The Grignard solution is stirred for 1/2 hour and 28 g of 2-acetyl-3,3-dimethyl-5-norbornene is added over a 20 minute period. The mixture is stirred at reflux for 1/2 hour and then is hydrolyzed by the addition of saturated ammonium chloride solution. The organic layer is washed with water and dried over magnesium sulfate. The mixture is then filtered and the solvent evaporated to yield 40 g of an oil, which is then fractionated on a micro Vigreux column after adding thereto 5 g Primol® and a trace quantity of Ionox®.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]3[CH2:22][CH2:23][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>C(O)(=O)C>[CH2:32]([N:35]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:14](=[O:21])[N:13]4[CH2:22][CH2:23][C@H:12]4[C:11]=23)=[N:4][CH:1]=1)[CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: CCCNCCC
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)o1
Temperature: 25 °C
Reaction time: 47 h
Yield: 26.9 %

Procedure:
A solution of 3.06 g (0.010 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 47 hrs. the dark brown suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The red-brown solid residue was dissolved in 100 ml of THF, treated with 11.9 ml (0.0865 mol) of dipropylamine and stirred at room temperature for 17 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with dichloromethane. The organic phase was concentrated, the brown product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There were obtained 1.09 g (27%) of (S)-1-(5-dipropylaminomethyl-oxazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as yellowish crystals; m.p. 132-134° and [α]D20 =-187.8° (MeOH, c=1%).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[N:12]1([C:18]([S-:20])=[S:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[NH2+]1CCCCC1.C(=S)=S>CO>[N:12]1([C:18]([S:20][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: S=C([S-])N1CCCCC1
Agent: C1CC[NH2+]CC1
Solvent: CO
Solvent: S=C=S
Product: O=[N+]([O-])CC(SC(=S)N1CCCCC1)c1ccccc1
Temperature: 8 °C

Procedure:
β-Nitrostyrene (14.9 grams, 0.10 mole) was added in portions to a stirred mixture of piperidinium 1-piperidinecarbodithioate (24.6 grams, 0.10 mole), and carbon disulfide (7.6 grams, 0.10 mole) in methanol (200 ml.). During the addition, the reaction temperature was 25° C.-29° C. After the addition of β-nitrostyrene, the reaction mixture was cooled to 8° C., and the precipitated product was filtered off, washed with water, and dried in air. The yield of product melting at 85° C.-87° C. (prior sintering) was 29.0 grams (93%). Repeated recrystallizations without heating from methylene chloride-hexane and methylene chloride-methanol solutions gave pure α-(nitromethyl)benzyl 1-piperidinecarbodithioate melting at 86° C.-90.5° C. (prior sintering).
Reaction SMILES: [C:1]([CH:5]=[C:6]([Cl:8])[F:7])([F:4])([F:3])[F:2].[C:9]([O:14]F)([O:12]F)([F:11])[F:10]>>[Cl:8][C:6]1([F:7])[CH:5]([C:1]([F:4])([F:3])[F:2])[O:14][C:9]([F:11])([F:10])[O:12]1
Reactant: FOC(F)(F)OF
Reactant: FC(Cl)=CC(F)(F)F
Product: FC1(F)OC(C(F)(F)F)C(F)(Cl)O1

Procedure:
In a 200 ml 5 necked reactor, equipped with a mechanical stirrer, thermocouple, bubbling inlet for introducing the reacting gaseous mixture and an inert gas, 51.3 g (0.346 moles) of CF3—CH═CFCl are introduced. The reactor is then brought, by a cryostat, to the temperature of −70° C. At this point, under strong stirring, a mixture of CF2(OF)2 (BDM) (1 nl/h) and He (3 nl/h) for 3h 52′ (equivalent to 0.173 moles of BDM) is added in a continuous way.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=[O:19].C(N(CC)CC)C.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:28][SH:29]>N1C=CC=CC=1>[CH2:32]([O:31][C:27]([CH2:28][S:29][C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=[O:19])=[O:30])[CH3:33]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C=O)=C2Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC1=C(C=O)CCc2c(C(=O)OCC)sc(SC)c21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a mixture of ethyl 4-chloro-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (3.00 g), triethylamine (1.44 g) and pyridine (25 ml), ethyl thioglycolate (1.37 g) was added at 0° C., followed by stirring at 0° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure; the residue was poured over water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and water in that order and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:7 to 1:5, v/v) to yield ethyl 4-ethoxycarbonylmethylthio-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (3.07 g, 81.0%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 102-103° C.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]2[C:26]([O:28]CC)=[O:27])=[CH:9][C:8]1=[O:31].[OH-].[Li+]>CO>[CH3:25][C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C@@H:13]([C:10]2[CH:11]=[CH:12][N:7]([CH3:6])[C:8](=[O:31])[CH:9]=2)[C@H:14]([C:26]([OH:28])=[O:27])[CH2:15]1)=[O:20])([CH3:23])[CH3:24]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccn(C)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 3:2 (v/v) THF:MeOH solution (0.07 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(1-methyl-2-oxo-1,2-dihydro-4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added lithium hydroxide (1 M aq. solution, 3.1 eq.). The resulting cloudy solution was stirred vigorously at RT for 18 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and 10% aq. HCl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: COC(C1OC(C2[Se]C=CC=2[C:15]([C:17]2[CH:21]=[CH:20][Se:19][C:18]=2[C:22]2[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=2)=O)=CC=1)=O.[CH2:31]([NH:38][NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[CH2:31]([N:38]1[C:15]2[Se:19][CH:20]=[CH:21][C:17]=2[C:18]([C:22]2[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(-c2[se]ccc2C(=O)c2cc[se]c2-c2ccc(C(=O)OC)o2)o1
Reactant: NNCc1ccccc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3[se]ccc23)o1

Procedure:
Compound 73 (5.6 g, 0.02 mole), benzylhydrazine 50 (4.88 g, 0.04 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 79. Yield: 0.82 g (10.6%); white crystals;
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([CH:16]=[N:21][OH:22])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(N1CCc2ccc(C=NO)cc2CC1)C(F)(F)F
Yield: 81.5 %

Procedure:
3-Trifluoracetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde (20.0 g) and hydroxylamine hydrochloride (6.1 g) in pyridine (140 ml) were stirred overnight and the reaction then evaporated in vacuo. The residue was partitioned between ethyl acetate and 10% sodium carbonate solution and the combined organic layers dried and evaporated to give 3-trifluoracetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde oxime (17.2 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O[K])=O>C1COCC1.O.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Pd]
Agent: O=CO[K]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(O)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 72.3 %

Procedure:
A suspension of 3-fluoro-4-nitrophenol (2.0 g, 12.73 mmol), 10% Pd/C (0.4 g) and HCOOK (8.75 g, 101.85 mmol) in THF/H2O (70 mL/20 mL) was stirred at 50° C. for 5 hours, then cooled to rt, and filtered through CELITE®. The filtrate was diluted with water (30 mL) and extracted with THF (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (1.17 g, 72.3%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:48]=[O:49])C>C1COCC1>[O:1]([C:8]1[CH:25]=[CH:24][CH:23]=[C:10]2[C:9]=1[CH:48]([OH:49])[N:13]([C:14]([CH3:15])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:22])[C:11]2=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(NC(=O)c1cccc(Oc2ccccc2)c1)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(Oc3ccccc3)c2C1O
Yield: 90.1 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-phenoxy-N-(1-methyl-1-phenylethyl)benzamide (4.00 g, 12.1 mmol) was dissolved in THF (160 mL), and the solution was treated with TMEDA (5.80 mL, 38.7 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 39.0 mL, 38.7 mmol) and DMF (2.10 mL, 26.6 mmol), followed by purification by slurry using diisopropylether to obtain 4-phenoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.92 g, yield 90%).
Reaction SMILES: [C:1]1(NC2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[K+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([OH:27])[CH:26]=1>CN1CCN(C)C1=O>[CH3:1][O:27][C:25]1[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: COc1cc(F)ccc1[N+](=O)[O-]

Procedure:
5.4 g (32.1 mmol) of diphenylamine was dissolved in 50 ml of 1,3-dimethyl-2-imidazolidinone (DMI) and stirred under cooling in an ice-bath. Next, 3.6 g (32.1 mmol) of t-BuOK was added thereto. Subsequently, 5.0 g (29.2 mmol) of 2-methoxy-4-fluoronitrobenzene (obtained by methylation of commercially available 5-fluoro-2-nitrophenol) dissolved in 5 ml of DMI was dropped thereinto. After the completion of the dropping, the ice-bath was taken off and the mixture was allowed to stand at room temperature overnight. Next, the liquid reaction mixture was poured into water and extracted with ethyl acetate thrice. After washing with water, drying and concentrating under reduced pressure, the residue was recrystallized from methanol containing a small amount of acetonitrile. Thus, 6.0 g (yield 65%) of the compound (II-2) (2-methoxy-4-diphenylaminonitrobenzene) could be obtained as yellow powdery crystals.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1)C.[NH2:30][NH:31][C:32](=O)[CH2:33][N:34]([CH3:36])[CH3:35].C[O-].[Na+]>CO>[CH3:35][N:34]([CH2:33][C:32]1[NH:31][N:30]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:36]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)CC(C)(C)C)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)CC(C)(C)C)c4)c3c2)n[nH]1

Procedure:
The title compound was prepared according to the procedure described in Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3,3-dimethylbutanamide hydrochloride (0.360 g, 0.87 mmol), N-amino-2-(dimethylamino)acetamide (0.304 g, 2.60 mmol) and sodium methoxide in methanol (0.398 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.093 g, 25% yield): 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.16 (t, 1H), 8.08 (dt, 1H), 7.75 (dt, 2H), 7.66 (d, 1H), 7.50 (t, 1H), 3.71 (s, 2H), 2.37 (s, 6H), 2.30 (s, 2H), 1.12 (s, 9H),
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1>ClCCl>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:22])/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Aminobenzophenone (10.00 g, 0.0507 mol) was added to a stirred solution of maleic anhydride (4.98 g, 0.0508 mol) in dichloromethane (200 ml). After 10 minutes of stirring at room temperature, yellow precipitate was formed. Stirring was continued for a further 3 hours, following which the solid was collected, washed with dichloromethane (3×30 ml) and diethyl ether (2×30 ml) and finally air dried to yield the maleanmic acid. (Found: C, 68.74; H, 4.57; N, 4.41%. C17H13NO4 requires C, 69.15; H, 4.44; N, 4.74%). H.p.l.c (Kromazil C18, 49.95% MeOH, 49.95% H2O, 0.1% CF3CO2H): 99.7% λmax 306 nm; ε 20560. 1H-n.m.r (DMSO): δ 10.62 (1H, s, NH); 7.8-7.5 (9H, m, phenyl); 6.45 (1H, d; CH=CH); 6.31 (1M, d, CH=CH); 3.38 (1H, S, CO2H).