Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[CH:6]=[CH:5]2.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[CH2:6][CH2:5]2
Reactant: CC1(C)OC[C@H](C2C=Cc3cc(F)ccc3O2)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)OC[C@H](C2CCc3cc(F)ccc3O2)O1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A 75:25 diastereoisomeric mixture of 6-fluoro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (50 mg, 0.18 mmol, 90.4% A) was dissolved in ethanol and stirred under nitrogen atmosphere at 25° C. Ammonium formate (60.5 mg, 0.96 mmol) and 10% palladium on carbon (50 mg) were added to the stirred solution and the reaction mixture refluxed for 15 h. The reaction mixture was checked to show complete conversion of the starting material. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to furnish 6-fluoro-3,4-dihydro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (40 mg, 0.115 mmol, 72.6% A, 64% yield) as a 75:25 mixture of diastereoisomers.
Reaction SMILES: O=[C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:15]=2)[O:10][C:4]2([CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH2:3]1.C[Si]([N:29]=[C:30]=[N:31][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:20]([C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:4]2([CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:3]/[C:2]/3=[N:29]/[C:30]#[N:31])[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCOCC2)O3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC2(CCOCC2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 60 °C
Yield: 80.8 %

Procedure:
A solution of 3-(4-oxo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-6-yl)benzonitrile (170 mg, 0.53 mmol) and TiCl4 (403 mg, 2.12 mmol) in anhydrous DCM (5 mL) was heated at 50° C. under microwave for 5 mins. Then bis-trimethylsilylcarbodiimide (198 mg, 1.06 mmol) was added and the mixture was heated at 60° C. for another 30 mins. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give (Z)—N-(6-(3-cyanophenyl)-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-ylidene)cyanamide (147 mg, crude), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[CH3:8][N:9]=[C:10]=[O:11]>C1(C)C=CC=CC=1>[CH3:8][NH:9][C:10]([N:5]1[C:6]([Cl:7])=[C:2]([CH3:1])[N:3]=[CH:4]1)=[O:11]
Reactant: Cc1nc[nH]c1Cl
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)n1cnc(C)c1Cl
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
Using a procedure similar to that described in Example 1, 582.5 g of 4-methyl-5-chloroimidazole were dissolved in 1,500 ml of toluene at 70° C., and 313.5 g of methyl isocyanate were slowly run into the solution. During the addition, the temperature increased to about 90° C. Refluxing was then carried out for 30 minutes, after which the solution was cooled and then stirred for a further hour while being cooled with ice, and the precipitate which separated out was filtered off under suction, washed with ether and dried to give 826 g (95.2%) of 1-N-methylcarbamyl-4-methyl-5-chloroimidazole of melting point 95.6° C.
Reaction SMILES: C1(CC([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]3[CH:25]=[CH:24][N:23]=[C:22]4[C:17]=3[C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=3[C:20](=[O:26])[NH:21]4)[CH2:11]2)=O)C=CC=CC=1.Cl[CH2:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>>[O:26]=[C:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[C:17]2[C:22](=[N:23][CH:24]=[CH:25][C:16]=2[NH:15][CH:12]2[CH2:13][CH2:14][N:10]([CH2:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:34])[CH2:11]2)[NH:21]1
Reactant: O=C(Cc1ccccc1)N1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1
Reactant: O=C(CCl)Nc1ccccc1
Product: O=C(CN1CCC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1)Nc1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 370 using the amine intermediate from example 369 and 2-chloro-N-phenylacetamide to provide 371. LC-MS (M+H=414, obsd.=414).
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9]([NH2:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12]Cl>O>[Cl:12][NH:11][C:9]([NH:8][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:10]
Reactant: ClCl
Reactant: CC1(NC(N)=O)CCCCC1
Solvent: O
Product: CC1(NC(=O)NCl)CCCCC1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a rapidly stirred slurry of 7.5 g (.048m) of N-(1-methylcyclohexyl)urea in 75 ml. water at 15°C was added 3.36g. (.048 m) of chlorine at 0.5 g/minute. The reaction mixture was stirred an additional 1/2 hour at 15°C and filtered. The filter cake was washed with cold water until free of acid and air dried overnight. The white solid weighed 6.0 g (66% yield) and contained 18.9% active chlorine (calculated value for 1-chloro-3-(1-methylcyclohexyl)urea = 18.5% active chlorine).
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:14][O:13][C:3]1[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[N:7]2[CH3:11]
Reactant: OB(O)c1cccnc1
Reactant: COc1c(Br)ccc2c1CC(=O)N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1c(-c2cccnc2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 5-bromo-4-methoxy-1-methyl-1,3-dihydro-indol-2-one (105 mg, 0.410 mmol) was added 3-pyridineboronic acid (CAS#1692-25-7, 60.5 mg, 0.492 mmol), 1,2-dimethoxyethane (3 mL) and 2 M aqueous sodium carbonate (0.513 ml, 1.025 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (186 mg, 0.021 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2.25 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 20 to 100%) to afford 4-methoxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 255.1136 (M+H)4; 1H NMR (400 MHz, CO2Cl2) δ ppm 3.20 (s, 3H), 3.66 (s, 2H), 3.72 (s, 3H), 6.68 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.38 (dd, J=7.9, 4.9 Hz, 1H), 7.79-7.96 (m, 1H), 8.52 (d, J=4.0 Hz, 1H), 8.71 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.Cl.[OH-].[Na+]>>[NH2:9][CH2:8][C:7]1[C:6]([NH:10][C:11]2[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=2[F:17])=[N:5][C:4]([S:19][CH3:20])=[N:3][C:2]=1[Cl:1]
Reactant: CSc1nc(Cl)c(C#N)c(Nc2c(F)cccc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(Cl)c(CN)c(Nc2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
To the solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbonitrile (0.938 g) was added borane●THF complex (1.0 M, 15 mL). The reaction mixture was then heated at reflux for about 4 h until all the starting material disappeared. The solution was cooled to r.t., mixed with HCl solution (6 M, 5 mL), and stirred at room temperature for about 30 minutes. The solution was then mixed with NaOH solution (3 M) to pH 9.0-10.0. The organic phase was separated and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL), collected, dried over Na2SO4 and concentrated to afford the title compound 0.97 g (quantative). LC-MS m/z 317 (M+H)+, 1.5 min (ret. time).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.[CH2:19]1[C:24](=O)[CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20]1>C(O)(C)C>[CH2:26]([N:21]1[CH2:22][CH2:23][C:24]2[NH:2][C:4]3[C:18]([C:19]=2[CH2:20]1)=[C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Agent: Cl
Solvent: CC(C)O
Product: c1ccc(CCN2CCc3[nH]c4ccc5scc(-c6ccccc6)c5c4c3C2)cc1
Temperature: 190 °C

Procedure:
28.0 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride are allowed to react with 21.0 g of N-(2-phenethyl)-4-piperidone in 500 ml of isopropanol at room temperature for 2 hours. After filtering off the crystall sludge, this is suspended in 150 ml of N NaOH and the suspension is extracted with methylene chloride. The organic phase is washed with water until neutral and evaporated, the oily residue is taken up in 400 ml of ethylene glycol and the mixture is heated to 190° C. for 30 minutes. The substance which has crystallised out after cooling is filtered off and recrystallised from toluene. Melting point: 220°-221° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:19])=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6].[CH3:20][O:21][C:22]1[C:23](=O)[C:24](=[O:28])[C:25]=1[O:26]C.C(OCC)(=O)C>C(O)C>[OH:19][C:3]1[C:2]([NH:1][C:23]2[C:24](=[O:28])[C:25](=[O:26])[C:22]=2[O:21][CH3:20])=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COC(=O)[C@H]1CCCN1C(=O)c1cccc(N)c1O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCCN1C(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1O
Temperature: 50 °C
Yield: 33.9 %

Procedure:
A mixture of 2.64 g (10 mmol, 1 eq) of methyl (R)-1-(3-amino-2-hydroxybenzoyl)pyrrolidine-2-carboxylate and 2.84 g (20 mmol, 2.0 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione in 80 ml of ethanol was heated at 50° C. for four and a half hours. The residue was taken up with ethyl acetate and washed three times with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The oil was chromatographed on silica gel (300 g prepacked column) eluted with heptane/ethyl acetate (gradient). 1.27 g of methyl (R)-1-[2-hydroxy-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]pyrrolidine-2-carboxylate were obtained in the form of white solid. Yield=34%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[C:8]([C:12]1([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:14][O:13]1)([CH3:11])([CH3:10])[CH3:9].C(=O)=O>CN1CCCC1=O.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:12]([CH2:14][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)([OH:13])[C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:22][CH:21]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
20.7 g (0.3 mole) of 1,2,4-triazole, 4.15 g (0.103 mole) of sodium hydroxide and 1 ml of water were added to a solution of 71.55 g (0.3 mole) of 2-tert.-butyl-2-(4-chloro-phenyl-ethyl)-oxirane in 125 ml of N-methyl-pyrrolidone at room temperature, with stirring. The reaction mixture was heated at 120° C. for 4 hours, with stirring, during which a dry stream of CO2 -free air was slowly passed through. Thereafter, the mixture was worked up by a procedure in which the solvent was distilled off under reduced pressure and the residue which remained was washed with water and then dried and stirred with 150 ml of benzine. The solid product which deposited was filtered off and dried again. 81.9 g (88.8% of theory) of 1-(4-chloro-phenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-pentan-3-ol were obtained in this manner.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[NH2:27][OH:28]>C1COCC1>[OH:28][NH:27][C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:25]=[C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:24]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)NO)cc1OCC2

Procedure:
Following the same procedure as for 133, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (20 mg, 0.06 mmol) was reacted with hydroxylamine hydrochloride (8 mg, 0.1 mmol) in THF to provide 173. LC/MS (ESI+): m/z 355 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[F:40])=[O:31])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:16])[S:14][C:7]=12.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[F:40])=[O:31])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[S:14][C:7]=12
Reactant: CCOC(=O)CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCC(=O)O)sc34)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred solution of ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate (110 mg, 0.19 mmol) in 10 ml of THF was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 60° C. for 2 hours, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid as white solid. Yield: 95 mg, 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C1(C)C(C)=CC=CC=1.[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: Cc1cc(Cl)cc(Cl)c1OC(=O)c1ccc(CCl)cc1

Procedure:
88.5 g (0.5 mole) of 2,4-dichloro-6-methylphenol, 180 ml of dry xylene, 95 g (0.5 mole) of p-chloromethylbenzoyl chloride and 0.5 ml of pyridine were refluxed for 24 hours in a weak current of nitrogen with the exclusion of moisture. After cooling, the slightly turbid (pyridine hydrochloride), orange-colored solution was filtered free of a small amount of a blackish brown resin, and the filtrate was freed of xylene at diminished pressure. The residue (165 g=100%) crystallized after two days of standing to a light brown crystal mass, which was triturated in 200 ml of ice-cold petroleum ether and suction filtered. After drying, nearly colorless crystals were obtained with a melting point of 71°-73° C. Recrystallization from petroleum ether (1:10) yielded white needles melting at 74°-75° C.; no change in the melting point was brought about by repeated recrystallization.
Reaction SMILES: [Na].O[C:3]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:4]=1[NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Br:30][CH2:31][CH2:32][P:33](Cl)(Cl)=[O:34].O>C1C=CC=CC=1>[Br:30][CH2:31][CH2:32][P:33](=[C:3]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:4]1[NH:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:34]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc([N+](=O)[O-])ccc1O
Reactant: O=P(Cl)(Cl)CCBr
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)NC1C=C([N+](=O)[O-])C=CC1=[P+]([O-])CCBr
Temperature: 10 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
In 400 ml of benzene was suspended 4.15 g (10 mmol) of the sodium salt of 2'-hydroxy-5'-nitrohexadecananilide. The suspension was stirred and heated to boiling. Benzene, 100 ml was collected through a concentrator condenser. The condenser was then replaced with a reflux condenser on which a drying tube was mounted. The temperature of the mixture was lowered to 25° C and 4.84 g (20 mmol; 2.64 ml) of β-bromoethylphosphoryl dichloride was added. The slightly yellow solution was stirred for 1 hour at room temperature and then it was heated under reflux for 24 hours. After cooling to 10° C, 10 ml (0.56 mol) of water was added and the stirring was continued for 72 hours at room temperature. The precipitate 4.2 g was filtered from the mother liquor and washed with 100 ml of benzene. (Subsequent treatment of the mother liquor is described in part (d) of this example.) The dried and pulverized product was then suspended in 90 ml of 0.2 M sodium acetate buffer (pH 5.0) and stirred for 3 hours. The mixture was filtered through a coarse filter paper and the filtrate was acidified with 90 ml of 1 N hydrochloric acid and extracted twice with 180 ml of ethyl acetate. After evaporation of the solvent the residue (2.7 g) was recrystallized from 70 ml of acetone to yield 2.2 g (38%) of 2'-(β-bromoethylphosphoryl)-5'-nitrohexadecananilide. Mp 117°-118° C. The compound was water soluble as a sodium salt, 10-4M pH 3.7, and in 0.2 M sodium acetate buffer (pH 5.0), 100 mg per ml. It was insoluble in water; slightly soluble in ethyl ether; soluble in methyl and ethyl alcohol, ethyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, benzene and chloroform. Thin-layer chromatography: Chloroform-methanol-water (75:25:3). Rf 0.5. 2'-hydroxy-5'-nitrohexadecananilide, Rf 0.95). The ir spectrum displayed the following additional bands when compared with the spectrum of 2'-hydroxy-5'-nitrohexadecananilide, 1210 (P=0 str.), 1005, 950, 920 (P=0 (OH)), 730, 560 cm-1 (bromine ?).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][C:6]([CH2:7][S:8][C:9]([CH3:40])([CH3:39])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][CH2:35][N:36]=[C:37]=[S:38])[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][S:22][C:20]([CH3:32])([CH3:21])[C:19]([NH:18][CH2:17][CH2:16][N:15]([CH2:34][CH2:35][NH:36][C:37]([NH:58][C:55]2[CH:56]=[CH:57][C:52]([O:51][CH3:50])=[CH:53][CH:54]=2)=[S:38])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]([CH3:40])([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:42][CH:41]=2)[CH3:39])=[O:33])=[CH:29][CH:28]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(CSC(C)(C)C(=O)NCCN(CCN=C=S)CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CSC(C)(C)C(=O)NCCN(CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)CCNC(=S)Nc2ccc(OC)cc2)cc1
Yield: 87.7 %

Procedure:
A solution of the isothiocyanate 25 (18.9 mg, 0.02986 mmol), triethylamine (7.26 mg, 0.07175 mmol), anisidine (6.9 mg, 0.05602 mmol), and CHCl3 (15 mL) was refluxed for 3 hours and the solvent was removed in vacuo. Flash chromatography of this crude product using 100% EtOAc gave the anisidine derivative 26 as a clear oil (19.8 mg, 87.6% yield). 1H NMR (in CDCl3): δ8.17 (brs,lH,NH--CS--NH--Ar), 7.28 (d,j=8.8 Hz,2H,H2 &H6 --Ar--N), 7.15 (d,j=8.6 Hz,4H,2H3 &H5 --Ar--OCH3), 7.06 (brs,lH,NH--CS--NH--Ar), 7.06 (t,j=5.7 Hz,2H,2NH--CO), 6.90 (d,j=8.9 Hz,2H,H3 &H5 --Ar--N), 6.82 (d,j=8.6 Hz,4H,2H2 &H6 --Ar--OCH3), 3.79 (s,3H,CH3O--Ar--N), 3.77 (s,6H,2CH3O--Ar--CH2), 3.67 (s,4H,2S--CH2 -Ar), 3.61 (q,j=5.3 Hz,2H,N--CH2CH2 --NHCS), 3.14 (q,j=6.2 Hz,4H,2N-CH 2CH2 --NHCO), 2.69 (t,j=5.6 Hz,2H,N--CH2CH2 --NHCS), 2.52 (t,j=6.3Hz,4H 2N--CH2CH2 --NH--CO), 1.51 (br s,12H,4CH3 --C--S) ppm. 13C NMR (in CDCl3): δ181.9 (s,N--CS--N), 175.2 (s,2NH--CO), 158.8 (s,3C1 --Ar--OCH3), 130.0 (s,C1 --Ar--N), 130.0 (d,2C2 &C6 --Ar--OCH3), 129.2 (s,2C4 --Ar--OCH3), 127.0 (d,C2 &C6 --Ar--N), 114.5 (d,C3 &C5 --Ar--N), 114.2 (d,2C3 &C5 --Ar--OCH3), 55.4 (q,3CH3O), 54.4 (t,2N-CH 2CH2 --NHCO), 52.9 (t,N--CH2CH2 --NHCS), 50.1 (s,2S--C--CH3), 42.8 (t,N--CH2CH2 --NHCS), 38.3 (t,2N--CH2CH2 --NHCO), 34.2 (t,2S--CH2 --Ar), 28.3 (q,4CH3 --C--S) ppm. MS (m/z,FAB): 756(4.2, M+). IR (CDCl3): 3320, 2960, 1720, 1655, 1510, 1290, 1245, 1030 cm-1.
Reaction SMILES: Cl[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(Cl)Cl>[CH:21]([NH:24][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([C:18](=[O:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:23])[CH3:22]
Reactant: CC(=O)N(C1=C(Cl)C(=O)c2c(cnn2C)C1=O)C(C)C
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(=O)N(C1=C(NC(C)C)C(=O)c2c(cnn2C)C1=O)C(C)C

Procedure:
6-Chloro-5-(N-acetyl-N-isopropylamino)-1-methyl-1H-indazole-4,-7-dione (3 grams) and isopropylamine (3 grams) in methylene chloride (25 milliliters) were heated under reflux for 15 minutes. The solvent was then removed under reduced pressure and the residue recrystallized from ethanol to give 6-isopropylamino-5-(N-acetyl-N-isopropylamino)-1-methyl-1H-indazole-4,7-dione as a red solid having a melting point of 123°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:5][CH:6]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:7]([N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH3:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:5][CH:6]([CH2:20][OH:21])[CH:7]([N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14])[CH3:8]
Reactant: CC(C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C(CO)Cc1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
1.07 g of the phthalimide compound thus obtained was dissolved in 15 ml of tetrahydrofuran, and 2.6 ml of a 1M tetrahydrofuran solution of tetrabutylammonium fluoride was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was dissolved in a liquid mixture of water and ethyl ether. The organic layer was collected by separation and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to medium pressure liquid chromatography (hexane/ethyl acetate=4/1→2/1) to obtain 0.39 g (yield: 47%) of N-{(1RS, 2SR)-2-(3,4-dichlorobenzyl)-3-hydroxy-1-methylpropyl}phthalimide.