Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28](=[O:41])[C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH2:23]1.Cl.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([N:27]3[CH2:26][CH2:25][N:24]([C:28](=[O:41])[C:29]4[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=4)[CH2:23][CH:22]3[CH2:21][O:20][CH3:19])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: COc1cc2c(cc1OC)OCCC(C(=O)Cl)=C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2OCC1
Reaction time: 0.5 h

Procedure:
A solution of 7,8-dimethoxy-2,3-dihydro-1-benzoxepine-4-carbonyl chloride (300 mg) in dichloromethane (10 ml) is added dropwise, taking 30 minutes under ice-cooling while stirring, to a mixture of 3-methoxymethyl-1-(3,4,5-trimethoxybenzoyl)piperazine×hydrochloride (400 mg) obtained in Reference Example 6, triethylamine (1 ml) and dichloromethane (30 ml). The reaction mixture is washed with an aqueous solution of citric acid and an aqueous solution of sodium hydrogencarbonate, then dried over magnesium sulfate, followed by concentration. The concentrate is subjected to a silica gel column chromatography (eluent: ethyl acetate-methanol =95:5) to afford 1-(7,8-dimethoxy2,3-dihydro-1-benzoxepin-4-ylcarbonyl) -2-methoxymethyl4-(3,4,5-trimethoxybenzoyl)piperazine (520 mg) as colorless crystals, m.p. 142° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[CH2:15]([NH:14][C:4]1[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=[C:2]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C1CNCCN1
Reactant: CCCCCCNc1nc(Cl)nc2c(SC)ncnc12
Solvent: CS(C)=O
Product: CCCCCCNc1nc(N2CCNCC2)nc2c(SC)ncnc12

Procedure:
Prepared analogously to Example 2 from 2-chloro-4-n-hexylamino-8-methylthio-pyrimido[5,4-d]pyrimidine and piperazine in dimethylsulphoxide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[N:10]1([CH2:15][CH2:16][CH2:17][NH2:18])[CH:14]=[CH:13][N:12]=[CH:11]1.CC1(C)C(C)(C)OB([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([CH:15]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:16][CH2:17][NH2:18])[C:5]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: NCCCn1ccnc1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: NCCC(c1nc(Cl)ncc1-c1cccs1)n1ccnc1

Procedure:
Preparation according to procedures 2 and 3 with the use of 2,4-dichloro-5-iodo-pyrimidine, 3-imidazol-1-yl-propylamine and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:36])[CH:19](Br)[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:36])[CH:19]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: COC(=O)C(Br)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A mixture of 2, 4 difluorophenol (0.28 g, 2.18 mmol) and cesium carbonate (0.39 g, 1.19 mmol) in acetonitrilie (20 ml) stirred for 30 mins. A solution of bromo-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.75 g, 1.98 mmol) in acetonitrile (5 ml) was added drop wise at room temperature and stirred further for 2 hrs. Reaction mixture was diluted with ethyl acetate (50 ml), washed with water, 1N NaOH (cold, 50 ml), and brine (50 ml) dried over anhydrous sodium sulfate, filtered and concentrated to provide (2,4-difluoro-phenoxy)-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.35 gm).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]4[CH:37]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:40][N:39]=[N:38][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:29]3[N:30]=[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]4[CH:37]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2ccc(-c3ccsc3)s2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2ccc(-c3ccsc3)s2)s1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.3 %

Procedure:
To a solution of 5-formyl-2,2':5', 3"-terthiophene (0.5 g) in methanol (15 ml) was added excess amount of sodium borohydride. The reaction mixture was stirred at room temperature for 40 minutes. Methanol was removed and water was added. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give brownish solid product (0.5 g), melting point 158°-160° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[Cl:27][C:23]1[CH:24]=[C:25]([CH3:26])[C:20]([O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10]([C:29]#[N:30])=[N:9][C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])=[C:17]3[OH:18])=[C:21]([CH3:28])[CH:22]=1
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cc(Cl)cc3C)cc2c1O
Product: Cc1cc(Cl)cc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2c1

Procedure:
The title compound was synthesized from 6-(4-Chloro-2,6-dimethyl-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=424.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].Cl.[P:12](Cl)([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13]>ClCCl.C(N(CC)CC)C>[P:12]([O:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5])([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)Oc1ccc(C)cc1C=O
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-hydroxy-5-methyl benzaldehyde (4A) (1000 mg) in dry dichloromethane (20 mL) and triethylamine (2 mL), diethyl chlorophosphate (1.17 mL) was added in a dropwise manner. The mixture was stirred for overnight and the reaction mixture was acidified using 5% HCl and extracted with ethyl acetate and the extracts were combined, washed with sodium bicarbonate and then concentrated. Flash column chromatography furnished the pure product as colorless oil (1620 mg, 81%): 1H-NMR (500 MHz, CDCl3) δ 10.34 (s, 1H), 7.7 (s, 1H), 7.3-7.4(d, J=8.4 Hz, 1H)7.3 (d, J=8.4 MHz), 4.2-4.3 (m, 4H) 2.3 (s, 3H), 1.3(t, J=6 Hz, 6H) (FIG. 7). 13C-NMR (CDCl3, 50.3 MHz) δ 188.5, 136.1, 135.1, 128.7, 120.8, 664.8, 20.4, 15.9. 31P-NMR (CDCl3, 81 MHz) δ −6.18 (FIG. 8). MS calcd for C12H17O5P 272.23, found 272.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:22]([Si:26]([CH3:46])([CH3:45])[O:27][CH2:28][CH2:29][N:30]([CH2:35][CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:31](=[O:34])[CH2:32]Cl)([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[C:41]([Si:38]([CH3:40])([CH3:39])[O:37][CH2:36][CH2:35][N:30]([CH2:29][CH2:28][O:27][Si:26]([CH3:45])([CH3:46])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:31]([CH2:32][O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)=[O:34])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCC(=O)N(CCO[Si](C)(C)C(C)(C)C)CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
(R)-tert-Butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (1.0 g, 3.741 mmol) was dissolved dry N,N-dimethylformamide (10 mL) and cooled in an ice bath. To this was added portionwise a 60% dispersion of sodium hydride in mineral oil (344 mg, 8.604 mmol). The mixture was then warmed to 10° C. for 0.5 hours, then cooled in an ice bath and N,N-bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-chloro-acetamide (2.13 g, 4.67 mmol) added slowly in dry N,N-dimethylformamide (5 mL). The reaction mixture was warmed to ambient temperature and stirred overnight. Analysis of the reaction mixture by 1H NMR indicated 75% conversion to product. The reaction mixture was cooled in an ice bath and a 60% dispersion of sodium hydride in mineral oil (68 mg, 0.748 mmol) added. After a few minutes N,N-bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-chloro-acetamide (0.46 g, 0.426 mmol) was added. The reaction mixture was warmed to ambient temperature over 1 hour. The reaction mixture was then poured into water (50 mL) and extracted with diethyl ether (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo to give (R)-[4-({bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-carbamoyl}-methoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid (2.2 g, 45.9%) which was used in step 14-E without further purification.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([OH:6])([CH3:5])[CH3:4].[H-].[Na+].F[C:12]1[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]([F:8])([F:7])[C:3]([CH3:5])([CH3:4])[O:6][C:12]1[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: N#Cc1ccc(F)cn1
Reactant: CC(C)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(Oc1ccc(C#N)nc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
Add 2-trifluoromethyl-2-propanol (1.1 g, 8.3 mmol) slowly to a slurry of sodium hydride (202 mg, 60% mineral oil, washed with hexane) in HMPA (3 mL) under nitrogen. Stir the slurry for 15 min, then add 5-fluoro-pyridine-2-carbonitrile (510 mg, 4.2 mmol). Stir the slurry for 16 h at ambient temperature. Adjust the mixture to pH 9 with sodium carbonate then extract with diethyl ether (3×50 mL). Collect the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95/5 to 80/20) to obtain the desired intermediate (768 mg, 79%). GC-MS m/z: 230 (Me).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH:48]([CH3:50])[CH3:49])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH:48]([CH3:49])[CH3:50])[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C(C)C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C(C)C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogen carbonate (2.6 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.63 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.58 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.88 g, 60%) as a colorless solid.
Reaction SMILES: Cl.[O:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1>C(OCC)C>[O:27]=[C:25]1[NH:24][C:23]2[CH:28]=[CH:29][C:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([O:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:14][CH2:13]3)=[CH:21][C:22]=2[O:26]1
Reactant: O=C(O)CN1CCC(Oc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: Cl
Solvent: CCOCC
Product: O=C(CN1CCC(Oc2ccccc2)CC1)Nc1ccc2[nH]c(=O)oc2c1

Procedure:
The title compound is prepared from (4-phenoxy-piperidin-1-yl)-acetic acid hydrochloride and 6-amino-3H-benzoxazol-2-one according to the method described in Example 161c. Melting Point: 193-195° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[C:9]3([CH2:11][CH2:10]3)[O:8][C:7]=2[CH:14]=1.C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:22]([O-:24])=[O:23])=[CH:5][C:6]2[C:12](=[O:13])[C:9]3([CH2:10][CH2:11]3)[O:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)OC1(CC1)C2=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)C1(CC1)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.4 g. of 6-Methoxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one was dissolved in a mixture of 25 ml. of acetic anhydride and 7 ml. of glacial acetic acid. While keeping the reaction temperature at 10°-15° C., 3 ml. of fuming nitric acid (d=1.52) was added dropwise to the mixture. After stirring for 30 minutes, the reaction mixture was poured into ice-water. The resulting precipitates were collected by filtration, washed with water and recrystallized from ethanol. By the above procedure, there was obtained 6-methoxy-5-nitrospiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one as pale yellow prisms melting at 160°-163° C. Yield: 4.5 g.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH3:10])[CH2:3][O:4][N:5]=C(C)C.OCC(ON=C(C)C)CC.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:1]([CH:2]([CH2:9][CH3:10])[CH2:3][O:4][NH2:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1
Reactant: CCC(O)CON=C(C)C
Agent: CCC(CO)ON=C(C)C
Product: CCC(CON)Oc1ccccc1
Yield: 50 %

Procedure:
The starting material was a mixture of 2-propanone O-(2-hydroxybutyl)oxime and 2-propanone O-(2-hydroxy-1-ethylethyl)oxime in the ratio 96.7:3.3. Phenol was used in place of 4-chlorophenol, otherwise the procedure was as in Example 1. This resulted in O-(2-phenoxybutyl)hydroxylamine (yield: 50%) and O-(2-phenoxy-1-ethylethyl)hydroxylamine in the ratio 99.8:0.2.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:11]2[CH2:14][CH:13]([CH:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)C(OC)=O)[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.CC[O:37][CH2:38][CH3:39]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[N:11]2[CH2:14][CH:13]([CH:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[C:38]([CH3:39])([OH:37])[CH3:1])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: [Li]C
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(Cl)c2)C1
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 0.985 g (4.0 mmole) of finely powdered CeCl3 (Strem Chemical Co.) in 10 mL anhydrous THF was stirred at room temperature under N2. After 1 h, the solution was cooled to −78° C. in a dry ice-acetone bath and 2.5 mL of a 1.6M solution of methyllithium in ether was added dropwise at such a rate that the solids remained dispersed. After 30 minutes, a solution of 0.485 g (1.1 mmole) of methyl {1-[(3-chlorophenyl)(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)acetate in 5 mL of THF was added and the solution was left stirring at −78° C. for 1 h. The reaction was quenched by addition of 0.1 mL CH3OH, diluted with 40 mL of ether and allowed to warm to −10° C. Then aqueous NH4Cl solution was added dropwise until the cerium salts precipitated onto the surface of the flask. The supernatant was decanted and the solids were triturated with two 20 mL portions of CH2Cl2 and two 20 mL portions of ether. The combined organic extracts were washed with saturated aqueous NH4Cl solution and brine, dried over Na2SO4 and concentrated to afford the title compound as a mixture of 4 diastereomers. The mixture was purified by flash chromatography on silica gel using a step gradient of 3 column volumnes each of 1%, then 2%, then 4%, then 6% ethyl acetate-hexane to afford two diastereomers of the title compound. The enantiomers of the faster diastereomer were separated by chromatography on an AD column chiral using 6% isopropanol in heptane. Faster diastereomer: 1H-NMR(CDCl3) δ 1.07 (s, 3H), 1.14 (S, 3H), 2.28 (t, 1H, J=7.5Hz), 2.74 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2H), 3.62 (in, 1H), 4.20 (s, 1H), 6.67-6.73 (m, 3H), 7.21-7.33(m, 8H); Mass Spectrum: m/e=476 (M+1 35Cl, 35Cl) and 478 (M+135Cl, 37Cl). Slower diastereomer 1H-NMR(CDCl3) δ 1.06 (s, 3H), 1.14 (S, 3H), 2.29 (t, 1H, J=7.5 Hz), 2.75 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2H), 3.62 (m, 1H), 4.22 (s, 1H), 6.67-6.73 (m, 3H), 7.21-7.33(m, 8H); Mass Spectrum: m/e=476 (M+1 35Cl, 35Cl) and 478 (M+1 35Cl, 37Cl).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12](=[C:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:13]>ClCCl>[CH3:13][CH:12]1[C:14]2([CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[O:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=C1CCOCC1
Solvent: ClCCl
Product: CC1OC12CCOCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (1.23 g, 7.13 mmol) was added to a solution of 4-ethylidenetetrahydro-2H-pyran (800 mg, 7.13 mmol) in dichloromethane (80 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for two hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate then saturated sodium thiosulfate. The layers were separated and the aqueous layer was re-extracted with dichloromethane (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 2-methyl-1,6-dioxaspiro[2.5]octane as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 3.88-3.76 (m, 4H), 2.92 (q, J=5.5 Hz, 1H), 1.91-1.81 (m, 2H), 1.58-145 (m, 2H), 1.30 (d, J=5.5 Hz, 3H).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7](O)=[O:8])[O:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].C(Cl)(Cl)(Cl)Cl>C1CCCCC1>[CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7]([Cl:17])=[O:8])[O:2]1
Reactant: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: O=C(Cl)c1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
Reaction of 31.7 g of 4,5-methylenedioxy-2-nitrobenzoic acid and 31.2 g of phosphorus pentachloride in 250 ml of cylohexane at reflux for 30 minutes followed by treatment of the crude oil twice with carbon tetrachloride gave 4,5-methylenedioxy-2-nitrobenzoyl chloride. The acid chloride was dissolved in 50 ml of tetrahydrofuran and added to a warm solution of 30.9 g of 5-aminotetrazole monohydrate in 750 ml of tetrahydrofuran and 30 ml of water. The solution was stirred for 30 minutes and then diluted with 3 liters of water. The solid which formed was separated by filtration and dried to give 4,5-methylenedioxy-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 279° C. after recrystallization from a mixture of dimethylformamide and water.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:19].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNC>C(Cl)(Cl)Cl.CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](=[O:13])[N:18]([CH3:19])[CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70.8 %

Procedure:
General procedure A was followed using N-Boc-isonipecotic acid (0.20 g, 0.86 mmol), HATU (0.43 g, 1.1 mmol), DIPEA (0.76 mL, 4.4 mmol), dimethylamine hydrochloride (92 mg, 1.1 mmol) and DMF (4 mL) to furnish the title compound as a pale brown oil (156 mg, 70%), umax (CHCl3)/cm−1 3020, 2861, 1684, 1631, 1417, 1367, 1151, 1030; m/z (ESI) C13H24N2NaO3 requires 279.1679, found [M+Na]+ 279.1677.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21]O)=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:27])[CH3:26])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:51]3[C:47](=[O:57])[C:48]4=[CH:56][CH:55]=[CH:54][CH:53]=[C:49]4[C:50]3=[O:52])=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:27])[CH3:26])=[C:6]([C:7](=[O:8])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 5-chloro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazo1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-chloro-2-(benzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.