Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CN(C=O)C>O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of 3 g of cis-4-hydroxy-cyclohexanecarboxylic acid ethyl ester, 3 g of imidazole, 33 g of tert-butyldimethylsilyl-chloride, and 6 mL of DMF was stirred under inert atmosphere overnight. The mixture was diluted with 250 mL of water and extracted into 3×50 mL portions of ether. The combined ether extracts were washed with 2×50 mL of water, dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum overnight gave 4.5 g of product as a colorless oil: 1H NMR (400 MHz, CDCl3) 4.1 (dd, 2H), 3.58 (m, cis isomer, 0.85H), 2.2 (m, 1H), 1.95 (m, 4H), 1.6 (m, 1H), 1.5 (m, 1H), 1.22 (m, 6H), 0.9 (s, 9H), 0.04 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:29][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ncc(C#N)cc2-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: N#Cc1cnc(-c2ccc(CBr)cc2)c(-c2ccccc2)c1

Procedure:
To a mixture of 6-(4-methylphenyl)-5-phenylnicotinonitrile (0.250 g, 0.925 mmol) in CDCl3 (6 mL) was added NBS (0.173 g, 0.971 mmol) and benzoyl peroxide (0.045 g, 0.185 mmol). The reaction was heated to reflux for 15 hr. The reaction mixture was then cooled and concentrated to give crude 6-[4-(bromomethyl)phenyl]-5-phenylnicotinonitrile. LRMS m/z (M+H) calcd: 348.9, found: 348.9.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[O:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[N-:21]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:21][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[OH:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: Cc1ccnc(C(=O)c2ccc(F)cc2C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccnc(C(O)c2ccc(N)cc2C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
2-(4-fluoro-2-trifluoromethylbenzoyl)-4-methylpyridine (4.5 g) and sodium azide (1.3 g) were suspended in dimethylsulfoxide (30 ml), and the mixture was heated with stirring overnight under nitrogen atmosphere at 90° C. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (30 ml), and to the solution was added aluminum lithium hydride (1.2 g) under ice-cooling, and the mixture was stirred for 1 hour under nitrogen atmosphere under ice-cooling. Water (1.2 ml), 15% aqueous solution of sodium hydroxide (1.2 ml) and water (3.6 ml) were added to the mixture, and the mixture was stirred, dried over anhydrous magnesium sulfate, and filtrated. The solvent of the filtrate was distilled off, to give (4-amino-2-trifluoromethylphenyl)(4-methylpyridin-2-yl)methanol (3.6 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O.CO>O1CCCC1>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of 2-chloro-3-nitrobenzoic acid (100 g, 0.496 mol) in tetrahydrofuran (1000 mL) was added dropwise oxalyl chloride (46.8 mL, 0.546 mol) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the mixture was added dropwise methanol (300 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was concentrated and the residue was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound (103 g, 0.478 mol, 96%).
Reaction SMILES: C1O[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:7][CH2:6]2)[O:4]C1C.Cl>C(O)(=O)C.O>[F:22][C:19]([F:20])([F:21])[CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: CC1COC2(CCN(c3ccccc3OCC(F)(F)F)CC2)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCN(c2ccccc2OCC(F)(F)F)CC1

Procedure:
A solution of 51 (410 mg, 1.23 mmol) in acetic acid (20 mL), water (20 ml), and concetrated HCl (5 mL) was heated in an oil bath (60° C.) overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (52)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[CH3:38][N:36]([CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([O:19][C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:40][CH:39]=3)[CH:25]=[CH:24][N:23]=2)=[O:28])[CH2:34][CH2:33]1)[CH3:37]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 30 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (79 mg) and (+)-10-camphorsulfonic acid (49.7 mg) in ethanol (3.0 ml) at room temperature, the mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=4:1) to provide the title compound (36.5 mg, 30%) as white powder.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH:23][C:33](=[O:35])[CH3:34])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)c1ccc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of Example 1F (0.15 g, 0.0004 mol) and excess triethylamine (2 mL) in methylene chloride (5 mL) was added excess acetic anhydride (1 mL) and the mixture was stirred at room temperature for 15 minutes. After quenching with methanol (5 mL), the solvent was concentrated and the residue was purified on silica gel (50˜75% ethyl acetate in hexane) to give 0.12 g of the title compound (76% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=6.25 Hz, 6 H) 1.49 (d, J=6.99 Hz, 3 H) 2.00 (s, 3 H) 4.44-4.60 (m, 1 H) 5.06-5.20 (m, 1 H) 5.67 (d, J=6.99 Hz, 1 H) 6.87-6.97 (m, 2 H) 7.16-7.24 (m, 2 H) 7.27-7.34 (m, 2 H) 7.37 (s, 1 H) 7.38-7.44 (m, 2 H). MS (ESI), m/z 396.9 (M+H)+.
Reaction SMILES: C([Si](CC)(CC)[O:4][C@H:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:7][CH:8]([C:13]([O:15]C)=O)[C:9]([O:11]C)=O)C.[O:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[NH:34])[CH2:28][CH2:27]1.CC[O-].[Na+].Cl.O1CCOCC1>CCO>[CH2:20]([O:19][C:17](=[O:18])[C@@H:5]([OH:4])[CH2:6][CH2:7][C:8]1[C:9]([OH:11])=[N:34][C:33]([NH:32][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[N:35][C:13]=1[OH:15])[CH3:21]
Reactant: CCOC(=O)[C@H](CCC(C(=O)OC)C(=O)OC)O[Si](CC)(CC)CC
Reactant: N=C(N)NC1CCOCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](O)CCc1c(O)nc(NC2CCOCC2)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A solution of 398 (3.75 g, 9.46 mmol), 24 (1.63 g, 11.4 mmol), EtOH (30 mL) and NaOEt (3.86 g, 11.4 mmol) was heated to 85° C. and stirred overnight. The reaction was cooled to RT and quenched reaction by addition of 4N HCl in dioxane (2.37 mL, 9.46 mmol) and the solution concentrated. The crude product was purified by reverse phase chromatography (Biotage 40 M C18 using a C18 samplet loaded using water) eluting with a MeCH/H2O chromatography (0-60% MeCN) over 30 column volumes to afford 1.25 g (37%) of (S)-ethyl-4-(4,6-dihydroxy-2-(tetrahydro-2H-pyran-4-ylamino) pyrimidin-5-yl)-2-hydroxybutanoate (400): MS m/z (APCI-pos) M+1=342.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:25]([OH:27])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O[N:62]=[C:63]([O:65][CH2:66][CH3:67])[NH2:64]>CN(C)C=O>[CH2:66]([O:65][C:63]1[N:64]=[C:25]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)[O:27][N:62]=1)[CH3:67]
Reactant: CCOC(N)=NO
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccc(CC(F)(F)F)cc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 459 mg (0.889 mmol, purity 75%, 2:1 cis/trans isomer mixture) of the carboxylic acid from Example 59A in 19 ml of N,N-dimethylformamide were added, at RT, 541 mg (1.42 mmol) of HATU and 0.45 ml (337 mg, 2.61 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 136 mg (1.30 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at room temperature overnight. The reaction solution was purified directly by means of preparative HPLC. The resulting intermediate was taken up in toluene (50 ml), admixed with 4 Å molecular sieve and stirred under reflux overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by means of preparative HPLC. Yield: 124 mg (31% of theory)
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[C:16](=[O:17])[O:18][CH2:19][CH3:20]
Reactant: ClCCNCCCl
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N(CCCl)CCCl
Temperature: 25 °C
Yield: 100 %

Procedure:
bis(2-Chloroethyl)amine hydrochloride (Tokyo Chemical Industry CO., LTD., 3.0 g) was dissolved in acetone (50 ml), potassium carbonate (3.0 g) and ethyl chloroformate (2.4 ml) were added, and the mixture was heated under reflux for 4 hr. After completion of the reaction, the mixture was cooled to room temperature, and the solid was filtered off. The filtrate was evaporated under reduced pressure to give ethyl bis(2-chloroethyl)carbamate (3.7 g, yield 100%).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Cl)=[CH:3][CH:2]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccc(C)cc1

Procedure:
0.1122 g (5×10-4 mols) of palladium acetate, 6.61 ml (50 millimols) of p-tolyl chloride, 6.78 ml (62.5 millimols) of ethyl acrylate and 11.91 ml (50 millimols) of tri-n-butylamine in 100 ml of p-xylene are stirred for 3 hours at 120° C. The mixture is extracted by shaking with 50 ml of 2 N HCl, 25 ml of 2 N NaOH and 25 ml of water, and is then dried for 15 minutes with 5 g of magnesium sulphate. The crude product is distilled in vacuo. 6.08 g (64% of theory) are obtained as a colourless liquid. Analysis for C12H14O2 : calculated C 75.77%, H 7.52%; found C 75.73%, H 7.54%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1C(OC)=O.CN1CCNCC1.CN1CCCC1=O>O>[C:7]1([C:5]2[S:4][CH:3]=[C:2]([NH2:1])[CH:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CN1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1csc(-c2ccccc2)c1
Temperature: 160 °C
Yield: 45.3 %

Procedure:
A mixture of methyl 3-amino-5-phenylthiophene-2-carboxylate (2.50 g, 10.7 mmol), 3.5 mL of N-methylpiperazine and 12 mL of N-methylpyrrolidinone is heated at 160° C. for 4 hours. The reaction mixture is cooled to room temperature and poured into 100 mL of water. The solids are collected by filtration washing with 50 mL of water. Ethyl acetate and hexane are added and the filtrate is decanted off from the gummy black residue. The filtrate is concentrated to provide 850 mg of 5-phenyl-3-thienylamine as a yellow solid, mp 76-78° C.; 1H NMR (DMSO-d6) δ 4.87 (s, 2H), 5.98 (d, J=1.5 Hz, 1H), 6.95 (d, J=1.5 Hz, 1H), 7.28 (m, 1H), 7.37 (t, J=7 Hz, 2H), 7.53 (d, J=7 Hz, 2H); MS 176.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.[CH3:22][N:23](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:22]#[N:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2cc(Cl)c[n+]3[O-])cc1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(Cl)cc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-4-oxide (8.75 g, 27.12 mmol) in 1,2-dichloroethane (250 mL) was added dimethylcarbamic chloride (4.37 g, 40.66 mmol) and trimethylsilyl cyanide (4.03 g, 40.66 mmol) successively. The mixture was stirred under nitrogen at 80° C. overnight. The reaction mixture was quenched by adding sat'd. aq. NaHCO3 solution. The organic layer was washed with water (50 mL×3), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with petroleum ether EtOAc (8:1) to afford 4.8 g (53%) of 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile as a white solid. MS (ESI): m/z=332.0 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10](=[O:24])[CH:11]([N:13]2[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]2=[O:23])O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:29])=O>O1CCOCC1>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10](=[O:24])[CH:11]([N:13]2[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]2=[O:23])[Cl:29])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2 g of poly-Hunig base in 8 ml of dioxan is stirred for 30 minutes at room temperature, 832 mg of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester dissolved in 12 ml of dioxan are added and then slowly a solution of 0.54 ml of thionyl chloride in 10 ml of dioxan is added. The mixture is stirred for 2 hours at room temperature, the poly-Hunig base is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is purified by chromatography over silica gel with toluene/ethyl acetate (1:1) and yields the 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in crude form.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[P:27]([O-:39])([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28]>>[P:27]([O:39][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:28]
Reactant: CCCCOP(=O)([O-])OCCCC
Reactant: CN1CCC(=NO)CC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CCCCOP(=O)(OCCCC)OC1(N=O)CCN(C)CC1

Procedure:
Dibutyl 1-methyl-4-nitrosopiperidin-4-yl phosphate was prepared from 1-methyl-piperidin-4-one oxime, lead tetraacetate and dibutyl phosphate using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 4.03-4.17 (4H, m), 2.77-2.88 (2H, m), 2.27-2.40 (6H, m), 2.12-2.24 (4H, m), 1.59-1.83 (6H, m), 1.38 (4H, q, 7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]=[N+:15]=[N-:16])[CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: COc1cccc(N=[N+]=[N-])c1
Reaction time: 2 h

Procedure:
A solution of 9.26g. (0.08 mole) of 3-methoxyaniline in 40 ml. of water and 20 ml. of concentrated HCl was cooled to 0° C. There was then added a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water, and the reaction mixture was aged for 1/2 hour. There was next added 70 ml. of hexane followed by dropwise addition of a solution of 5.72g. (0.088 mole) of NaN3 in 20 ml. of water. After addition was complete, the reaction mixture was aged for 2 hours at room temperature. The aqueous and organic components were separated and the aqueous component was extracted with 50 ml. of hexane. The hexane component and extract were dried over MgSO4 and concentrated under reduced pressure to 10.77g. (50.5%) of a yellow oil. Structure of the product as 3-methoxyphenylazide was confirmed by IR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) was dissolved in DMF (50 mL). K2CO3 (6.48 g, 46.9 mmol) and benzyl bromide (2.80 mL, 23.6 mmol) were added. The reaction mixture was stirred at room temperature overnight, quenched with H2O (150 mL), and extracted with EtOAc (2×150 mL). The organic layers were dried over MgSO4 and concentrated to give a white solid (7.18g, 98% yield) which was used as it is for the next step. 1H NMR (400 MHz, CDCl3) δ 7.34-7.46 (m, 5 H) 7.21 (s, 1 H) 7.08 (s, 1 H) 5.13 (s, 2 H) 3.90 (s, 3 H) 3.02 (s, 2 H) 1.49 (s, 6 H); LCMS for C19H20O4 m/z 313.20 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:15]2[CH:16]=[CH:17][CH:18]=[N:12][CH:13]=[CH:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CNCCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1C=CC=NC=C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromophenylsulphonyl chloride (1.50 g) in dicbloromethane (50 ml) was added slowly to a solution of homopiperazine (3.0 g) in dichloromethane (100 ml). The reaction was stirred at room temperature for 18 hours. The reaction mixture was washed with water (40 ml) and brine (150 ml), dried (MgSO4) and solvent removed in vacuo. The product was recrystallised from dichloromethane/hexane to give 1-(4-bromophenylsulphonyl) 1,4-diazepine a white solid (650 mg, mp 95-97° C.;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCc2cc(O)ccc2C1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1

Procedure:
The 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid obtained in the above is caused to react with benzyl bromide in the presence of potassium hydroxide, to obtain 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid. The compound thus obtained is heated under reflux in the presence of an acid catalyst to obtain 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[H-].[Na+]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: Oc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)nc(Oc2ccc(I)cc2)n1
Yield: 68.4 %

Procedure:
Under an argon atmosphere, phosphorus oxychloride (2 ml) was added to 4,6-dimethyl-2-hydroxypyrimidine (400 mg), and the resulting mixture was stirred for 1 hour while heating the mixture to reflux. The reaction solution was cooled to room temperature, and the cooled solution was added in small portions to water. After adding sodium hydrogen carbonate in small portions to the resulting mixture to neutralize it, the mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to obtain 2-chloro-4,6-dimethylpyrimidine (350 mg). (2) In the same manner as in Reference Example 8, 4-iodophenol (223 mg) and 2-chloro-4,6-dimethylpyrimidine (157 mg) were reacted by using sodium hydride to obtain 2-(4-iodophenoxy)-4,6-dimethylpyrimidine (226 mg).