Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[C:11]=1[O:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1.[CH2:28]([NH2:34])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:28]([NH:34][C:2]([N:24]1[C:25]([CH3:27])=[CH:26][C:22]([O:21][C:11]2[C:12]([F:20])=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][C:10]=2[Cl:9])=[N:23]1)=[O:3])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NCC1CCCO1
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)nn1C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
Trichloromethyl chloroformate (0.39 g, 2.0 mmol) was added to a chloroform (10 mL) solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.59 g, 2.0 mmol) at 0° C., and while the mixture was allowed to gradually warm up to a room temperature, it was further stirred at room temperature for 3 hours. Tetrahydrofurfurylamine (0.61 g, 6.0 mmol) and triethylamine (0.4 g, 4.0 mmol) were added to the reaction mixture, and the mixture was refluxed under heating for 5 hours. After completion of the reaction, the reaction mixture was poured into ice and extracted with chloroform (20 mL×3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate, the desiccant was removed by filtering, and the solvent was distilled off the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane= 1/10˜⅕) to give a colorless viscous substance of N-tetrahydrofurfuryl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.25 g, yield: 29.6%). 1H-NMR (CDCl3, TMS, ppm): δ1.50-1.65 (m, 1H), 1.75˜2.05 (m, 3H), 2.58 (s, 3H), 3.32 (dt, J=6.3 and 13.9 Hz, 1H), 3.48 (ddd, J=3.7, 5.7 and 13.9 Hz, 1H), 3.74 (dq, J=7.0 and 8.6 Hz, 2H), 4.03 (dq, J=3.7 and 7.0 Hz, 1H), 5.79 (s, 1H), 6.85˜7.10 (m, 1H), 7.39 (dd, J=1.9 and JHF=9.3 Hz, 1H), 7.56 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Si:18]([O:35][CH:36]1[CH2:39][C:38](=O)[CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[Si:18]([O:35][CH:36]1[CH2:37][C:38](=[CH:9][C:7]#[N:8])[CH2:39]1)([C:31]([CH3:33])([CH3:34])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](OC1CC(=O)C1)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1.0 M potassium tert-butoxide in tetrahydrofuran (46.0 mL, 46.0 mmol) at 0° C. was added diethyl cyanomethylphosphonate (7.8 mL, 48 mmol). The bath was removed and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction was re-cooled to 0° C., and a solution of 3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutanone (15.7 g, 48.4 mmol, from Step 3) in tetrahydrofuran (80 mL) was added. During the course of the addition, additional tetrahydrofuran (50 mL) was added into the receiving flask to facilitate stirring. Upon complete addition of the ketone, the bath was removed and the reaction allowed to reach room temperature and stirred overnight. The reaction mixture was partitioned between water and ethyl acetate and the aqueous was extracted with ethyl acetate a total of three times. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography, eluting with a gradient of 0-10% ethyl acetate in hexanes afforded product (16.1 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.74-7.58 (m, 4H), 7.49-7.34 (m, 6H), 5.13 (dddd, 1H), 4.34 (tt, 1H), 3.16-2.90 (m, 4H), 1.05 (s, 9H).
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])(=O)OC.O.[NH2:27][NH2:28]>>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[N:28]=[N:27][C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]=2[CH:16]=1
Reactant: O=C1CCCCCC1=O
Reactant: COP(=O)(CC(=O)c1ccccc1C)OC
Reactant: NN
Solvent: O
Product: Cc1ccccc1-c1cc2c(nn1)CCCCC2

Procedure:
light yellow solid. MS (EI): 238.2 (M+). Prepared from cycloheptane-1,2-dione, (2-Oxo-2-o-tolyl-ethyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH2:22][CH2:23][O:24][CH3:25])[CH2:18][CH2:19][O:20][CH3:21])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][C:30]2[NH:31][C:32](=[O:34])[S:33][C:29]=2[CH:28]=1>>[CH3:21][O:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24][CH3:25])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([NH:26][C:27]4[C:36]([O:37][CH3:38])=[CH:35][C:30]5[NH:31][C:32](=[O:34])[S:33][C:29]=5[CH:28]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:16]
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: COCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: COCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
150 mg (391 μmol) (RS)-4-chloro-N,N-bis(2-methoxyethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 93a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 27.1 mg (12%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[OH:29][CH2:30]C1CNCC1O>>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][C@@H:25]([CH2:30][OH:29])[C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OCC1CNCC1O
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](CO)[C@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35) and 4-(hydroxymethyl)pyrrolidin-3-ol hydrochloride to afford an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=476.2/478.2 [M+H]+, m/z=474.0/476.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.11-2.23 (m, 1H) 3.25-3.34 (m, 2H) 3.39-3.49 (m, 1H) 3.50-3.62 (m, 2H) 3.83-3.96 (m, 2H) 4.04-4.12 (m, 1H) 4.70 (t, J=5.27 Hz, 1H) 5.07 (d, J=4.37 Hz, 1H) 7.33 (d, J=8.75 Hz, 2H) 7.83 (d, J=9.00 Hz, 2H) 8.32 (d, J=2.06 Hz, 1H) 8.66 (d, J=1.80 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([P:17]([O-:20])(=[O:19])[O-:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C([O-])(O)=O.[Na+:27].[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34](Cl)=[O:35].Cl>CC(C)=O.CCOC(C)=O.O>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([NH:1][C@@H:2]1[C:21](=[O:22])[N:4]2[C:5]([P:17]([O-:18])(=[O:20])[O-:19])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:35].[Na+:27].[Na+:27]
Reactant: Cn1nnnc1SCC1=C(P(=O)([O-])[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)Cc1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cn1nnnc1SCC1=C(P(=O)([O-])[O-])N2C(=O)[C@@H](NC(=O)Cc3ccco3)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of 10 mmoles 7β-amino-3-(N-methyltetrazolylthiomethyl)-3-cephem-4-phosphonate in 100 ml. water and 100 ml. acetone containing 5 g. NaHCO3 is added 20 mmoles 2-furylacetyl chloride in 40 ml acetone at 0° C. After 1 hr. stirring at 0° and 2 hrs at 25° the acetone is pumped off in vacuo and the aqueous solution added to 100 ml. water and 200 ml. EtOAc. The pH is adjusted to 2 with HCl and the ethyl acetate layer separated, and evaporated. The residue is taken up in 50 ml water containing 1.6 g. NaHCO3 and lyophilized, providing the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:44]2[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[C:26]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][C:24](=[O:31])[N:23]([CH2:32][C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[O:34])[C:22]1=[O:43]>C(Cl)(Cl)Cl>[F:13][C:14]1[CH:15]=[C:16]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[NH:3][C:4](=[O:7])[O:5][N:51]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[C:26]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][C:24](=[O:31])[N:23]([CH2:32][C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[O:34])[C:22]1=[O:43]
Reactant: O=C([O-])O
Reactant: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCCOc1cc(=O)n(CC(=O)c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.44 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.45 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.15 g, 30%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][O:23][NH2:24])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)C(C)C)C.S(=O)(=O)(O)O.[NH2:39][C:40]1[CH:41]=[N:42][N:43]([CH3:46])[C:44]=1[NH2:45]>C(Cl)Cl>[NH2:45][C:44]1[N:43]([CH3:46])[N:42]=[CH:41][C:40]=1[NH:39][C:1]([NH:24][O:23][CH2:22][CH2:21][NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])=[O:2]
Reactant: Cn1ncc(N)c1N
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)NOCCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (973 mg) in methylene chloride (10 ml) was added O-[2-(tert-butoxycarbonylamino)ethyl]hydroxylamine (1.11 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added N-ethyldiisopropylamine (1.28 g) and 4,5-diamino-1-methylpyrazole sulfuric acid salt (1.05 g), and the mixture was stirred under reflux for 4 hours. The reaction mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 10% methanol/chloroform to give 5-amino-4-(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}ureido)-1-methylpyrazole (255 mg) as a solid.
Reaction SMILES: [S:1]([C:5]1[N:6]=[C:7]2[N:11]([C:12]=1C(OCC)=O)[CH:10]=[CH:9][S:8]2)([CH3:4])(=O)=O.[CH2:18](S)[CH2:19]C>>[CH2:4]([S:1][C:5]1[N:6]=[C:7]2[N:11]([CH:12]=1)[CH:10]=[CH:9][S:8]2)[CH2:18][CH3:19]
Reactant: CCCS
Reactant: CCOC(=O)c1c(S(C)(=O)=O)nc2sccn12
Product: CCCSc1cn2ccsc2n1

Procedure:
In a manner similar to the procedure in Reference Example 1, the oily title compound was prepared from ethyl 6-mesylimidazo[2,1-b]thiazole-5-carboxlate and n-propyl mercaptan. ##STR9## NMR(CDCl3) δ: 1.00(t, 3H), 1.43-1.90(m, 2H), 2.88(t, 2H), 6.83(d, 1H), 7.38(s, 1H), 7.47(s, 1H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.ClC1C=CC=CC=1>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCOC(=O)CNC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: Clc1ccccc1
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: -10 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A chlorobenzene solution (45.0 ml) of N-acetylglycine ethyl ester (1.50 g, 10.33 mmol) and N-methylimidazole (1.02 g, 12.40 mmol) was cooled to −10° C., and palmitoyl chloride (2.84 g, 10.33 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 45 minutes at the same temperature, titanium tetrachloride (6.86 mg, 36.16 mmol) and tributylamine (7.66 g, 41.32 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −10° C. Water (20 mL) was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 3.33 g of the title compound (yield: 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:22])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Li])(=O)=O.[CH3:28][S:29]([CH3:32])(=[O:31])=[O:30]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([OH:22])([CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Reactant: CS(C)(=O)=O
Agent: [Li]S(C)(=O)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)CC1(O)CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl sulfone (64 mg) in tetrahydrofuran (4 mL) stirring at −78° C. under nitrogen was slowly added lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 0.67 mL). The resulting mixture was stirred for 1 h to form lithio methyl sulfone, and then a solution of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene (40 mg) in tetrahydrofuran (0.4 mL) was added. Upon completion of addition, the resulting mixture was stirred for 30 min at −78° C. After this time, the reaction mixture was allowed to warm to room temperature at which it was stirred for 16 h. At the conclusion of this period, the reaction mixture was analyzed by HPLC, which indicated that starting material was still present. The reaction mixture was again cooled to −78° C. and additional lithio methyl sulfone mixture (prepared from methyl sulfone, 64 mg, in the manner set forth above) was added. The resulting mixture was stirred for 30 minutes and then analyzed by HPLC, which indicated that the starting material had been consumed. The reaction mixture was quenched at −78° C. with saturated aqueous ammonium chloride solution, warmed to room temperature, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to yield a residue. The residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain the title compound (23 mg) as a racemic diastereomeric mixture, predominantly the diastereomer leading to Example 12 that results from nucleophilic addition of lithio methyl sulfone to the carbonyl of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene anti to the benzyloxycarbonylamino group.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(#N)C>[Br:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([N:25]=[N+:26]=[N-:27])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Br)o1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of 3-(5-bromo-2-furyl)acrylic acid (41.5 g) in acetonitrile (200 mL) were added triethylamine (23.0 g) and ethyl chloroformate (26.1 g). The mixture was stirred at room temperature for 30 min. To the obtained mixture was added a saturated aqueous solution of sodium azide (18.7 g) at 0° C. and the mixture was stirred at room temperature for 5 hr. The reaction mixture was filtered, and the obtained solid was washed with water. The solid was recrystallized from dichloromethane to give the title compound (20.7 g) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[N:22]C(OCC)=O)=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[NH:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH:30]([CH2:31][OH:32])[CH2:33][OH:34]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(CO)CO)c3cc2Br)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=N)(=O)c1cccc(COc2cc3ncnc(NC(CO)CO)c3cc2Br)c1
Yield: 24 %

Procedure:
According to GWP 6, the conversion of (RS)-S-(3-{[(6-bromo-4-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}quinazolin-7-yl)oxy]methyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide (45 mg, 0.081 mmol) and preparation thin layer chromatography (silica gel, dichloromethane/methanol: 4/1) gives the desired product in 24% yield (9 mg).
Reaction SMILES: CO[C:3]([CH:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7](=[O:17])(=[O:16])[N:6]1[CH3:18])=[O:4].[CH3:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([NH2:30])=[CH:27][CH:28]=2)[O:23][C:22](=[O:31])[CH:21]=1>C1(C)C(C)=CC=CC=1>[CH3:18][N:6]1[CH:5]([C:3]([NH:30][C:26]2[CH:27]=[CH:28][C:29]3[C:20]([CH3:19])=[CH:21][C:22](=[O:31])[O:23][C:24]=3[CH:25]=2)=[O:4])[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1(=[O:16])=[O:17]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)oc2cc(NC(=O)C3C(=O)c4ccccc4S(=O)(=O)N3C)ccc12
Temperature: 170 °C

Procedure:
8.1 g of 2-methyl-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 5.7 g of 4-methyl-7-amino-coumarin are dissolved in 280 ml of xylene and the solution is heated for 21/2 hours in a bath of 170° C. to distill off the methanol formed during the reaction. The reaction mixture is refluxed for a further 5 hours, cooled, and the precipitate is collected by filtration. The precipitate is digested with 100 ml of 2N-hydrochloric acid at elevated temperature, treated with 100 ml of chloroform and extracted. The residue is collected by suction, washed successively with water, ethanol, methylene chloride and diethyl ether, washed, and dried, affording 2-methyl-3,4-dihydro-4-oxo-N-(2-oxo-4-methyl-2H-1-benzopyran-7-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide with a melting point above 285° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[C:37]2[C:43]1[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=1>O1CCCC1.CN(C)C=O>[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[C:37]2[C:43]1[CH2:44][CH2:45][N:46]([CH2:12][CH:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)[CH2:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6c(c5O4)OCCC6)CC3)c2c1

Procedure:
To a mixture of (2R)-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]chromen-2-ylmethyl 4-methylbenzenesulfonate (0.25 g, 0.66 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethylformamide (20 mL) was added 0.45 g (2.08 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The reaction mixture was refluxed under nitrogen for six hours. After completion, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and 4% methanol/methylene chloride to elute the desired product as an oil, which was crystallized from isopropanol with the addition of a solution of oxalic acid in hot isopropanol to give 0.040 g (6%) of the (S)-enantiomer of the title compound as a dark yellow solid, m.p. 146-148° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][CH:6]=1.C1O[C:26]2[CH:25]=[C:24]3[C:20]([C:21]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:22][NH:23]3)=[CH:19][C:18]=2O1>>[ClH:1].[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[CH:26][CH:25]=2)[C:21]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:4]([C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=4)[NH:7][CH:6]=3)[CH2:3][CH2:2]2)=[CH:22]1
Reactant: COc1ccc2[nH]cc(CCCCl)c2c1
Reactant: c1[nH]c2cc3c(cc2c1C1CCNCC1)OCO3
Product: COc1ccc2[nH]cc(C3CCN(CCCc4c[nH]c5ccccc45)CC3)c2c1
Product: Cl

Procedure:
of 3-(3-chloropropyl)-5-methoxyindole with 4-(5,6-methylenedioxyindol-3-yl)piperidine:
Reaction SMILES: [CH3:1][C:2]1=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:12]1)=[CH2:7].C(C1C=CC=CC=1)(=O)C>CCCCCC>[CH3:14][CH:13]([C@H:10]1[C@@H:11]2[C@H:12]3[C:2](=[CH2:1])[CH2:3][CH2:4][C@H:5]3[C@:6]2([CH3:7])[CH2:8][CH2:9]1)[CH3:15]
Reactant: C=C1C=C[C@H](C(C)C)CCC(C)=CCC1
Agent: C=C1/C=C/[C@H](C(C)C)CC/C(C)=C/CC1
Solvent: CCCCCC
Solvent: CC(=O)c1ccccc1
Product: C=C1CC[C@@H]2[C@H]1[C@H]1[C@H](C(C)C)CC[C@]12C
Yield: 83.3 %

Procedure:
60 kg of leaves of Solidago viragaurea L. subsp. asiatica Kitamura was steam-distilled and 102 g of essential oil was obtained. 100 g of the essential oil containing 30 g of germacrene D was dissolved in 20 l of n-hexane with addition of 50 g of acetophenone and was subjected to internal irradiation with the light of high pressure mercury lamp for 10 hours. 25 g of β-bourbonene was obtained by fractional distillation under reduced pressure. (Conversion Ratio: 83%)
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].Cl[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:8]=1[S:15]([OH:18])(=[O:17])=[O:16].[Cl:19][CH2:20][CH2:21][C:22]#[N:23]>C(Cl)Cl.CC(C)=O>[Cl:14][C:9]1[CH:10]=[C:11]([Cl:13])[C:12]([Cl:19])=[CH:7][C:8]=1[S:15]([OH:18])(=[O:17])=[O:16].[S:1]([NH:5][C:22](=[NH:23])[CH2:21][CH2:20][Cl:19])(=[O:3])(=[O:2])[NH2:4]
Reactant: O=S(=O)(O)c1c(Cl)cc(Cl)cc1Cl
Reactant: N#CCCCl
Reactant: NS(N)(=O)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: N=C(CCCl)NS(N)(=O)=O
Product: O=S(=O)(O)c1cc(Cl)c(Cl)cc1Cl
Temperature: 57.5 °C

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a solution of 2,4,6-trichlorobenzenesulfonic acid (52.2 g, 0.2 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the heating period, the mixture was cooled to room temperature, diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml) and the suspension filtered and the product dried.