Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](O[Si](C)(C)C)=[CH:3][C:4]([O:6][Si](C)(C)C)=[CH2:5].[CH2:16]([NH:18][S:19](Cl)(=[O:21])=[O:20])[CH3:17].Cl>O1CCCC1>[CH2:16]([N:18]1[C:2]([CH3:1])=[CH:3][C:4](=[O:5])[CH2:6][S:19]1(=[O:21])=[O:20])[CH3:17]
Reactant: C=C(C=C(C)O[Si](C)(C)C)O[Si](C)(C)C
Reactant: CCNS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCN1C(C)=CC(=O)CS1(=O)=O
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution, cooled to -75°, of 24.5 g of 1-methyl-1,3-bis(trimethylsiloxy)-1,3-butadiene and 10.1 g of triethylamide in 100 ml of dry tetrahydrofuran was treated dropwise at -80° to -70° under argon with a solution of 14.4 g of N-ethyl-sulfamoyl chloride in 50 ml of dry tetrahydrofuran and the mixture was subsequently stirred at the same temperature for 2 hours. The temperature was then allowed to rise to room temperature, the mixture was stirred for 1 hour, acidified at 15°-20° with 110 ml of 2N hydrochloric acid and stirred for a further 15 minutes. The mixture was extracted with ether and the extracts, dried over sodium sulfate, were evaporated to dryness. The residual oil was dissolved in 250 ml of toluene, 0.4 g of methanesulfonic acid was added thereto and the mixture was heated to reflux for 15 hours with a water separator. The solution obtained was cooled, concentrated to dryness under reduced pressure and the residual oil was chromatographed on 280 g of silica gel with methylene chloride/ethyl acetate (9:1) as the elution agent. The uniform fractions were combined and evaporated. After triturating the residue with ether there were obtained 13.8 g of 2-ethyl-3-methyl-1,2-thiazin-5-(6H)-one 1,1-dioxide in the form of almost colorless crystals, m.p. 90°-92°. Recrystallization from ethanol did not increase the melting point.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[S:7][CH:8]=[C:9]([CH2:12]O)[C:10]=1[Cl:11]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[S:7][CH:8]=[C:9]([CH2:12][Cl:3])[C:10]=1[Cl:11]
Reactant: O=S(Cl)Cl
Reactant: OCc1csc(Cl)c1Cl
Solvent: ClC(Cl)Cl
Product: ClCc1csc(Cl)c1Cl
Temperature: 10 °C
Reaction time: 0.58 h

Procedure:
A mixtures of 357 g of thionyl chloride and 150 ml of chloroform is placed in a 1 liter flask and cooled to 10° C. At 10° to 15° C. and over a period of 35 minutes, a solution of 238 g of 2,3-dichloro-4-hydroxymethylthiophene in 350 ml of chloroform is added. After the exothermic reaction has subsided, the solution is stirred for 1 hour at 30° C., concentrated under reduced pressure and, after a small amount of triethylamine has been added, purified by distillation at 66° to 69° C./0.2 mbar. The yield is 192 g, equivalent to 70% of theory.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[CH:25]=1>CN(C=O)C.O>[Br:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: BrCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3cccc(CBr)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.15 g, 0.74 mmol) in DMF (7.5 mL) was added cesium carbonate (0.72 g, 2.2 mmol) and 1,3-bis(bromomethyl)benzene (0.29 g, 1.1 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% EtOAc/DCM) to afford methyl 2-[3-(bromomethyl)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.12 g, 42%). LC-MS: (FA) ES+ 388.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O>[NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(N)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(C(=O)O)cc1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A mixture of methyl 5-amino-2,4-dimethylbenzoate (1.2 g, 6.70 mmol, 1.00 equiv) and sodium hydroxide (1.5 g, 37.50 mmol, 5.60 equiv) in methanol/H2O (20/20 mL) was stirred overnight at 50° C. After cooling to ambient temperature, the organic phase was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to ˜4-5 with hydrogen chloride (aq., 2 M). The resulting solids were collected by filtration and dried to yield 1.0 g of a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc2cc(OC)ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1coc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6-Methoxy-benzofuran-3-carboxylic acid ethyl ester (25) (9.3 g, 42 mmol) is dissolved in 80 ml of dichloromethane and cooled to 0° C. 1M solution of BBr3 in dichloromethane (84.5 ml, 84.5 mmol) is added and the mixture is stirred at rt for 2 h. The mixture is poured on ice water and neutralized with sodium hydrogen carbonate. The organic layer is dried over sodium D sulfate, filtrated and evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:17][C:5]2=[N:6][C:7]=1[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[H-].[Na+].[CH3:30]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:17][C:5]2=[N:6][C:7]=1[CH2:8][N:9]([CH3:30])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1nc2ccn(COCC[Si](C)(C)C)c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1nc2ccn(COCC[Si](C)(C)C)c2cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a mixture of tert-butyl (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)methylcarbamate (300 mg, 0.75 mmol) in THF (5 mL) was added NaH (60% dispersion in mineral oil, 110 mg, 2.25 mmol). After stirring at RT for 30 min, CH3I (320 mg, 2.25 mmol) was added, followed by stirring at RT for 3 h. The reaction mixture was quenched by adding a sat'd. aq.solution of NH4Cl and extracted with EtOAc (30 mL×2). The combined extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a petroleum ether:EtOAc gradient (10:1 to 1:1) to afford 200 mg (66.6%) of tert-butyl (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl(methyl)carbamate as a brown oil. MS (ESI): m/z=410.3 [M+1]+.
Reaction SMILES: [CH2:1]([C:7]1[C:8]([CH:21]=[O:22])=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:1]([C:7]1[C:8]([CH2:21][OH:22])=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCc1cc2c(cc1CO)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
A solution of 4.14 g of 3-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-aldehyde (from Example 4.1) in 20 ml of THF was cooled to 0° C. and treated with 13.8 ml of borane-THF complex sol. 1M in THF (3 H eq.). The mixture was stirred at room temperature for 90 min., then cooled back at 0° C. and quenched carefully by the addition of 30 ml of hydrochloric acid 3N. The mixture was stirred at room temperature for 30 min., then was extracted with 3 portions of 100 ml ether. The combined extracts were washed with water (100 ml) and a saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo, giving a pale yellow oil. Flash chromatography (SiO2, 10% ethyl acetate/hexane) afforded 3.80 g of the title compound as a colourless oil. 1 H NMR (CDCl3): 7.27 (s, 1H), 7.11 (s, 1H), 4.67 (d, J=5.7 Hz, 2H), 2.59 (t, J=8.3 Hz, 2H), 1.67 (s, 4H), 1.50-1.65 (m, 2H), 1.20-1.45 (m,6H), 1.28 (s, 6H), 1.27 (s, 6H), 0.89 (t, J=6.6 Hz, 3H).
Reaction SMILES: N.Cl.C[NH:4]C.[O:6]=[C:7]1[C:15]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:27][C:28]1[O:29][CH:30]=[C:31]([C:33](O)=[O:34])[N:32]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1OC(C(O)=O)=CC=1>O1CCOCC1>[O:6]=[C:7]1[C:15]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:27][C:28]1[O:29][CH:30]=[C:31]([C:33]([NH2:4])=[O:34])[N:32]=1
Reactant: CNC
Reactant: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Agent: Cl
Agent: N
Agent: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Solvent: C1COCCO1
Product: NC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1

Procedure:
Following the procedure as described in EXAMPLE 13.1 and making non-critical variations using 4 M ammonia solution in dioxane to replace dimethylamine hydrochloride, 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid to replace 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid, 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide was obtained (19%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.53 (d, J=10.2 Hz, 2H), 7.33-6.99 (m, 4H), 6.54 (s, 1H), 6.38 (s, 1H), 5.22-5.01 (m, 2H), 4.75 (ABq, 2H), 4.46 (t, J=8.8 Hz, 2H), 2.92 (t, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.3, 161.9, 161.6, 160.9, 159.2, 143.2, 142.2, 136.8, 132.5, 129.2, 124.1, 123.8, 120.8, 120.4, 119.7, 109.6, 92.8, 80.0, 72.5, 57.3, 37.4, 28.7; MS (ES+) m/z 403.8 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:80][C:81]1[CH:87]=[CH:86][CH:85]=[CH:84][C:82]=1[NH2:83].C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:80][C:81]1[CH:87]=[CH:86][CH:85]=[CH:84][C:82]=1[NH:83][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:24]
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: Nc1ccccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1F)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 6 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-fluoroaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (6%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[N:8]=1)(=O)=O.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>>[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Sn:17]([CH3:19])([CH3:18])[CH3:16])[N:8]=1
Reactant: O=S(=O)(Oc1cccc(Cl)n1)C(F)(F)F
Reactant: C[Sn](C)(C)Cl
Product: C[Sn](C)(C)c1cccc(Cl)n1

Procedure:
6-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mmol) was used in Procedure I with trimethyltin chloride to yield 2-chloro-6-(trimethylstannyl)pyridine. The crude material (˜4 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (2 mmol). Purified by silica gel chromatography (5-45% ethyl acetate/hexane) to yield N-(4-chloro-3-(6-chloropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.45 (25% ethyl acetate/hexanes); MS (Q1) 426 (M)+.
Reaction SMILES: B.[CH3:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7].[ClH:13]>O1CCCC1.CO>[ClH:13].[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[C:10]([OH:11])=[C:9]([CH3:12])[CH:8]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CN)cc(C)c1O
Temperature: 25 °C

Procedure:
A solution of borane in tetrahydrofuran (1M in tetrahydrofuran, 27.1 mL, 27.1 mmol) was added dropwise to a solution of 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in tetrahydrofuran (70 mL) and the resulting solution was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature, treated with 6N hydrochloric acid (20 mL) and heated under reflux for a further 30 minutes. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo. The residue was purified using a strong cation exchange resin eluting with methanol followed by 2M ammonia in methanol, to give an orange oil. This oil was then treated with 1M hydrogen chloride in methanol (20 mL) and the reaction mixture was concentrated in vacuo to afford the title compound as a pale yellow solid in quantitative yield, 1.12 g. 1HNMR (400 MHz, CDCl3) δ: 2.22 (6H, s), 3.75 (2H, s), 6.90 (2H, s).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[NH2:20].N1C=CC=CC=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[NH:20][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(F)cc1-c1ccc2c(Br)c(N)ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2c(Br)c(NC(=O)C3CC3)ncc2c1

Procedure:
To 4-bromo-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (46 mg, 140 μmol) and pyridine (110 μl, 1.4 mmol) in dichloromethane (3.0 mL) at ambient temperature was added dropwise cyclopropanecarbonyl chloride (60 μl, 0.66 mmol). After 1 h the mixture was poured into saturated aqueous sodium bicarbonate, extracted twice into dichloromethane and the combined organic phases dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by reverse phase HPLC (gradient of acetonitrile in water with 0.1% formic acid) to yield the title compound as a white amorphous solid (57 mg, quant.). 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.26 (s, 1H), 8.27-8.14 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.49-7.33 (m, 1H), 7.21 (t, J=9.2 Hz, 2H), 2.25 (s, 3H), 1.98-1.84 (m, 1H), 0.90-0.78 (m, 4H). LCMS (Method E): RT=5.299 min, M+H+=399.0 & 401.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][SH:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][S:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Reactant: Fc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccc(F)cc2)C1
Yield: 100.2 %

Procedure:
Using a similar method to that described in Example 93, step 1, (3R)-1-(tert-butoxycarbonyl)-3-[(methanesulfonyloxy)methyl]pyrrolidine (1.5000 g, 5.37 mmol) was reacted with 4-fluorobenzyl mercaptan (1.5511 g, 10.91 mmol) and potassium carbonate (1.1132 g, 8.05 mmol) in DMF (30 ml) at room temperature for 24 h to give 1.7507 g (100%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.45 (9H, s), 1.60 (1H, m), 2.00 (1H, m), 2.44 (2H, m), 2.97 (1H, m), 3.28 (1H, m), 3.46 (2H, m), 3.69 (2H, s), 7.00 (2H, t, J=8.6 Hz), 7.25-7.29 (2H, m). m/e (ES+) 348 (M+Na)+, 326 M+H)+, 270 (M-CMe3 +2H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9](O)=O)=[CH:4][CH:3]=1.[I-].[NH:29]=[C:30]([NH2+:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([C:9]2[NH:38][N:37]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=2)[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: N=C([NH2+]N)c1ccccc1
Reactant: CC[C@](C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [I-]
Product: CC[C@@](c1ccc(Cl)cc1)(c1nc(-c2ccccc2)n[nH]1)n1ccc2c(NS(C)(=O)=O)cccc21

Procedure:
Compound 64 was synthesized from compound 4a following procedures similar to those presented in Example 6, substituting [imino(phenyl)methyl]hydrazinium iodide for N′-hydrozybenzenecaroximidamide. m/z (ES) 506 (MH)+; IP=C rating.
Reaction SMILES: C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([Li])(C)(C)C.[OH:17][C:18]1[CH:35]=[CH:34][C:33]2[C@:32]3([CH:36]=O)[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[CH2:27][C@H:26]([OH:38])[CH2:25]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1.[Cl-].[NH4+]>C(COC)OC.CCCCC>[F:11][C:9]([F:10])=[CH:36][C@:32]12[CH2:31][CH2:30][C@@:28]3([CH3:29])[C@@H:24]([CH2:25][C@@H:26]([OH:38])[CH2:27]3)[C@@H:23]1[CH2:22][CH2:21][C:20]1[CH:19]=[C:18]([OH:17])[CH:35]=[CH:34][C:33]2=1
Reactant: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Reactant: CCOP(=O)(OCC)C(F)F
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: COCCOC
Solvent: CCCCC
Product: C[C@]12CC[C@]3(C=C(F)F)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Temperature: -75 °C

Procedure:
1.5 ml of dimethoxyethane (molecular sieve), 0.3 ml of pentane and 0.13 ml (0.77 mmol) of diethyl(difluoromethyl)-phosphonate are introduced into a reaction flask that was rendered inert, and cooled to about −75° C. After 0.72 ml (1.07 mmol) of tert-butyllithium (1.5 M in pentane) is added and after 30 minutes of reaction time, 0.14 g (0.31 mmol) of 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde, dissolved in a mixture of 1.5 ml of dimethoxyethane/0.3 ml of pentane, is added to the reaction solution. The reaction solution is refluxed until the reaction is completed. After being added into cooled ammonium chloride solution, it is extracted with ethyl acetate. The organic phase is concentrated by evaporation under vacuum, the residue is taken up in 5 ml of methanol and mixed with 0.5 ml of dilute hydrochloric acid (1/1). Ethyl acetate is added to the reaction solution, the organic phase is washed with sodium bicarbonate solution and concentrated by evaporation under vacuum. The crude product that is obtanied is purified by column chromatography on silica gel (cyclohexane/ethyl acetate, 2/1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:22](=[O:28])[CH:23](OCC)O)[C:12]2[O:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[NH:14][C:13]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]([OH:28])[CH2:23][NH:40][C:37]([CH3:38])([CH3:39])[CH2:36][C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[C:12]2[O:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[NH:14][C:13]=2[CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2
Reactant: CC(C)(N)Cc1ccc(F)cc1
Product: CC(C)(Cc1ccc(F)cc1)NCC(O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2

Procedure:
385 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one and 167 mg (1 mmol) 2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamine are reacted and worked up analogously to Example 14. However, the resulting benzylether is chromatographed on a silica gel column (dichloromethane/methanol gradient).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[S:38][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:41]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[S:38][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:25]([F:28])([F:27])[F:26])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:40][CH:41]=1)(=[O:35])=[O:36])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F

Procedure:
N-tert-Butyl-5-{3-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.49) (0.46 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light brown solid (0.46 g), which was subsequently deprotected.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:5])C.[OH-].[Na+]>CO.O1CCCC1>[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of 1-(3-ethoxycarbonylpropyl)-2,4(1H,3H)-quinazolinedione (552 mg) and 1N sodium hydroxide (6.0 ml) in methanol-tetrahydrofuran (26 ml, 3.3:1 V/V) was stirred for 3 hours at room temperature. After evaporation of the organic solvents, the mixture was adjusted to pH 4~5 with 1N hydrochloric acid to give precipitates. Collected precipitates were washed in turn with water and ethanol to give 1-(3-carboxypropyl)-2,4(1H,3H)-quinazolinedione (393 mg) as a powder.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](=[O:22])[NH:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (520 mg, 1.73 mmol) in dichloromethane (60 ml) was added pyridine (690 mg, 8.72 mmol) followed by the addition of Tf2O (1.22 g, 4.32 mmol), and the resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of ice-water (200 ml) and extracted with dichloromethane (2×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (880 mg, crude).