Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:12][CH2:13][CH2:14][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:10])[F:11]
Reactant: FC(F)(F)c1ccccc1S
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccccc1SCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)thiophenol (2.96 ml, 22 mmol; CAS Reg. No. 13333-97-6) in DMF (65 ml) were added 1,2-dibromoethane (9.67 ml, 112 mmol) and potassium carbonate (3.41 g, 25 mmol). The reaction mixture was stirred for 2 h 30 min at ambient temperature. AcOEt (30 ml) and water (30 ml) were added and the layers were separated. The aqueous layer was extracted three times with AcOEt (3×20 ml). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give the title compound as yellow oil (6.0 g, 22 mmol; quant.) which was sufficiently pure to be used in the next step.
Reaction SMILES: [BH4-].[Na+].[N+:3]([CH:6]=[CH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([O-:5])=[O:4].C(O)(=O)C>O1CCOCC1.C(O)C>[N+:3]([CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCO
Product: O=[N+]([O-])CCc1ccc2ccccc2c1
Temperature: 0 °C
Yield: 6.7 %

Procedure:
To a suspension of sodium borohydride (4 g) in a mixture of dioxane (85 ml) and ethanol (30 ml) was added dropwise a solution of 2-(2-nitroethenyl)naphthalene (100 g) in dioxane (90 ml) over 30 minutes. The flask was cooled with a cold water bath during addition. Stirring was maintained for an additional 11/2 hours. Ice (100 ml) and 50% aqueous acetic acid (12 ml) were added and the mixture was stirred for 2 hours at room temperature, concentrated in vacuo and extracted with methylene chloride. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo to yield an oil which was crystallized from acetic acid to give the title compound (6.79 g) as a yellow solid, m.p. 59-60° C.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](OC)=O.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1ccccc1OC
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3OC)nc(=O)c1-2
Yield: 52.7 %

Procedure:
Sodium (590 mg) was dissolved in ethanol (45 mL) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.65 g, 12 mmol), followed by methyl 2-methoxyphenylacetate (4.7 g, 26 mmol) were added. The reaction mixture was refluxed overnight, the solvent was stripped and the residue was treated with water and then 2N HCl. The product was collected by filtration and recrystallized from ethyl acetate to afford 2.23 g of 1-cyclopentyl-3-ethyl-6-(2-methoxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 145-146° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].O>C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(Br)cn1
Temperature: 160 °C
Yield: 89 %

Procedure:
2,5-Dibromo-pyridine (3.0 g, 12.7 mmol) and sodium thiomethoxide (0.84 g, 12 mmol) were dissolved in 18 ml anhydrous N N-dimethylformamide. The mixture was heated at 160° C. under nitrogen for 6 hrs. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The aqueous layer was extracted with ethyl acetate several times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→6% EtOAC/Hexane) to give 5-Bromo-2-methylsulfanyl-pyridine as a white solid (2.18 g, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.09 (dd, 1H, J=0.7, J=8.6), 7.59 (dd, 1H, J=2.4, J=8.6), 8.50 (m, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.CN1CCOCC1.C(Cl)(=O)OCC(C)C.Cl.[C:22]12([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:22]12([CH2:32][CH2:33][N:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:3](=[O:5])[CH2:2][Br:1])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: CCCCCNCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)CBr
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CBr
Temperature: -15 °C

Procedure:
Bromoacetic acid (0.50 g, 3.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), and the solution was stirred at −15° C. under a nitrogen atmosphere. N-Methylmorpholine (0.40 ml, 3.6 mmol) and isobutyl chlorocarbonate (0.45 ml, 3.5 mmol) were added to the solution. Then, a solution of a free base of 2-(1-adamantyl)-N-pentylethylamine hydrochloride (Intermediate No. 1-1) (1.0 g, 3.5 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise to the mixture. The whole was stirred at 0° C. for 1.5 hours, a saturated aqueous sodium hydrogencarbonate solution (70 ml) and ethyl acetate (70 ml) were added to the reaction mixture, and the reaction mixture was distributed. The ethyl acetate layer was washed with water (70 ml) and a saturated aqueous sodium chloride solution (70 ml) successively and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure to give 1.3 g (quantitatively) of 2-bromoacetic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide as a oily matter.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH2:5][CH2:4]1>C(O)C>[CH3:1][NH:2][CH:3]1[CH2:4][CH2:5][C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9]1
Reactant: CNC1C=C(c2ccccc2)c2ccccc2CC1
Solvent: CCO
Product: CNC1CCc2ccccc2C(c2ccccc2)C1
Yield: 73.1 %

Procedure:
A mixture of 2.47 g of 7-methylamino-9-phenyl-6,7-dihydro [5H] benzocycloheptene, 130 ml of ethanol, and 3.67 g of palladized carbon [10% pd(OH)2 ] was maintained under a hydrogen atmosphere until absorption ceased and the mixture was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 4-6-1 benzene-ethyl acetate-triethylamine mixture yielded 1.82 g of 7-methylamino-5-phenyl-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([O:13]C)=[O:12])[N:10]=2)[CH:7]=1.[OH-].[K+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[CH:7]=1
Reactant: COC(=O)c1nc2ccc(Cl)cn2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)nc2ccc(Cl)cn12
Temperature: 50 °C

Procedure:
To a solution of methyl 6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylate (1.01 g, 4.50 mmol) in MeOH (18 mL) at room temperature was added potassium hydroxide (407 mg, 7.25 mmol). The reaction mixture was heated to 50° C. for 15 h, and additional KOH (293 mg) was added. The reaction mixture was heated to reflux for 1 h, cooled to room temperature and 5 M HCl (2.5 mL) was added and the reaction mixture was concentrated. toluene (25 mL) was added to the concentrate and the toluene was evaporated under reduced pressure. This was repeated a second time and the concentrate was dried under high vacuum to give 6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid as an off white solid. MS m/z=210.9 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:33]1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C1CC1>>[CH:15]1([C:14]2[N:13]=[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])[C:11]([CH2:30][CH3:31])=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:33][CH2:16]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.96–1.00, 1.26–1.32, 2.04, 2.35–2.40, 2.61–2.66, 3.0–3.04, 3.22–3.27, 4.09–4.14, 4.68–4.70, 5.08, 5.45–5.48, 7.23–7.31; MS (ESI+) for C24H23Cl2N3O m/z 440 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2OS(C(F)(F)F)(=O)=O)=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:29])=[CH:6][C:7]([CH3:28])([CH3:27])[NH:8]2.C(N(CC)CC)C.C(O)=O>CN(C)C=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:29])=[CH:6][C:7]([CH3:28])([CH3:27])[NH:8]2
Reactant: CC1=CC(C)(C)Nc2ccc(-c3ccccc3OS(=O)(=O)C(F)(F)F)c(CO)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=CC(C)(C)Nc2ccc(-c3ccccc3)c(CO)c21
Temperature: 60 °C
Reaction time: 10 h

Procedure:
5-Hydroxymethyl-6-(2-trifluoromethylsulfonyloxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 6-1, 136 mg, 0.318 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.5 mL), then the solvent was bubbled with argon for 2 minutes, and then tetrakis(triphenylphosphine)palladium(0) (35.6 mg, 0.0308 mmol), triethylamine (221 μL, 1.59 mmol) and formic acid (60 μL, 1.6 mmol) were added thereto. After the reaction mixture was stirred at 60° C. for 10 hours, it was diluted with ethyl acetate (50 mL). The whole was washed with saturated NaHCO3 solution (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (93.0 mg) as a yellow oil. (quantative)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH:16]([F:18])[F:17])[NH:13][C:12](=O)[CH:11]([CH3:15])[O:10][CH2:9]2)[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH:16]([F:18])[F:17])[NH:13][C:12](=[S:21])[CH:11]([CH3:15])[O:10][CH2:9]2)[CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1OCC(c2cc(Br)ccc2F)(C(F)F)NC1=O
Solvent: c1ccncc1
Product: CC1OCC(c2cc(Br)ccc2F)(C(F)F)NC1=S
Temperature: 80 °C
Yield: 102 %

Procedure:
To a solution of 5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-morpholin-3-one (659 mg, 1.949 mmol) in 6.6 mL pyridine was added phosphorus pentasulfide (433 mg, 1.949 mmol) and the mixture was heated to 80° C. for 120 minutes. The reaction mixture was cooled to room temperature and partitioned between 0.1 N NaOH and EtOAc. The layers were separated, washed with brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated to give 704 mg of the title compound as a diastereomeric mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][CH:21]=1>O1CCOCC1.CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[CH:22][CH:21]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=c1ccc2cc(-c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 110 °C

Procedure:
A solution of 22.7 g (0.101 mol) 6-bromo-1H-quinolin-2-one in 380 mL 1,4-dioxane and 380 mL MeOH is combined with 141.5 ml (0.283 ml) 2 M Na2CO3 solution and saturated with argon. Then 3.735 g (3.23 mmol) tetrakis-triphenyl-phosphane-palladium and 4-chlorophenylboric acid are added successively. The reaction mixture is heated to 110° C. for four hours and then evaporated down to a volume of 300 mL. 1.2 L water are added and the precipitate is filtered off. The solid is dried at 55° C. in the drying cupboard, washed with diisopropylether and dried again.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH:16]2[CH2:18][CH2:17]2)[C:14](=[O:19])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1>>[C:1]([NH:5][C:6]1[N:15]([CH:16]2[CH2:18][CH2:17]2)[C:14](=[O:19])[C:13]2[C:8](=[C:9]([C:28]3[NH:27][C:26]4[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=4[CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nc2c(I)cccc2c(=O)n1C1CC1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C5CC5)c(NC(C)(C)C)nc34)[nH]c21
Yield: 58.3 %

Procedure:
This compound (73 mg, 57% yield) as a tan amorphous solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-3-cyclopropyl-8-iodoquinazolin-4(3H)-one (718) (125 mg, 0.32 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (85 mg, 0.32 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 7.89 (1H, d, J=7.4 Hz), 7.85 (1H, d, J=7.8 Hz), 7.65 (1H, s), 7.16 (1H, t, J=7.7 Hz), 6.74 (1H, s), 6.15 (1H, s), 4.48-4.59 (1H, m), 2.88 (1H, br. s.), 1.54 (9H, s), 1.38 (3H, d, J=6.5 Hz), 1.27 (2H, d, J=6.7 Hz), 0.78 (2H, br. s.). m/z (ESI, +ve) 392.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=O)[CH:3]=1.[NH3:14]>>[CH3:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[NH:14][C:4](=[O:5])[CH:3]=1
Reactant: Cc1cc(=O)oc2c1C(=O)CCC2
Reactant: N
Product: Cc1cc(=O)[nH]c2c1C(=O)CCC2

Procedure:
4.46 g (0.025 mol) of 4-methyl-5,6,7,8-tetrahydro- cumarin-5-one are heated to 180° C. for 3 hours in 150 ml of saturated methanolic ammonia in a stirred autoclave. After cooling, the methanolic ammonia is distilled off using a rotary evaporator and the residue is recrystallised from ethanol using activated charcoal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=[C:7]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:6]=2.C(N(CC)CC)C.[CH2:37]([O:39][CH2:40][C:41](Cl)=O)[CH3:38]>ClCCl>[CH2:23]([O:22][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])([CH3:16])[CH3:15])[C:38]([CH2:37][O:39][CH2:40][CH3:41])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
Under a nitrogen atmosphere, a solution of N-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide (12.6 g, 30.4 mmol) in dichloromethane (300 mL) was cooled to approximately 0° C.; triethylamine (4.23 mL, 30.4 mmol) was added. Ethoxy acetyl chloride (3.33 mL, 30.4 mmol) was added dropwise, and the reaction was stirred at ambient temperature for 1.5 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (300 mL). Triethylamine (13 mL) was added, and the reaction was heated at reflux overnight and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure. The residue was dissolved in dichloromethane (300 mL), and the resulting solution was washed with water (2×100 mL) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil. The oil was purified by column chromatography on silica gel (eluting with 97.5:2.5 chloroform:methanol) to provide 12.4 g of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][C:5](=[O:7])[C:4]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.NN>C1COCC1.CO.CCOC(C)=O>[NH2:8][C:4]1[C:5](=[O:7])[O:6][C:2]([CH3:1])([CH3:25])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)C(N2C(=O)c3ccccc3C2=O)=C1c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)OC(=O)C(N)=C1c1ccccc1
Reaction time: 8 h

Procedure:
To a 0° C. solution of 2-(5,5-dimethyl-2-oxo4-phenyl-2,5-dihydro-3-furanyl)-1H-isoindole-1,3(2H)-dione (0.90 g, 2.7 mmol) in THF (40 mL) and MeOH (30 mL) was added hydrazine hydrate (1 mL). The mixture was stirred overnight then diluted with EtOAc and washed with saturated NH4Cl. The organic phase was concentrated, then dissolved in dichloromethane, washed with brine, filtered through cotton and concentrated. This material was combined with the 0.29 g from the previous step and purified by flash chromatography (25% EtOAc/hexanes) to provide 3-amino-5,5-dimethyl-4-phenyl-2(5H)-furanone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[Na+].[C:25]([Cl:28])(=[O:27])[CH3:26].Cl>CC(C)=O>[ClH:28].[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)NCC(O)COc1ccc(O)c2c1CCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(OCC(O)CNC(C)(C)C)c2c1NC(=O)CC2
Yield: 45.5 %

Procedure:
0.7 g of 8-hydroxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril was suspended in 20 ml of acetone, and 3.0 ml of 1 N NaOH was added to the suspension to form a homogeneous solution. 0.2 g of acetyl chloride dissolved in a small amount of acetone was added dropwise to the solution under ice-cooling and stirring. After the mixture was allowed to stand under ice-cooling for 30 minutes, 2 ml of 1 N hydrochloric acid was added to the mixture, and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform:methanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.4 g of 8-acetoxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 247°-248° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](Cl)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:25])[CH3:24])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)cc1OC
Temperature: 25 °C

Procedure:
After 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate phase was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 341.3 mg.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[C:16]1([CH:4]([NH:3][S:32]([CH2:31][C:30]([F:37])([F:36])[F:29])(=[O:34])=[O:33])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)CC(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (120 mg, 0.36 mmol) in DCM (4 ml) and triethylamine (105 μl, 1.44 mmol), was added 2,2,2-trifluoroethanesulfonyl chloride (47.5 μl, 0.43 mmol). The reaction was stirred at RT for 3 hours, and then it was diluted with DCM and washed with water, brine and 1M K2CO3. The organic phase was dried with Na2SO4, filtered, and evaporated. The crude was purified with flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(2,2,2-trifluoroethylsulfonamido)acetate (60 mg; 41% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.C[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](=O)[O-:13]>>[C:4]1([NH:1][C:12]([NH:11][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C(=O)[O-])c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1
Temperature: 135 °C
Reaction time: 5 h

Procedure:
The experiment as described in Example 10 was repeated at a temperature of 110° C. using nitrobenzene (7.5 ml) and aniline (4 ml) as feed. Gas-liquid chromatography indicated that the initial amount of aniline had been converted completely and that 1,3-diphenylurea had been formed in high yield (90%, based on aniline. Methyl carbanilate had been obtained in 60% yield, based on nitrobenzene with a nitrobenzene conversion of about 70%). The reaction temperature was then raised to 135° C. and the reaction was allowed to proceed at that temperature for another 5 hours. The total conversion of nitrobenzene amounted to 90% and more methylcarbanilate had been formed, corresponding to the amount of 1,3-diphenylurea converted.