Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][Si](C(C)(C)C)(C)C)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy) quinoline (18.92 g, 50.25 mmol) in anhydrous THF (400 mL) at 0° C. was added tetrabutylammonium fluoride (75.4 mL, 1.0 M/THF, 75.4 mmol). After stirring for 1 hour at this temperature the mixture was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with CH2Cl2, filtered and dried in vacuo to provide 11.91 g (90%) of desired product as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]2[CH2:10][CH2:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=12>CO>[CH3:1][C:2]1[N:3]=[CH:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C:6]=12
Reactant: CCOC(=O)C1=Cc2c(C)ncn2CC1
Solvent: CO
Product: CCOC(=O)C1CCn2cnc(C)c2C1
Yield: 97.9 %

Procedure:
Ethyl 1-methyl-5,6-dihydroimidazo[1,5-a]pyridine-7-carboxylate (0.90 g) was subjected to catalytic reduction in 30 ml methanol at room temperature for ten hours by using 0.02 g of 5% paradium-carbon as the catalyst. The reaction mixture was filtered, the filtrate was concentrated to dryness under reduced pressure, ethyl acetate was added to the residue, and the resulting mixture was extracted with 0.5N-HCl. The aqueous layer collected was alkalized by addition of potassium carbonate and then extracted with dichloromethane, the organic layer collected was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure, thus giving 0.89 g (98%) of ethyl 1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylate.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(O)(=O)C.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:3]=[CH:20][C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccncc1
Reactant: CN(N)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CN(N=Cc1ccncc1)c1ccccc1
Temperature: 0 °C

Procedure:
One equivalent of methyl phenylhydrazine (58.76 g; 0.4809 mol, compound 2) was diluted in 50 ml of ethanol and 1.5 ml of acetic acid in a three-necked flask on which was mounted a condenser. The reaction medium was then stirred at 0° C. Using a dropping funnel, 1 equivalent of 4-pyridinecarboxaldehyde (51.5 g; 0.4808 mol, compound 1) was added. After addition of the aldehyde, the reaction medium was heated at 65° C. (oilbath temperature) for 13 hours.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH3:3].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:19]=1[O:14][C:13](=[O:15])[C@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:7][C:5]([O:4][C:2]([CH3:3])([CH3:1])[CH3:16])=[O:6]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 100.6 %

Procedure:
N-(1,1-Dimethylethoxycarbonyl)leucine (6.32 g, 15 mmol) was stirred with 2,4,5-trichlorophenol (3.01 g, 15.2 mmol) and dicyclohexylcarbodiimide (3.14 g, 15.2 mmol) in ethyl acetate (50 mL) at -10° C. for 4 h. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate. The residue was dissolved in ethyl acetate. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate to give N-(1,1-dimethylethoxycarbonyl)leucine 2,4,5-trichlorophenyl ester (6.2 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCSCc1ccsn1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1ccsn1)c1ccccc1

Procedure:
By the procedure of Example 18, 3-[(2-aminoethyl)thiomethyl]isothiazole is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-isothiazolylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([NH:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2c(c1)OCO2)c1ccccc1
Yield: 84.2 %

Procedure:
To a mixture of piperonylamine (20.0 g, 0.133 mol), tetrahydrofuran (87.5 mL) and triethylamine (13.9 g, 0.137 mol) was added dropwise benzoyl chloride (18.6 g, 0.133 mol), at −10-+6° C., and during dropwise addition, tetrahydrofuran (total 123 mL) was appropriately added thereto to stir the content. After adding dropwise, the dropping funnel was washed with tetrahydrofuran (10 mL). The reaction mixture was stirred at 2-11° C. for 15 hr under a nitrogen atmosphere. The consumption of the starting material was confirmed by TLC (eluent: hexane/ethyl acetate 1:1)). To the reaction mixture was added water (50 mL) at 11° C., and then added ethyl acetate (128 mL). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (44 mL). The combined organic layers were washed successively with 10% hydrochloric acid (40 mL), saturated aqueous sodium hydrogen carbonate solution (40 mL), water (40 mL) and saturated brine (44 mL), and dried over magnesium sulfate (18 g). The large part of the solvent was evaporated under reduced pressure at 35° C. or lower (content 61 g), and ethyl acetate (61 mL) was added to the residue. The crystals were collected by filtration, washed with ethyl acetate (46 mL), and dried under reduced pressure at 50° C. or lower to give N-benzoylpiperonylamine (28.6 g, 84.7%) as white crystals.
Reaction SMILES: [Br-].[C:2]([CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[OH-].[Na+].[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>O.C(Cl)Cl>[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:4][C:2]#[N:3])=[CH:34][CH:33]=1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#CC=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of (cyanomethyl)triphenylphosphonium bromide (8.61 g, 22.54 mmol) and NaOH (1.127 g, 28.2 mmol) in water (24 mL) and DCM (12 mL) was added 4-(3-(trifluoromethyl)phenoxy)benzaldehyde (5 g, 18.78 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. DCM (50 mL) and water (50 mL) was added to the mixture, the organic phase was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Purification via flash chromatography afforded the title compound (5.07 g, 17.26 mmol, 92% yield) as pale yellow oil (slowly solidify to white solid). LCMS: rt=1.67 min, [M+H+]=290
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[CH:12]1([CH:15]=O)[CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH:12]1([CH2:15][N:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:1][CH2:2]2)[CH2:14][CH2:13]1
Reactant: O=CC1CC1
Reactant: C1CCC2(CC1)CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: C1CCC2(CC1)CCN(CC1CC1)CC2
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 3-azaspiro[5,5]undecane (0.34 g, 2.2 mmol), cyclopropanecarbaldehyde (0.14 g, 2 mmol) and NaBH(OAc)3 (0.64 g, 3 mmol) in dichloroethane (10 mL) were added AcOH (0.12 mL, 2 mmol), the resulting suspension was stirred overnight, quenched with NaHCO3 and extracted with CH2Cl2 twice, the combined organic layer was washed with brine, and dried with MgSO4. The solution was filtered, concentrated in vacuo and purified by flash chromatography. The compound was converted to the hydrochloride by passing HCl gas into the ether solution of 3-(cyclopropylmethyl)-3-azoniaspiro[5,5]undecane at 0° C., followed by decanting the ether supernatant, the final white solid (0.39 g, 80% yield) was dried in vacuo. 1H NMR (360 MHz, CDCl3) δ 2.45 (t, J=5.66 Hz, 4H), 2.23 (d, J=6.51 Hz 2H), 1.49 (t, J=5.66 Hz, 4H), 1.48-1.40 (m, 6H), 1.38-1.30 (m, 4H), 0.92-0.82 (m, 1H), 0.52-0.47 (m, 2H), 0.11-0.17 (m, 2H); 13C NMR (90 MHz, CDCl3) δ 64.55, 49.67, 36.47, 35.46, 31.00, 27.12, 21.73, 8.74, 4.19; ESI-MS: Calculated for C14H25N (M+H)+ 208.4, Found: 208.4.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][O:8][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])[S:5][CH:6]=1
Reactant: OCc1nc(Br)cs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1nc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-bromothiazol-2-yl)methanol (1.30 g) and imidazole (600 mg) in THF (10 mL) was added dropwise tert-butyldimethylchlorosilane (1.60 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.CO>C(O)C>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([CH:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: CCO
Solvent: CO
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A stirred mixture of 7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (1.0 g, 2.5 mmol) and cyclopropane carbonyl chloride (1 mL) was heated to reflux for 7 min. To the cooled mixture was added methanol (3 mL) at 0° C. and the mixture was stirred for 30 min. To the suspension was added ethanol (5 mL). The suspension was filtered and washed with ethanol to give cyclopropyl-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as an off-white solid (1.0 g, 86% yield); mp, 115-117° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S+0.9H2O: C, 58.98; H, 6.15; N, 5.73; H2O, 3.32. Found: C, 58.62; H, 5.99; N, 5.53; H2O, 3.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][C:30]#[C:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[ClH:41].C(O)C>O1CCCC1>[ClH:1].[ClH:41].[NH2:33][CH2:32][C:31]#[C:30][CH2:29][N:28]1[C:21]2[C:20]([NH:19][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:25][CH:24]=[N:23][C:22]=2[CH:26]=[CH:27]1
Reactant: CC(C)(C)OC(=O)NCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 60 °C
Reaction time: 16 h

Procedure:
tert-Butyl {4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn-1-yl}carbamate (1.90 g) was dissolved in tetrahydrofuran (35 mL), 2N hydrochloric acid (18 mL) was added, and the mixture was stirred at 60° C. for 16 hrs. To the reaction mixture was added ethanol, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (802 mg) as a white powder.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:39][CH:36]2[CH2:38][CH2:37]2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: NC1CC1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CNC4CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 72.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (50 mg, 0.100 mmol) was dissolved in acetonitrile (2.9 mL), and the solution was treated with cyclopropylamine (0.069 mL, 1.0 mmol), acetic acid (0.115 mL, 2.00 mmol) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(cyclopropylaminomethyl)indol-2-yl]isoindolinone (39.1 mg, yield 72%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[N+]([C:13]1[C:14]([N+]([O-])=O)=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)([O-])=O>C1(C)C=CC=CC=1>[N+:1]([C:18]1[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][CH:13]=1)([O-:4])=[O:2]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
Aromatic nitro compounds like dinitrotoluene (DNT) or mononitrobenzene (MNB) are commercially produced through nitration of an aromatic with a mixture of nitric acid and sulfuric acid. The reaction is a biphasic reaction, typically the reaction rate is determined by the mass transfer between the two phases. In case of toluene nitration the reaction is typically carried out isothermally, toluene is present in molar substochiometry which means the molar ration of nitric acid to toluene is >1, typically 1.01-1.2. In a first step the toluene is nitrated to form mononitrotoluene (MNT). The biphasic reaction mixture undergoes phase separation into an aqueous phase containing the main part of sulfuric acid and an organic phase containing the main part of MNT. The organic phase then undergoes nitration to DNT in a further biphasic reaction. Again the reaction mixture undergoes phase separation into an aqueous phase and an organic phase containing DNT.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].O.O.O.C([O-])(=O)C.[Na+].CO>O>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: COC(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CNc1cccc(Br)c1

Procedure:
A mixture of 3-bromoaniline (88.6 g), methyl chloroacetate (44 ml), sodium acetate trihydrate (114 g) and methanol (70 ml) was heated under reflux for 18 h. The mixture was poured into water (500 ml) and extracted with dichloromethane (3×250 ml). The combined, dried organic extracts were evaporated and the residue was treated with 10% concentrated sulphuric acid in methanol (250 ml). After 3 h the solution was poured carefully into 8% sodium bicarbonate (1200 ml). The resulting solid was filtered off, dissolved in dichloromethane (1000 ml), and this solution was dried and evaporated to give a solid (94 g). A portion of this solid (1 g) was purified by FCC eluting with System A (1:1) to give a semi-solid which was recrystallised from System A to give the title compound, m.p. 66°-68°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[CH:13]=[N:12]2)[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: NCCc1ccccc1Cl
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)O
Product: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCCc1ccccc1Cl

Procedure:
The title compound was prepared using the method outlined in Example 48, coupling 2-methyl-5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-benzoic acid with 2-(ortho-chlorophenyl)ethylamine. The product was a colorless oil. MS (ES+) 385.2; (ES−) 383.2; LC retention time=2.1 min (using the LC/MS and method outlined for the examples in Table 1).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]3)[C@@H:18]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>N1C=CC=CC=1>[C:42]([O:15][CH2:14][C@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)[O:16][C@H:17]1[CH2:25][CH2:24][C@H:23]2[C@@H:19]([CH2:20][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]2)[C@@H:18]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CC[C@@H]1O[C@H](COC(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 102 %

Procedure:
To a solution of the (1S) isomer of EXAMPLE 1 (tert-Butyl (3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate, 8.61 g, 14.65 mmol) in 50 mL pyridine was added benzoyl chloride (3.40 mL, 29.3 mmol). The mixture was stirred at 50° C. for 16 hr. The volatiles were removed in vacuo. The residue was dissolved in 200 mL ethyl acetate, washed with sodium bicarbonate aqueous and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexane, 15% to 30% for 2900 mL, then 30% to 50% for 1250 mL) to give 10.38 g (102% yield) of the title compound. M++1: 588.1.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:10]=1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C1COCC1>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)[N:16]=[CH:15][N:14]=1
Reactant: [H][H]
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OCCCN4CCCC4)c23)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OCCCN4CCCC4)c23)c1
Yield: 72.1 %

Procedure:
A mixture of 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-(3-pyrrolidin-1-ylpropoxy)quinazoline (0.68 g), 10% palladium on charcoal catalyst (0.16 g), ethanol (13 ml) and THF (13 ml) was stirred under 5 atmospheres pressure of hydrogen for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated under methanol. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.405 g); NMR Spectrum: (DMSOd6) 1.65 (br s, 4H), 2.1 (m, 2H), 2.4 (br s, 4H), 2.55 (t, 2H), 3.8 (s, 3H), 4.4 (t, 2H), 6.7 (m, 2H), 6.75 (m, 1H), 7.48 (d, 1H), 8.3 (d, 1H), 8.4 (s, 1H), 10.05 (s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[CH2:14][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)C(=O)CBr
Agent: [K]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CN1C(=O)c2ccccc2C1=O
Yield: 76.2 %

Procedure:
Potassium phthalimide (82.86 g, 0.447 mol) is added to a stirred solution of bromopinacolone (80.10 g, 0.447 mol) in toluene (300 ml). The-suspension is refluxed for 19 h, cooled, and then the precipitate is filtered off and discarded. The filtrate is cooled in an ice-bath and treated with petroleum ether (550 ml). The resulting precipitate is collected by filtration. The mother liquor is reduced to circa 100 ml by evaporation in vacuo, and a further quantity of precipitate which forms is collected by filtration and combined with the first crop, giving 2-(3,3-dimethyl-2-oxo-butyl)-isoindole-1,3-dione (total yield 83.5 g, 76%) as colourless crystals, m.p. 96-99° C.