Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C2N(CC3C=CC(CCC(O)=O)=CC=3)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49](CC3C=C(C=CC=3)C(O)=O)[C:48]3[CH:60]=[C:61]([F:65])[C:62]([F:64])=[CH:63][C:47]=3[N:46]=2)=[C:41]([O:66][CH2:67]C2CCCC2)[CH:40]=1.Br[CH2:74][C:75]1[CH:82]=[CH:81][C:78]([C:79]#[N:80])=[C:77]([F:83])[CH:76]=1>>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]([CH2:74][C:75]3[CH:82]=[CH:81][C:78]([C:79]#[N:80])=[C:77]([F:83])[CH:76]=3)[C:48]3[CH:60]=[C:61]([F:65])[C:62]([F:64])=[CH:63][C:47]=3[N:46]=2)=[C:41]([O:66][CH3:67])[CH:40]=1
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Agent: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-2-fluoro-benzonitrile (CAS Reg. No. 222978-03-2). Brown sticky solid (39%). MS (Turbo Spray): m/z=428.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21].Cl>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][N:10]3[C:20](=[O:21])[C:19](=[O:23])[O:12][C:11]32[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(NCCc1ccc(Cl)cc1)C1CCCCC1
Agent: Cl
Solvent: ClCCCl
Product: O=C1OC2(C3CCCCC3)c3cc(Cl)ccc3CCN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[2-(4-chlorophenyl)ethyl]cyclohexanecarboxamide (2.03 g) was dissolved in 1,2-dichloroethane (15 mL), and oxalyl chloride (0.8 mL) was added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and then cooled to −20° C. Ferric chloride (1.49 g) was added to the mixture, followed by stirring at room temperature for 16 hours. An aqueous 1 M HCl solution was added to the mixture which was then stirred at room temperature for 30 minutes, followed by extraction with chloroform. The extract was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dried to obtain 9-chloro-10b-cyclohexyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (2.38 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[C:13]=1[C:20]([O:22][CH3:23])=[O:21].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1cccc(CN)c1C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCc1cccc(C(=O)OC)c1C(=O)OC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Triethylamine (1.57 g, 18.5 mmol) was added to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The mixture was cooled in an ice bath to 4° C. Ethyl chloroformate (1.0 g, 9 mmol) was added slowly keeping the mixture at 4-6° C. After addition was complete, the mixture was stirred in an ice bath for 30 minutes and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the residue was purified by flash chromatography (dichloromethane/ethyl acetate 95 to 5) to give 1.59 g (70%) of the product as an oil: 1H NMR (CDCl3) δ 7.87 (d, J=7.8 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 5.30 (b, 1H), 4.32 (d, J=6.3 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1([CH2:25][CH3:26])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[OH-].[Na+]>C(O)C>[CH2:18]([CH:8]1[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:5]([CH2:25][CH3:26])([CH2:4][C:3]([OH:27])=[O:2])[O:6][CH2:7]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC1(CC(=O)OC)OCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC1(CC(=O)O)OCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Yield: 82 %

Procedure:
To a solution of 4-benzyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (0.67 g, 1.8 mmol) in 30 mL of ethanol was added 30 mL of 10% solution of sodium hydroxide and heated at reflux for 2 hours under nitrogen. The reaction mixture was then cooled and concentrated in vacuo, diluted with 20 mL of H2O and extracted with ether. The aqueous layer was then acidified with 2N HCl and extracted with chloroform (3×100 mL), dried over magnesium sulfate and concentrated in vacuo to give 0.516 g (80%) of the product, m.p. 142°-143° C.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>CCCCCC.C(OCC)C>[CH:26]([C:19]1[C:10]([O:9][CH2:8][O:7][CH3:6])=[CH:11][C:12]2[C:13]([CH3:23])([CH3:22])[CH2:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]=2[CH:18]=1)=[O:27]
Reactant: COCOc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.2 %

Procedure:
22 ml of a 1.56M solution of n-butyllithium in hexane was dropwise added to 40 ml of a solution of 5.7 g of 5,6,7,8-tetrahydro-2-methoxymethoxy-5,5,8,8-tetramethylnaphthalene in anhydrous diethyl ether at -78° C. The temperature of the mixture was gradually raised to room temperature (in 10 minutes). The resulting mixture was stirred for 5 hours and cooled to -78° C., followed by the dropwise addition thereto of 5 ml of a solution of 2.6 g of N,N-dimethylformamide in diethyl ether. The temperature of the obtained mixture was gradually raised to room temperature (in 10 minutes). The resulting mixture was stirred for 3 hours, followed by the addition thereto of 30 ml of a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 10% ethyl acetate/n-hexane) to give 4.2 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:15]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of resorcinol (10 g, 90.8 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (12.6 g, 90.8 mmol) and benzyl bromide (10.8 mL, 90.8 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 3-benzyloxy-phenol (6.0 g, 33%) was obtained as a pale brown oil.
Reaction SMILES: S([O-])([O:4][CH3:5])(=O)=O.[CH3:7][N:8]1[C:13](=[O:14])[NH:12][C:11](=O)[O:10][C:9]1=[O:16]>O.C(Cl)(Cl)(Cl)Cl>[CH3:11][N:12]1[C:13](=[O:14])[N:8]([CH3:7])[C:9](=[O:10])[O:16][C:5]1=[O:4]
Reactant: Cn1c(=O)[nH]c(=O)oc1=O
Reactant: COS(=O)(=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)oc(=O)n(C)c1=O
Yield: 92 %

Procedure:
The process disclosed in example 1 is used, except that the solvent is not distilled. 15.1 g of methyl sulfate (0.12 mole) are added to the solution of 3-methyl-1,3,5-oxadiazine-2,4,6-trione. The solvent is evaporated after 10 minutes of reaction at a temperature of 25° C. After washing with water and carbon tetrachloride, 14.6 g of 3,5-dimethyl-1,3,5-oxadiazine-2,4,6-trione (yield: 92%) which is a symmetrical disubstituted 1,3,5-oxadiazine trione are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH:5][CH:6]=[C:7]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]1=[O:16].[N:22]1([CH2:27][CH2:28][CH2:29]Cl)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[N:22]1([CH2:27][CH2:28][CH2:29][O:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[NH:5][CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:14])([CH3:15])[O:9][C:8]2=[O:16])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCCN1CCCC1
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCCCN1CCCC1
Temperature: 80 °C
Yield: 37 %

Procedure:
A mixture of 5-((3-hydroxy-4-methoxyanilino)methylene)-2,2-dimethyl-1,3dioxane-4,6-dione (10 g, 34.1 mmol), (prepared as described for the starting material in Example 3), 3-(pyrrolidin-1-yl)propyl chloride (7.55 g, 51.1 mmol), (J. Am. Chem. Soc. 1955, 77, 2272), potassium carbonate (7.06 g, 51.1 mmol) and potassium iodide (600 mg, 3.41 mmol) in DMF (100 ml) was heated at 80° C. for 2 hours. The mixture was poured into water (800 ml) and the precipitate was collected by filtration. The solid was dissolved in methylene chloride and the organic solution was washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was dissolved in ether and the insoluble materials were removed by filtration. The volatiles were removed by evaporation and the residue was precipitated by trituration with petroleum ether, collected by filtration and dried under vacuum to give 5-((3-(3-pyrrolidin-1-ylpropoxy)-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.1 g, 37%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.ClCCl.[Br:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>>[Br:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[CH2:7][CH2:8]3)=[CH:20][CH:19]=2)=[CH:49][CH:48]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Reaction time: 48 h

Procedure:
A solution of 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid (1.0 g, 3.6 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.70 g, 3.6 mmol) and 1-hydroxy-7-azabenzotriazole (0.50 g, 3.6 mmol) in dichloromethane (39 mL, 610 mmol) was stirred for 20 min at room temperature and then p-bromoaniline (0.52 g, 3.0 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) were added and the reaction mixture was stirred for 2 days. The reaction mixture was filtered; the filtrate was dissolved in 1:1 acetic acid:water (8 mL). A precipitate formed. This material was filtered to provide the title product as the acetic acid salt (225 mg). (m/z): [M+H]+ calcd for C21H22BrN3O2 428.09 found 428.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH:10]=[CH:11][CH:12]=1)[N:7]([CH3:9])[CH3:8].[CH:21](O)=O>>[CH2:14]([O:13][C:5]1[C:6]([N:7]([CH3:8])[CH3:9])=[CH:10][CH:11]=[C:12]2[C:4]=1[CH2:3][CH2:2][NH:1][CH2:21]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CO
Reactant: CN(C)c1cccc(CCN)c1OCc1ccccc1
Product: CN(C)c1ccc2c(c1OCc1ccccc1)CCNC2
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(2-aminoethyl)-2-(benzyloxy)-N,N-dimethylaniline (1 g, 3.70 mmol, 1.00 equiv), formic acid (10 mL) and (CHOH)n (89 mg). The resulting solution was stirred overnight at 55° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The pH value of the solution was adjusted to 10 with sodium hydroxide (10 mol/L). The resulting solution was extracted with 1×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1 g (96%) of 5-(benzyloxy)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-amine as brown oil. MS (ESI) m/z 283 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCc2ccccn2)cc1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
2 g of 4-fluoronitrobenzene, 2.07 g of 2-(2-aminoethyl)pyridine, and 2.35 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 18 hours and, after cooling to room temperature, was then poured into a water+ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 3.3 g of N-(4-nitrophenyl)-N-(2-pyrid-2-ylethyl)amine (5) were obtained.
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[O:13])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[NH2:8][C:9]1([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[O:13])[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(NC(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 4′-{[({1-[(tert-butoxycarbonyl)amino]cyclopropyl}carbonyl)-amino]methyl}-1,1′-biphenyl-2-carboxylate (0.84 g, 2.0 mmol) dissolved in a mixture of DCM (3 mL) and MeOH (45 mL) was cooled to 0° C. This homogenous solution was saturated with anhydrous hydrogen chloride and allowed to sit for 30 minutes. Dry nitrogen was then bubbled through the solution for about 30 min. Solvent was then removed under reduced pressure to yield an oily residue. The oil was then dissolved in DCM and the solvent removed. This process being repeated until a solid amine hydrochloride was obtained. Alternatively, the residue could be dissolved in chloroform followed by saturation with ammonia gas, filtration and solvent removal to obtain solid methyl 4′-({[(1-aminocyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate as the free-base.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][C:5]=1[CH3:11])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: Cc1cc(O)ccc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc(C(C)C)c(C)c1

Procedure:
A solution of 4-isopropyl-3-methylphenol (10.0 g, 67 mmol), methyl bromoacetate (6.6 mL, 70 mmol) and anhydrous potassium carbonate (10.1 g, 73 mmol) in 2-butanone (100 mL) was heated to reflux for 20 h. The mixture was cooled and partitioned between water (350 mL) and ethyl acetate (100 mL). The organic phase was washed with brine, and the aqueous phases were back-extracted in sequence with more ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford sufficiently pure product, methyl 2-(4-isopropyl-3-methylphenoxy)acetate, as an oil (15.0 g, 67 mmol, 100%). 1H NMR (CDCl3, 300 MHz): δ 7.05 (1H, d, J=9.3 Hz), 6.64-6.58 (2H, m), 4.51 (2H, s), 3.71 (3H, s), 2.98 (1H, J=7.0 Hz), 2.22 (3H, s), 1.11 (6H, d, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]#[N:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:3]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C#N)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To a stirred suspension of 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide (0.1 g, 0.25 mmol) in DCM/pyridine (2.5 mL; 4:1) was added trifluoroacetic anhydride (0.138 mL, 1.0 mmol) at 0° C. and the mixture stirred for 4 hours. The reaction was quenched with ice and adjusted to pH 7 with saturated sodium hydrogen carbonate solution. The mixture was partitioned between DCM (10 mL) and water (10 mL). The aqueous phase was washed with DCM (10 mL) and the combined organic layers dried (MgSO4) filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (DCM→49:1 DCM/MeOH) to give the title compound as a pale yellow solid (0.065 g, 68%) after crystallisation from MeOH.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][N:39]=[N+]=[N-])[NH:13]2)=[O:11])[CH2:4][O:3]1>C(OCC)(=O)C.O=[Pt]=O>[CH3:1][C:2]1([CH3:44])[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][NH2:39])[NH:13]2)=[O:11])[CH2:4][O:3]1
Reactant: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(C)(CCN)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 97.9 %

Procedure:
In a manner similar to the method described in Examples 118a, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 120d (0.5 g, 0.77 mmol) was treated with PtO2 and H2 in ethyl acetate to give rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a black gum (0.47 g, 98%)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C@@H:8]([CH3:13])[CH2:7][C@H:6]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:1][CH3:2])=[CH:12][CH:11]=2)[C@H:6]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[CH2:7][C@@H:8]1[CH3:13])(=[O:25])[CH3:24]
Reactant: CCc1ccc(N[C@@H]2C[C@H](C)Nc3ccc(CC)cc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1ccc(N[C@@H]2C[C@H](C)N(C(C)=O)c3ccc(CC)cc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The compound of Step 1 (59 mg, 0.20 mmol) was dissolved in pyridine (1 ml) and acetic anhydride (2.0 mmol) was added. After stirring at room temperature for 20 hours the solvent was evaporated and the crude product was purified on silica (ethyl acetate:heptane 1:2). The title compound was obtained as a colorless oil (0.12 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:19]([F:22])([F:21])[F:20])[O:8][C:9]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=2[C:11]=1[CH:12]=[CH2:13])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:19]([F:20])([F:22])[F:21])[O:8][C:9]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=2[C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: C=CC1=C(C(=O)OCC)C(C(F)(F)F)Oc2ccc(Cl)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1=C(CC)c2cc(Cl)ccc2OC1C(F)(F)F
Reaction time: 0.42 h
Yield: 64.8 %

Procedure:
Ethyl-6-chloro-4-ethenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 142,Step 5)(0.433 g, 1.30 mmol) was dissolved in methanol (10 mL). Palladium(5 wt % on activated carbon)(0.150 g) was slowly added. The reaction vessel was charged with hydrogen (25 psi) and was stirred for 25 minutes. Gas chromatographic analysis indicated that the reaction was complete. The reaction mixture was filtered through Celite and evaporated to yield a orange oil. The oil was purified by flash column chromatography(100 % hexanes) to yield the desired product as a yellow oil (0.282 g, 65%): 1H NMR (CDCl3/300 MHz) 7.43 (d, 1H, J=2.4 Hz), 7.25 (dd, 1H, J=2.4, 8.7 Hz), 6.92(d, 1H, J=8.7 Hz), 5.75 (q, 1H, J=7.0 Hz), 4.38–4.24 (m, 2H), 3.05–2.95 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.25, (t, 3H, J=7.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([S:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][N:13]=[CH:14]3)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[N:28]1([C:2]2[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([S:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][N:13]=[CH:14]4)[CH:7]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Sc1cccc2cnccc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1Sc1cccc2cnccc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
According to the method in Example 10, a mixture of 5-(5-chloro-2-nitrophenylsulfanyl)isoquinoline 630 mg (2.0 mmol), DMF 5 ml, potassium carbonate 300 mg (2.2 mmol) and imidazole 140 mg (2.1 mmol) was stirred at 140° C. for 3 hours, and 5-[5-(1H-1-imidazolyl)-2-nitrophenylsulfanyl)isoquinoline 340 mg (49.0%) was obtained.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].[OH-].[Na+].Cl.S(Cl)([Cl:21])=O>CO.ClCCl.CN(C=O)C>[F:12][C:11]([F:14])([F:13])[S:8]([NH:7][CH2:6][CH2:5][CH2:4][C:3]([Cl:21])=[O:2])(=[O:10])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)CCCNS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cl)CCCNS(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
4-Trifluoromethanesulfonylamino-butyric acid methyl ester (0.42 g, 1.77 mmol) [example 212, step a] was taken up in methanol [2 mL] and 1N NaOH was added [2.66 mL] and stirred for 2 hours. 1N HCl was added and the product was extracted with ethyl acetate, dried with magnesium sulfate and evaporated. The crude product (0.13 g, 0.57 mmol) was dissolved in dichloromethane/DMF [1 mL/1 drop] and thionyl chloride (0.08 mL, 1.14 was added. The reaction was stirred at room temperature for 2 hours and then evaporated and used directly in the next step.