Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:19]=2[CH2:18]1)(O)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:19]=2[CH2:18]1)=[O:2]
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 2 h

Procedure:
3.88 g of 2-[4-(5-carboxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine are suspended in 25 ml of toluene and, under N2 and while stirring, 3 time the molar amount of a 20% solution of diisobutylaluminium hydride in toluene is added dropwise, and the mixture is boiled for 2 hours, cooled, decomposition is carried out with water, the usual working up is carried out, and 2-[4-(5-formyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro-[2,3-c]pyridine is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:33]1[CH2:32][CH:31]2[CH:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 8619 %

Procedure:
N,N'-Carbonyldiimidazole (0.37 g) is added to a solution of 2-(tert-butoxycarbonylaminomethyl)phenylacetic acid (0.6 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.75 g) and triethylamine (0.6 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). (3aRS,7aRS)-2-[(2-(tert-butoxycarbonylaminomethyl)phenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (105 g) is obtained in the form of a white meringue.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18]CC)=O)[N:15]=2)[N:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.[OH-].[NH4+:26].C1COCC1>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[S:12][CH:13]=[C:14]([C:16]([NH2:26])=[O:18])[N:15]=2)[N:9]=[C:8]([C:21]([F:23])([F:22])[F:24])[CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1csc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1csc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 29 (345 mg, 0.966 mmol) in methanol (1.5 mL) at room temperature was added ammonium hydroxide (1.5 mL, 38.5 mmol). The resulting solution was allowed to stir for 1 h at 50° C. THF (1 mL) was then added and the mixture was stirred for 16 h at 50° C. Solvent was evaporated, and the crude product 30 was isolated. LRMS (ESI): calc. 328.0; found 329.0 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH:19]=O.[BH4-].[Na+].O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH2:19][NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(N)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(NCc2c(Cl)cncc2Cl)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Commercially available 3,4-dimethoxy-phenyl-amine (1.74 g, 11.3 mmoles) and 3,5-dichloro-pyridine-4-carbaldehyde (2.0 g, 11.3 mmoles) were dissolved in toluene (40 mL) under nitrogen atmosphere. Molecular sieves (4A, 1 g) were added, and the mixture was heated to reflux. Reaction monitoring was performed by TLC analysis (petroleum ether/AcOEt 7/3): formation of the imine intermediate was completed after 3 hours. Molecular sieves were removed by filtration and the solvent was evaporated. The residue was dissolved in ethanol (99%, 40 mL). The solution was cooled to 0° C. and NaBH4 (559 mg, 14.7 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours, then water was added (50 mL), and the mixture was extracted AcOEt (3×60 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 7/3). The title compound was obtained as a yellow solid (3.04 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].[CH3:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:22]#[C:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8][C:9]=1[N:10]([C:35]([C@H:32]1[CH2:33][CH2:34][C@H:29]([CH3:28])[CH2:30][CH2:31]1)=[O:36])[CH:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2cncn2)CC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(n2cncn2)CC1

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-(4-[1,2,4]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester (0.27 g, 0.70 mmol) is acylated with trans-4-methylcyclohexyl carboxylic acid chloride as previously described to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-[1,2,4]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.CO[CH:9]([O:28][CH3:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:29][O:28][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][CH:16]=1)[C:5]#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: COC(Cc1ccc(OCCN(C)c2ccccn2)cc1)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(C#N)Cc1ccc(OCCN(C)c2ccccn2)cc1
Reaction time: 1.5 h

Procedure:
Trimethylsilyl cyanide (3.4 mL) was added dropwise to a solution of 1,1-dimethoxy-2-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]ethane (2.64 g) in dichloromethane (70 mL) at room temperature. The mixture was stirred during the addition of boron trifluoride etherate (0.3 mL), and stirring continued at room temperature for 1.5 hrs prior to the addition of a further portion of boron trifluoride etherate (1 mL). After a further 2 hours the mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2×300 mL), water (2×300 mL) and brine (300 mL), dried (MgSO4) and evaporated The residue was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound, a gum, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:9][CH2:8]2)=[N:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].[CH3:14]C(C[AlH]CC(C)C)C>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:9][CH2:8]2)=[N:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: COC(=O)c1nc(C2CC2)oc1Br
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C2CC2)oc1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
Into a 5000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 5-bromo-2-cyclopropyloxazole-4-carboxylate (120 g, 487.80 mmol, 1.00 equiv.) in tetrahydrofuran (1200 mL). This was followed by the addition of DIBAL-H (1200 mL, 4.00 equiv., 25%) dropwise with stirring at −78° C. over 15 minutes. The resulting solution was stirred for 2 hours at −78˜−10° C., then quenched by the addition of 2000 mL of 2N HCl. The resulting solution was extracted with 3×3000 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from EAOAc:PE in the ratio of 1:20. This resulted in 70 g (66% yield) of ethyl 5-bromo-2-cyclopropyloxazole-4-carboxylate as a white solid. LC-MS (ES, m/z): 218 [M+H]+. H1NMR (400 MHz, CDCl3) δ: 4.459 (2H, s), 2.011˜2.065 (1H, m), 1.628 (1H, br), 1.020˜1.106 (4H, m).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:14])[C:9]([OH:11])=O)=[CH:3][CH:2]=1.[NH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[O:14]=[C:13]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]1[C@@H:8]([CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:9]([NH:23][CH2:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:11]
Reactant: NCC(=O)c1ccccc1
Reactant: O=C(O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: O=C(CNC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
N-Phthaloyl-L-phenylalanine (290 mg, 1 mmol) and 2-aminoacetophenone (171 mg, 1 mmol) were dissolved in 10 mL of pyridine. Bop reagent (470 mg, 1.1 mmol) was added The mixture was stirred at rt under N2 for 12 h. The solvent was removed. The residue was dissolved in EtOAc and washed with water and sat. NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated to yield 412 mg of the product (100% yield). MS 413.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([O:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: c1ccc(COc2ccc(Nc3ccccc3)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-hydroxy-N-phenyl-aniline (30 g; 162 mmol) in acetonitrile (400 mL) there are added 58 g of Cs2CO3 (178 mmol) and stirring is carried out for 15 minutes at ambient temperature. Benzyl bromide (22.5 mL; 178 mmol) is then added dropwise and then the reaction mixture is refluxed for 4 hours. After filtering and rinsing with acetonitrile, the filtrate is concentrated and purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The title product is then obtained in the form of a colourless solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[O:15]
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)c1c(C)nc2ccccc2c1O
Solvent: Cc1ccccc1C
Product: COc1ccc(NC(=O)c2c(C)nc3ccccc3c2O)cc1

Procedure:
Using the procedure of Example 11, ethyl 4-hydroxy-2-methyl-3-quinoline-carboxylate [described in J. Het. Chem., Vol. 16 (1979), p. 1605] and p-anisidine in xylene were refluxed for 24 hours to obtain 4-hydroxy-N-(4-methoxyphenyl)-2-methyl-3-quinoline-carboxamide melting at 222° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[CH:22][C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[CH:22][C:21]3[C:20](=[N:26][OH:27])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
Added to 30 ml of methanol were 2.6 g (8.07 mmol, Referential Example 48) of 2-(4-benzylpiperazino)-5-oxo-5,6,7,8-tetrahydroquinazoline and 0.67 g (9.64 mmol) of hydroxylamine hydrochloride. The resultant mixture was heated with stirring at 60° C. for 2 hours. The reaction mixture was cooled to 20° C. and the resultant precipitate was collected by filtration, thereby obtaining 2.85 g of white solid (yield: 95%).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.CN(C=O)C.[C:36]([O:42][CH2:43]Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>>[O:27]=[C:4]1[N:3]([CH2:28][CH2:29][CH3:30])[CH:2]=[N:10][C:9]2[N:8]=[C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)[N:6]([CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:5]1=2
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)n(COC(=O)C(C)(C)C)c2c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.35 gm, 0.87 mmol) in DMF (5 ml) K2CO3 (0.360 gm, 2.59 mmol) was added under nitrogen atmosphere. To this reaction mixture Chloromethyl pivalate (0.395 gm, 2.62 mmol) was added at room temperature. It was stirred at 50° C. for 24 hrs. Reaction mixture was filtered and DMF was evaporated. Residue obtained was purified by LCMS to obtain above two isomers, Example 5 and Example 6.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[C:8]([NH:15][CH3:16])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25].[Cl-].[NH4+]>O1CCCC1>[C:1]([N:5]1[CH2:6][C:7]2[C:8](=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=2)[N:15]([CH3:16])[C:24]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1nc(SC)ncc1CNC(C)(C)C
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(C)C(=O)N(C(C)(C)C)C2
Temperature: 0 °C
Yield: 82.6 %

Procedure:
A mixture of 240 mg (1 mmol) of 5-tert.butylaminomethyl-4-methylamino-2-methylthiopyrimidine and 0.28 ml of triethylamine in 5 ml of tetrahydrofuran was added dropwise to an ice-cooled solution of 1 ml (1.92 mmol) of phosgene (20% solution in toluene) in 5 ml of tetrahydrofuran. After 1 hour 30 ml of saturated aqueous ammonium chloride and 20 ml of tetrahydrofuran were added to the resulting mixture. The phases were separated. The organic phase was dried over magnesium sulfate, filtered and then evaporated to give 220 mg (83%) of 3-tert.butyl-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][O:13][C:12]([CH2:19][CH2:20][OH:21])([CH2:16][CH2:17][CH3:18])[C:5]=1[NH:6]2.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][O:13][C:12]([CH2:19][CH2:20][O:21][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])([CH2:16][CH2:17][CH3:18])[C:5]=1[NH:6]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCC1(CCO)OCCc2c1[nH]c1c(F)ccc(Br)c21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acid ethyl ester (2.0 g, 5.02 mmol) in THF (10 mL) was added LAH (5.27 mL of 1.0 M in THF, 5.27 mmol) slowly at room temperature. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was quenched by the addition of H2O (0.5 mL) and then 10% NaOH (0.5 mL) was added to the mixture. Na2SO4 was added to the mixture and the resulting mixture was filtered. The filtrate was concentrated to give 1.79 g (100%) of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol as yellow oil. A mixture of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.79 g, 5.02 mmol), imidazole (0.854 g, 12.55 mmol) and tert-butyldimethylsilyl chloride (0.909 g, 6.03 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL). The organic solution was washed with H2O (5×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 7% EtOAc in hexanes) to give 2.29 g (97%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 8.97 (bs, 1H), 6.95 (dd, J=8.37, 4.17 Hz, 1H), 6.57 (d, J=10.41, 8.37 Hz, 1H), 3.98–3.54 (m, 4H), 3.00 (m, 2H), 2.00–0.90 (m, 6H), 0.80 (s, 9H), 0.74 (d, J=7.32 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]1[C:7]([O:17][CH3:18])=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11](O)=[O:12].S(Cl)([Cl:25])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]1[C:7]([O:17][CH3:18])=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([Cl:25])=[O:12]
Reactant: COc1cc(OC)c(C(=O)O)cc1Cc1cccc(Cl)c1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)Cl)cc1Cc1cccc(Cl)c1F
Temperature: 75 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
Under a nitrogen atmosphere, 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid (4.7 g) was dissolved in DMF/toluene solution (25 mL) (DMF concentration: 300 ppm). Thionyl chloride (2.1 g) was added dropwise to this solution at 75° C. After stirring at 75° C. for 1 hr, completion of the reaction was confirmed by HPLC. Toluene and excess thionyl chloride were evaporated under reduced pressure. Toluene (20 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure to give 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid chloride (5.07 g). THF (15 mL) was added thereto to give a suspension of acid chloride (5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid chloride) in THF, which was directly used in the next step.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH3:14].[CH3:15][O:16]C(Cl)Cl>ClCCl>[CH3:6][C:7]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=1[S:13][CH3:14])[CH:15]=[O:16]
Reactant: CSc1ccccc1C
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc(C=O)cc1C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
Tin (IV) chloride (13.6 ml, 0.116 mol) was added to an ice-bath cooled solution of 1-methyl-2-(methylthio)benzene (10 g, 0.073 mol) in anhydrous dichloromethane (200 ml) under nitrogen and stirred for a further 2 hours at 0° C. α,α-Dichloromethyl methyl ether (6.56 ml, 0.073 mol) was introduced and the reaction stirred for 1 hour at <10° C. before the cooling was removed. After attaining room temperature, the reaction mixture was poured into ice/water (400 ml), stirred and then extracted with dichloromethane (×3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated onto silica gel and purified by flash chromatography, eluting with diethyl ether/isohexane (10:1) to yield the sub-title compound as a brown oil (6.54 g) in 54% yield.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=O)[CH2:21][CH2:22][CH:17]2[CH2:16]1>O.C(O)C>[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=[N:2][OH:3])[CH2:21][CH2:22][CH:17]2[CH2:16]1
Reactant: NO
Reactant: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (3.47 g, 50.0 mmol) and sodium acetate (4.27 g, 52.0 mmol) were dissolved in water (15 mL) and added to a solution of 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one (Example 56C, 11.33 g, 40 mmol) in ethanol (80 mL). The reaction was brought to reflux and then allowed to cool to 70° C. After 1 hour, the solvent was removed in vacuo to give the title compound.
Reaction SMILES: O=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[OH:16]/[N:15]=[C:2]1/[CH2:3][CH2:4][CH2:5][C:6]2[O:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7]/1=2
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1coc2c1/C(=N\O)CCC2
Yield: 95.4 %

Procedure:
To a solution of 30.0 g of 4,5,6,7-tetrahydro-4-oxo-3-benzofurancarboxylic acid in 225 ml of ethanol is added 22.97 g of hydroxylamine hydrochloride, followed by 18.10 g of sodium acetate and 55 ml of water. The reaction mixture is heated at reflux for 2.5 hours and concentrated in vacuo to a residue which is diluted with 600 ml of ethyl acetate, washed with 2×200 ml of water, brine and dried over Na2SO4. The organic layer is concentrated in vacuo to a residue which is dried under vacuum to give 31.0 g of the desired product as a solid.