Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12]CC1C=CC=CC=1)=[O:11].C(O)C.O.C([O-])(O)=O.[Na+:28]>O1CCOCC1.[Pd]>[N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O-:12])=[O:11].[Na+:28]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C([O-])C1C(=O)CC2CC(=O)N21

Procedure:
Benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (25 mg) is hydrogenated at 40 psi for 1 hr in dioxane (2 ml) containing ethanol (0.5 ml), H2O (0.5 ml), NaHCO3 (8.1 mg) and 10% Pd/C (10 mg). The mixture is filtered to remove the catalyst which is washed with more H2O (2.5 ml). The combined filtrate and washing is extracted with EtOAc (3×2 ml), concentrated under reduced pressure, and lyophilized to provide sodium 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>>[CH3:24][O:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: Oc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1
Reactant: COC(=O)CCCCCBr
Product: COC(=O)CCCCCOc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1

Procedure:
6-Hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole was reacted with 6-bromohexanoic acid methyl ester according to general operating instructions 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([O:14]C)=O)[C:9](=[O:16])[S:8][C:5]2=[N:6][CH:7]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]3)=[O:14])[C:9](=[O:16])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)Cn1c(=O)sc2ncc(Cl)cc21
Reactant: OCCN1CCNCC1
Product: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCN(CCO)CC1
Temperature: 130 °C
Yield: 40 %

Procedure:
A mixture of 6-chloro-1-methoxycarbonylmethyl-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (10.32 g) and N-(2-hydroxyethyl)piperazine (10.4 g) was heated at 130° C. for 15 min. After cooling, the reaction mixture was poured into an ice-water. The precipitates obtained were extracted with chloroform. The chloroform layer was dried over magnesium sulfate, and evaporated to give crude material. The crude material was purified on a silica gel column chromatography using a mixture of methylene chloride and methanol (10:1). The desired fractions containing the objective compound were collected and evaporated. The crude crystals obtained were recrystallized from a mixture of methanol and diethyl ether to give 6-chloro-2-oxo-1-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl}-1,2-dihydrothiazolo[5,4-b]pyridine (5.70 g).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[N:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19]1(=[O:33])[N:23]([CH2:24][C:25](Cl)=[O:26])[C:22](=[O:28])[C:21]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:20]12>C(Cl)Cl>[CH2:5]([N:4]1[C@H:3]([CH2:2][Cl:1])[C@H:24]([N:23]2[C:22](=[O:28])[C:21]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:20]3[C:19]2=[O:33])[C:25]1=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: ClCC=NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)[C@@H](CCl)N1Cc1ccccc1
Reaction time: 0.33 h
Yield: 19.7 %

Procedure:
A solution of 3.34 g of the product of Step A in 20 ml of methylene chloride was cooled to -50° C. and 2.8 ml of triethylamine were added all at once. A solution of 4 g of phthalimidoacetic acid chloride in 20 ml of methylene chloride was added thereto over 20 minutes. The mixture was stirred for one hour at 0° to -5° C. and was then poured into a decanting flask. The decanted organic phase was washed with 50 ml of demineralized water and 5 ml of a molar aqueous solution of sodium bicarbonate, and then twice with 30 ml of demineralized water. The wash water was re-extracted with 20 ml of methylene chloride and the combined organic phases were dried, rinsed and evaporated to dryness under vacuum. The 6 g of residue were chromatographed over silica gel and eluted with methylene chloride containing 5% ether. The fraction with an Rf=0.45 was evaporated to dryness and the residue was triturated with 10 ml of ether. The separated product was rinsed three times with 2 ml of ether and dried under vacuum to obtain 1.25 g of cis N-benzyl-3-phthalimido-4-chloromethyl-2-azetidinone melting at 149° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O.Cl>N1C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
After adding 4-nitrobenzoyl chloride (34, 7.534 g, 185.57 mmol) to p-anisidine (33, 5.00 g, 40.60 mmol) dissolved in pyridine (50 mL), the reaction mixture was heated for 2 hours at 100° C. After adding water and aqueous 4 N HCl (300 mL), extracting with ethyl acetate and removing water using sodium sulfate, column chromatography yielded the target compound N-(4-methoxyphenyl)-4-nitrobenzamide (36, 8.594 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1([C:19](N2C=CN=C2)=[O:20])C=CN=C1>O1CCCC1>[N+:11]([C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:19](=[O:20])[NH:1][C:2]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Into a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-amino-4-nitrobenzoic acid (54.6 g, 300.00 mmol, 1.00 equiv) in tetrahydrofuran (500 mL), di(1H-imidazol-1-yl)methanone (58.32 g, 360.00 mmol). The resulting solution was stirred for 2 h at 10° C. The solids were collected by filtration to yield 7-nitro-1H-benzo[d][1,3]oxazine-2,4-dione as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:5]([N:6]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:4][CH2:3][OH:2])[CH:16]=1
Reactant: COC(=O)CC(c1cccnc1)n1ccc2ncccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(c1cccnc1)n1ccc2ncccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a 0° C. solution of 3-pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propionic acid methyl ester (150 mg, 0.53 mmol) in THF (10 mL) was added LAH (1M in THF, 0.53 mL). The reaction mixture was stirred at RT for 2 h, and quenched by addition of freshly ground Na2SO4.10H2O (1 g). The mixture was filtered through a celite pad, and the filtrate was concentrated and purified via flash chromatography (DCM/MeOH/NH4OH, 8/2/0.1), affording 3-Pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propan-1-ol (66% yield, 85 mg).
Reaction SMILES: [O-][CH2:2]C.[Na+].[N:5]1[CH:10]=[C:9]([CH2:11][C:12]2[C:13](=[O:19])[NH:14][C:15](=[S:18])[NH:16][CH:17]=2)[CH:8]=[N:7][CH:6]=1.CI>CCO>[CH3:2][S:18][C:15]1[NH:16][CH:17]=[C:12]([CH2:11][C:9]2[CH:10]=[N:5][CH:6]=[N:7][CH:8]=2)[C:13](=[O:19])[N:14]=1
Reactant: CC[O-]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
Into a stirred solution of sodium ethoxide (157.7 mg, 2.32 mmol, 2 eq) in EtOH (5.2 ml) was added 5-pyrimidin-5-ylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (270 mg, 1.22 mmol, 1 eq) at rt. After 30 min, the reaction mixture was treated with methyl iodide (190.7 μl, 3.05 mmol, 2.5 eq) and was stirred at rt overnight. Solvent was evaporated and water (1 ml) was added. pH was adjusted ˜4 with 1N HCl and precipitate was formed to give 2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (196 mg, yield=62.4%, purity=91%). [M+H]+=235.28. 1H NMR (300 MHz; CDCl3) δ/ppm 2.45 (s, 3H), 3.62 (s, 2H), 3.50 (s, 2H), 7.89 (s, 1H), 8.69 (s, 2H), 9.00 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:23][CH2:24][CH3:25])[CH2:5][O:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:9][NH2:10])[CH3:2].C(N(CC)CC)C.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C(Cl)Cl>[CH2:24]([O:23][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][O:6][C:7]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:8][CH2:9][NH:10][C:36]([CH:33]1[CH2:35][CH2:34]1)=[O:37])[CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(COC(CCN)(c1ccccc1)c1ccccc1)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(COC(CCNC(=O)C1CC1)(c1ccccc1)c1ccccc1)OCC
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows. The solution of 3.4 g of 2-(3-amino-1,1-diphenylpropoxy)-acetaldehye diethyl acetal, 1.5 g of triethylamine and 35 ml of methylene chloride is stirred and cooled in an ice bath during the dropwise addition of the solution of 1.05 g of cyclopropane carboxylic acid chloride in 15 ml of methylene chloride. Upon stirring subsequently for 1/2 hour at 0°-5° C, the solution is washed successively with 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and evaporated, to yield the 2-(3-cyclopropylcarbonylamino-1,1-diphenylpropoxy)-acetaldehyde diethyl acetal.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C([O:22][C:23]1[C:32]([CH3:33])=[CH:31][C:26]([C:27]([NH:29][NH2:30])=O)=[CH:25][C:24]=1[CH2:34][CH3:35])C1C=CC=CC=1>>[CH2:34]([C:24]1[CH:25]=[C:26]([C:27]2[O:13][C:11]([C:8]3[CH:7]=[C:6]([CH3:14])[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:10][N:9]=3)=[N:30][N:29]=2)[CH:31]=[C:32]([CH3:33])[C:23]=1[OH:22])[CH3:35]
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Reactant: Cc1cc(C(=O)O)ncc1CC(C)C
Product: CCc1cc(-c2nnc(-c3cc(C)c(CC(C)C)cn3)o2)cc(C)c1O

Procedure:
The title compound is prepared in analogy to Example 18 starting from 5-isobutyl-4-methyl-pyridine-2-carboxylic acid and 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide; LC-MS: tR=1.07 min, [M+H]+=357.18.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C@@H:19]([OH:23])[C:20]#[C:21][CH3:22])[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:33]([O:37][C:38]([NH:40][C:41]1[CH:49]=[CH:48][C:47]([O:50][C:51]([F:54])([F:53])[F:52])=[CH:46][C:42]=1[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:33]([O:37][C:38]([NH:40][C:41]1[CH:49]=[CH:48][C:47]([O:50][C:51]([F:52])([F:53])[F:54])=[CH:46][C:42]=1[C:43]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C@@H:19]([OH:23])[C:20]#[C:21][CH3:22])[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4])=[O:44])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CNC(=O)c1cc(OC(F)(F)F)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of benzyl (2S,3S)-2-[2-(tert-butoxycarbonylamino)acetamido]-3-hydroxyhex-4-ynylcarbamate (700 mg; see WO-02/50019 for preparation) in methylene chloride (12 mL) was cooled to 0° C. and charged with trifluoroacetic acid (4 mL). The mixture was allowed to warm to RT and stirred for 45 min before being concentrated in vacuo. The residue was dissolved in methylene chloride and the resultant solution concentrated; this was repeated twice more to afford the TFA salt of benzyl (2S,3S)-2-(2-aminoacetamido)-3-hydroxyhex-4-ynylcarbamate, MS found: (M+H)+=320.6. A solution of this amine in 1:1 CH2Cl2/DMF (10 mL) was charged successively with N,N-diisopropylethylamine (0.84 mL), 2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoic acid (322 mg, see WO-02/50019), and HATU (544 mg). The reaction was stirred for 14 h at RT before being partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (2S,3S)-2-(2-(2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzamido)acetamido)-3-hydroxyhex-4-ynylcarbamate (182 mg). MS found: (M+H)+=623.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([C:29](=O)[CH2:30][CH2:31][CH3:32])[C:24](OCC)=[O:25])=[CH:18][CH:17]=1)#[N:9]>ClC1C=CC(Cl)=CC=1Cl>[CH3:1][C:2]1[N:3]=[C:4]2[NH:7][C:24](=[O:25])[C:23]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([C:11]4[C:10]([C:8]#[N:9])=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:17][CH:18]=3)=[C:29]([CH2:30][CH2:31][CH3:32])[N:5]2[N:6]=1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Cc1nnc(N)[nH]1
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Yield: 54.2 %

Procedure:
A solution of 5-methyl-4H-1,2,4-triazol-3-amine (1.7 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (7.1 g) in 1,2,4-trichlorobenzene (70 mL) was stirred at 190° C. for 6 hr. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the obtained residue. The precipitated solid was collected by filtration to give the title compound as a colorless solid (3.6 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(Nc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 4-amino-4′-(trifluoromethoxy)biphenyl (compound of Example 3(2); 112 mg, 0.442 mmol), 4-(tert-butyl)phenylboronic acid (87 mg, 0.486 mmol), copper(II) acetate (40 mg, 0.221 mmol), triethylamine (0.061 ml, 0.884 mmol) and pyridine (3.0 ml) was stirred at 50° for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with 1N hydrochloric acid (10 ml), and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (50 mg, 29%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:21]([O:25][N:26]1N=NC2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.Cl.CNOC.C(N(CC)C(C)C)C>CN(C=O)C>[CH3:21][O:25][N:26]([CH3:27])[C:13]([CH:12]1[CH2:11][S:10][C:9]([CH3:17])([CH3:16])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1(C)C
Agent: CCN(CC)C(C)C
Agent: CNOC
Agent: Cl
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CSC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.1 %

Procedure:
A flask containing 3-(tert-butoxycarbonyl)-2,2-dimethylthiazolidine-4-carboxylic acid (see Suaifan et al., Tetrahedron 62, 11245-11266 (2006); Kemp and Carey, J. Org. Chem. 54, 3640 (1989)) (4 g, 0.015 mol), HATU (7.3 g, 0.019 mol), HOAt (28 ml of 0.6M, 0.017 mol), N,O-dimethylhydroxylamine-HCl (2.92 g, 0.03 mol), diethylisopropylamine (5.1 L, 0.03 mol), and DMF (20 mL) was stirred at room temp for 17 h. Solvent was evaporated, and the residue was portioned between EtOAc (200 mL) and water (300 mL). The aqueous layer was extracted with EtOAc (50 mL), and the combined organic layers washed with 30% citric acid solution (2×100 mL), saturated bicarbonate (2×100 mL), and brine (1×50 mL). After evaporation, the crude residue was chromatographed on normal phase silica—eluting with heptane/EtOAc (2/1) to yield 3.84 g (84%) solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:16].[Na+].[OH-].[Na+].Cl[O-].[Na+].Cl>CO.[O-]S([O-])(=S)=O.[Na+].[Na+].CC(OC)(C)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([I:16])[CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: [I-]
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: Oc1ccc(I)cc1OCc1ccccc1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
A solution of 2-(benzyloxy)phenol (63.7 ml, 364 mmol) in MeOH (1050 ml) was cooled to −10° C. and sodium iodide (54.5 g, 364 mmol) and sodium hydroxide (382 ml, 764 mmol) were added (NaOH over 5 min, temp to 10° C. and dark solution with NaOH addition). Cooled back to <5° C. and added sodium hypochlorite (247 ml, 400 mmol) dropwise, keeping the temperature at <5° C. After 10 min, removed 500 mL MeOH by rotary evaporation, then added MTBE (730 mL) and 2 N HCl (909 ml, 1818 mmol), washed with 1 N Na2S2O3 (130 mL×3; lighter each time) and brine (64 mL), dried (Na2SO4), conc, and flushed with cyclohexane (100 mL) to a crude yellow solid. Added cyclohexane (130 mL), heated to 55° C. (yellow solution), then cooled slowly, seeding at 45° C. (˜50 mg-solution) and 40° C. (˜50 mg, slurry developed). Continued cooling to room temperature (˜20-25° C.) and stirred vigorously overnight. Filtered, washing with cyclohexane (64 mL), giving crop 1 material (69.93 g, 59%, very pure by 1H NMR, slightly off-white solid). Concentrated the mother liquors to ˜70 mL, seeded, aged 1 h, and sticky dark material was precipitating with product. Added MTBE (7 mL), sonicated (good for color dissolution), stirred 20 min, and filtered. Washed with 10% MTBE/cyclohexane (32 mL), giving crop 2 material (4.65 g, some small impurities by 1H NMR). Overall, isolated 2-(benzyloxy)-4-iodophenol (74.6 g, 229 mmol, 62.9% yield). 1H NMR (501 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.49-7.42 (m, 2H), 7.42-7.35 (m, 2H), 7.35-7.29 (m, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.3, 2.1 Hz, 1H), 6.64 (d, J=8.3 Hz, 1H), 5.09 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22](=[O:26])[NH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:10]([OH:12])([CH2:11][N:23]2[C:24]3[C:19](=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:25]=3)[CH:20]=[CH:21][C:22]2=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC2(CO2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(=O)n(CC3(O)CN(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 80 °C
Reaction time: 240 h
Yield: 9.7 %

Procedure:
A solution of oxa-5-azaspiro[2.3]hexane-5-carboxylic acid tert-butyl ester (69 mg; prepared according to WO 2007/044515) in DMF (1 mL) was added to a suspension of 7-methoxy-2(1H)-quinolinone (60 mg; commercial) and Cs2CO3 (223 mg, 2 eq.) in DMF (2 mL). The reaction mixture was stirred at 80° C. for 10 days. The solvent was removed under reduced pressure and the residue was partitioned between water and EA. The aq. layer was extracted with EA. The combined org. layers were dried over Na2SO4, filtered, evaporated and purified by CC (DCM-MeOH 19:1 to 9:1) to afford the title intermediate as a yellow oil (12 mg, 10% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH2:10][CH2:11][CH:12]1[O:17][C:16](=[O:18])[CH2:15][CH:14]([OH:19])[CH2:13]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.ClC1C=C(O)C(=C(Cl)C=1)C=O.C(Br)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)[C:3]=1[CH2:10][CH2:11][CH:12]1[O:17][C:16](=[O:18])[CH2:15][CH:14]([OH:19])[CH2:13]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C1CC(O)CC(CCc2c(O)cc(Cl)cc2Cl)O1
Agent: BrCc1ccccc1
Agent: O=Cc1c(O)cc(Cl)cc1Cl
Product: O=C1CC(O)CC(CCc2c(Cl)cc(Cl)cc2OCc2ccc(C(F)(F)F)cc2)O1

Procedure:
By following the procedure of Example 1, step A, but substituting equimolar amounts of 6-{2-(2,4-dichloro-6-hydroxyphenyl)ethyl}-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one and 4-trifluoromethylbenzyl bromide for the 4,6-dichlorosalicylaldehyde and benzyl bromide used therein, the title compound is obtained, m.p. 104°-105° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:17]C(=O)OC(C)(C)C)[CH:12]=[N:13][C:14]=1[O:15][CH3:16]>>[F:8][C:9]1[CH:10]=[C:11]([NH2:17])[CH:12]=[N:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ncc(NC(=O)OC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(N)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.6 %

Procedure:
TFA (2 ml) was added to tert-butyl (5-fluoro-6-methoxypyridin-3-yl)carbamate (279 mg) obtained in the 1st step, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure and a 5M sodium hydroxide aqueous solution was added to the obtained residue at 0° C. so as to alkalify the mixture, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. A light brown solid of 5-fluoro-6-methoxypyridin-3-amine (19 mg) was thus obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCO3)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.