Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:12]([NH:11][C:4]2[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=2)=[O:20])[CH:43]=[CH:44][CH:45]=1
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(C)n4)c3)c2cc1OC
Yield: 13 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 165A (0.114 g, 0.4 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.028 g, 13%). 1H NMR (300 MHz, CDCl3) δ 9.53 (br, 1H), 8.63 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.41 (t, 1H), 7.32 (m, 2H), 7.12 (s, 1H), 7.01 (d, 1H), 6.28 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.92 (s and t, 5H), 3.50 (s, 3H); LC-MS ESI) m/z 533 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH3:16])=[CH:14][C@H:13](O)[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:25]([O:28][NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:32])=[O:31])[CH:26]=[CH2:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:25]([O:28][N:29]([C@H:13]1[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3])[C:15]([CH3:16])=[CH:14]1)[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:32])=[O:31])[CH:26]=[CH2:27]
Reactant: CC1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a stirred suspension of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 79, 5.48 g, 15.33 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (7.92 g, 30.65 mmol) and triphenylphosphine (12.06 g, 45.98 mmol) in toluene (20 mL) was cooled in an ice-bath and added dropwise (E)-diisopropyl diazene-1,2-dicarboxylate (8.91 ml, 45.98 mmol). Reaction was let warm up to rt and continued to stir at rt for 2 h. The reaction mixture was evaporated and the crude product was loaded onto silica gel, purified via flash chromatography (750 g, 0-50%) to obtain the desired product (7.05 g, 77%) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26]>>[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]2[C:11](=[N:27][CH:25]=[N:26][C:15]2=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: N=CN
Agent: Cl
Solvent: CC(=O)O
Product: O=C1N=CN=C2CN(Cc3ccccc3)CCC12

Procedure:
Various N-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine derivatives are prepared using a general procedure described below. Accordingly, ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride is reacted with formamidine acetate to yield 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one, which, in turn, is reacted with POCl3 to afford the 4-chloro derivative. The intermediate chloro derivative is then condensed with substituted aniline or amine to give the desired N-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine. Debenzylation using standard procedures known in the art followed by nucleophilic displacement of an appropriate 2-halo-pyridine yields the appropriate N-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine. As a representative example, synthesis of N-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine is depicted in Scheme 1.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])(=[O:15])[CH3:14].[CH2:30](O)[CH:31]([OH:33])[CH3:32].C1(C)C=CC=CC=1>O>[CH3:14][C:13]1([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]3([CH3:29])[CH3:28])[O:33][CH:31]([CH3:32])[CH2:30][O:15]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1COC(C)(c2ccc3c(c2)C(C)(C)CCC3(C)C)O1
Temperature: 110 °C

Procedure:
p-Toluenesulphonic acid monohydrate (2 g) is added to a suspension of 120 g (0.5 mol) of 6-acetyl-1,1,4,4-tetra-methyl-tetralin, 120 g (1.6 mol) of propylene glycol and 600 ml of toluene. The mixture is heated to 110° C. The reaction water is removed azeotropically within 5 hours. After cooling to room temperature the mixture is adjusted to pH 7.5 to 8 by the addition of 10% potassium hydroxide in ethanol. Thereupon, the mixture is filtered. The solvent is evaporated and the residual liquid is distilled under a vacuum, whereby there separate as the main product 123 g of 2.4-dimethyl-2-(1,1,4,4-tetramethyl-tetralin-6-yl)-1,3-dioxolane as a mixture of the boiling point is 112° C. at 0.5 mmHg; nD20 =1.5130. The product has a strong woody, animalic odour.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][S:20]SC>>[CH3:19][S:20][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:16][CH:15]=2
Reactant: CSSC
Reactant: COc1ccc2cc(-c3ccccc3)ccc2c1
Product: COc1cc2ccc(-c3ccccc3)cc2cc1SC

Procedure:
3-Methylthio-6-phenyl-2-methoxynaphthalene (compound (4)-31) was synthesized from 6-phenyl-2-methoxynaphthalene (compound (3)-31) and dimethyl disulfide by the same method as that in Example 14.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH3:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(CBr)c1
Temperature: 0 °C
Yield: 65.2 %

Procedure:
A mixture of tert-butyl(4-fluoro-3-methylphenoxy)dimethylsilane (step 1, 30 g, 0.12 mol), N-bromosuccinimide (24 g, 0.13 mol) and benzoylperoxide (1.5 g, 6.2 mmol) in carbon tetrachloride (75 mL) was reflux under nitrogen atmosphere for 4 h. The reaction mixture was cooled at 0° C., and the white precipitate was filtered. The filtrate was washed with sodium bicarbonate aqueous solution, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane to afford 25 g (65%) of the title compound as a colorless oil:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:13][CH:14](OCC)OCC)[CH:5]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]2[O:12][CH:13]=[CH:14][C:5]=12)=[O:21]
Reactant: CCOC(COc1cc(OC)cc(C(=O)OC)c1)OCC
Solvent: c1ccccc1
Product: COC(=O)c1cc(OC)cc2occc12
Yield: 62.4 %

Procedure:
3-(2,2-Diethoxy-ethoxy)-5-methoxy-benzoic acid methyl ester (6b) (1.95 g, 6.53 mmol) was added to a solution of polyphosphoric acid (1.47 g) in benzene (10 mL). The reaction mixture was heated to reflux for 2 hr, filtered and concentrated. The residue was purified by flash column chromatography (5% EtOAc in hexanes) to give a pale yellow solid (840 mg, 62% yield). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=2.27 Hz, 1 H) 7.61 (d, J=2.27 Hz, 1 H) 7.26 (d, J=2.02 Hz, 1 H) 7.25 (d, J=2.27 Hz, 1 H) 3.99 (s, 3 H) 3.90 (s, 3 H).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([CH:17]=[O:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:5]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:3][C:4]=1[CH:17]=[O:18]
Reactant: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1ccccc1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(C=O)cc(-c2cccnc2)n1S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Under an argon atmosphere, a suspension of 5-bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (497 mg), 3-pyridineboronic acid (376 mg), sodium carbonate (481 mg) and tetrakis(triphenylphosphine)palladium (89.2 mg) in 1,2-dimethoxyethane (12 mL) and water (6 mL) was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:4) to give the title compound as a white solid (yield 353 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[C:12](I)[CH:11]=3)=[N:7][C:6]=2[CH:18]=1.[Cu](C#N)[C:20]#[N:21]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:20]#[N:21])[CH:11]=3)=[N:7][C:6]=2[CH:18]=1
Reactant: Nc1ccc(-c2nc3cc(F)ccc3s2)cc1I
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2nc3cc(F)ccc3s2)ccc1N
Reaction time: 0.5 h

Procedure:
5-Fluoro-2-(4′-amino-3′-iodophenyl)benzothiazole (5 g, 0.0135 mol), copper cyanide (3.65 g, 0.04 mol) and DMF (100 ml) were heated under reflux for 6 hrs, cooled and the solvent removed under vacuum. The residue was stirred in water (50 ml) for 30 mins, then the product extracted with ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4), evaporated and the residue recrystallised from ethanol to give a white solid.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26](OC)=[O:27])=[CH:22][N:21]=1)=[O:19])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.Cl>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=1)=[O:19])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)cn1
Yield: 53 %

Procedure:
Under ice cooling, lithium tetrahydroborate (2.1 g, 100 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-5-methoxycarbonylpyridine-2-carboxylic acid amide (Reference Compound No. 2-1, 38 g, 100 mmol) in THF (400 mL), and then the reaction mixture was stirred for 3 hours. Under ice cooling, water (200 mL) and 1.0 M aqueous hydrochloric acid (300 mL) were added thereto, the whole was extracted with ethyl acetate (300 mL), and then the organic layer was washed with water (500 mL) and brine (400 mL). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. Ethyl acetate (20 mL) and hexane (30 mL) were added to the residue, and then the resulting solid was collected by filtration to give 18 g of the title reference compound as a white solid. (Yield 53%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[C:7]=1[CH3:8])#[N:2].[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:8][C:7]1[N:6]([C:9]2[C:10]([Cl:20])=[CH:11][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:13][C:14]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Cc1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1CBr
Yield: 103.5 %

Procedure:
By the method of Example 5, Step D, 106 g (0.331 mole) of 4-cyano-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole was reacted with 71.1 g (0.40 mole) of N-bromosuccinimide in 2000 mL of carbon tetrachloride, yielding 136.7 g of 5-bromomethyl-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole as red oil, a portion of which later solidified.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CS([CH2:41][CH2:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[CH:48][CH:49]=1)(=O)=O>O>[O:46]1[CH:47]=[CH:48][CH:49]=[C:45]1[CH2:44][O:43][CH2:42][CH2:41][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)CCOCc1ccco1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CCOCc2ccco2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (0.5 g, 1.6 mmol) and tetrahydrofuran (10 mL). Cool to -78° C. Add dropwise, a solution of potassium bis(trimethylsilyl)amide (3.6 mL, 0.5M in toluene, 1.8 mmol). After 30 minutes, add fur-2-ylmethyl 2-methanesulfonylethyl ether (1.8 mmol). Warm to ambient temperature and heat to reflux. After 18 hours, cool to ambient temperature and add water. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give (1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine: Rf =0.55 (2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>C1COCC1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH3:8])[CH2:21][O:22]2)=[CH:16][CH:15]=1
Reactant: C[S+](C)C
Reactant: COc1ccc(C(C)=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(C2(C)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-methoxyphenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:16](OC(=O)C)(=O)C>>[CH3:16][O:11][C:10]([C:8]1[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(C2CC2)nc1C(=O)O
Product: COC(=O)c1nc(C2CC2)ccc1C(=O)O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 6-cyclopropyl-pyridine-2,3-dicarboxylic acid (D82, 19.8 g, 95.6 mmol) in acetic anhydride (100 ml) was heated at 110° C. for 2 hours and then was concentrated in vacuum. To the residue was added methanol (100 ml) and stirring was continued at room temperature for 2 hours. The reaction mixture was concentrated in vacuum and the residue was purified by column chromatography on silica gel (10% ethyl acetate in petroleum ether) and C-18 reversed phase column (5% methanol/water to methanol) to give D83 (10.7 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.Cl.[O:12]([NH2:14])[CH3:13].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:14][O:12][CH3:13]
Reactant: CON
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(Cl)c1

Procedure:
Reaction of 3-chloro-4-fluorobenzaldehyde with methoxylamine hydrochloride followed by reduction with sodium cyanoborohydride as described in the preparation of Compound 44-A and 44-B gave the title hydroxylamine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s), 3.98 (2H, s), 5.72 (1H, broad s), 7.10 (1H, t), 7.22 (1H, m), 7.42 (1H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:25]2[CH2:24][CH2:23][CH:22]([N:14]([CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:27][CH2:26]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Product: COc1cc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 4-fluoro-2-methoxy-1-nitrobenzene and tert-butyl methyl(piperidin-4-yl)carbamate. m/z 366.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]3[O:40][CH:39]=[CH:38][C:37]=3[CH:41]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[O:40]1[C:36]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:23][CH2:22]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[CH:4][CH:3]=3)=[CH:41][C:37]=2[CH:38]=[CH:39]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
In a microwave vial, a mixture of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (322 mg, 0.77 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (208 mg, 0.85 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (32 mg, 0.04 mmol) in 2M aq potassium carbonate solution (1.5 mL, 3 mmol) and 1,4-dioxane (3 mL) was stirred at 100° C. for 3 h. The reaction was cooled to room temperature. The layers were separated and an aliquot of the basic potassium carbonate aqueous layer was analyzed by LCMS and showed that desired product was present. The aqueous layer was acidified using 1N aq HCl solution to pH˜6 by pH paper and was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, 0-10% MeOH/CH2Cl2, SF15-12 g, 20 min) followed by another purification (100% EtOAc for 10 min and then 0-8% MeOH/CH2Cl2 for 15 min) and finally subsequent purification by silica gel chromatography (Analogix IF280, SF15-4-g, Solvent A=EtOAc; Solvent B=10% MeOH/CH2Cl2; Gradient: 100% A for 10 min then ramped to 100% B over 20 min (i.e. 0-100% of B/A) provided the title product as a pale yellow solid (232 mg, 0.53 mmol, 69%). MS(ES)+ m/e 428.9 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[NH2:14])[C:7]([O:9][CH3:10])=[O:8].[C:15](Cl)(=O)[CH2:16][CH2:17][CH3:18]>P(Cl)(Cl)(Cl)=O>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:13]2[N:14]=[C:15]([CH2:16][CH2:17][CH3:18])[NH:3][C:4]=2[CH:5]=1)=[O:8]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2ccc(C(=O)OC)cc2[nH]1

Procedure:
A solution of 23.9 g (100 mMol) of methyl 3,4-diaminobenzoate dihydrochloride and 11.7 g (110 mMol) of butyric acid chloride in 100 ml of phosphorus oxychloride is refluxed for 2 hours. Then about 80 ml of phosphorus oxychloride are distilled off and the residue is mixed with about 150 ml of water. The oily crude product precipitated is extracted three times with 50 ml of ethyl acetate and after evaporation purified by column chromatography (600 g of silica gel; eluant: methylene chloride/methanol (30:1)).