Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(Cl)(Cl)Cl.[NH2:12][C:13]1[C:18]([NH2:19])=[C:17]([N:20]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21]2)[C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:15]([CH3:34])[C:14]=1[C:35]#[N:36]>O>[NH2:12][C:13]1[C:14]([C:35]#[N:36])=[C:15]([CH3:34])[C:16]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:17]([N:20]2[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21]2)[C:18]=1[NH:19][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1c(C#N)c(N)c(N)c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(C#N)c(N)c(NC(=O)C(C)(C)C)c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Reaction time: 3 h
Yield: 43 %

Procedure:
With cooling with ice, pivaloyl chloride (0.46 ml, 3.73 mmol) was dropwise added to a chloroform (40 ml) solution of 4,5-diamino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-methylbiphenyl-3-carbonitrile (I-269) (1.25 g, 3.73 mmol). After stirring for 3 hours, water was added to the reaction liquid to stop the reaction, followed by extraction with chloroform. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, then the residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform/methanol (95:5, v/v) to obtain the entitled compound (675 mg, 43%) as a brown amorphous substance.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7]O.[C:9]1([NH:15][C:16]2([C:22](=[O:25])[CH2:23][CH3:24])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[C:9]1([NH:15][C:16]2([C:22](=[O:25])[CH2:23][CH3:24])[CH2:21][CH2:20][N:19]([CH2:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(=O)C1(Nc2ccccc2)CCNCC1
Reactant: OCCc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CCC(=O)C1(Nc2ccccc2)CCN(CCc2cccs2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4.1 parts of 2-thiopheneethanol, methanesulfonate ester, 3.5 parts of 1-[4-(phenylamino)-4-piperidinyl]-1-propanone, 5.3 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed for 18 hours. After cooling to room temperature, the reaction mixture is poured onto water and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-{4-(phenylamino)-1-[2-(2-thienyl)ethyl]-4-piperidinyl}-1-propanone; mp. 127.1° C.
Reaction SMILES: [F:1][C:2]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)([C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].[I-].[CH3:16][S+](C)(C)=O.CS(C)=O>O1CCCC1>[C:5]([C:4]1([C:2]([F:1])([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH3:3])[CH2:16][O:9]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)C(=O)C(C)(F)n1cncn1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C1(C(C)(F)n2cncn2)CO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
12.0 g of 2-fluoro-2-(1H-1,2,4-triazol-1-yl)-4,4-dimethyl-3-pentanone are added dropwise to a mixture of 13.2 g of trimethylsulfoxonium iodide, 7.3 g of potassium tertiary butylate, 20 ml of dimethyl sulfoxide and 80 ml of tetrahydrofuran, and the reaction mixture is stirred for 18 hours at 80° C. After cooling, the mixture is taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Distillation of the oily residue gives 6 g 2-tert.-butyl-2-[1-fluoro-1-(1H-1,2,4-triazol-1-yl)-ethyl]-oxirane, boiling point 60°-61° C./0.013 mbar.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4](=[O:18])[C:5]1[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[Si:14]([CH3:17])([CH3:16])[CH3:15])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4](=[O:18])[C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[C:7]([F:13])[C:6]=1[Si:14]([CH3:16])([CH3:15])[CH3:17])[CH3:20]
Reactant: CCN(CC)C(=O)c1c(C=O)ccc(F)c1[Si](C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)C(=O)c1c(CO)ccc(F)c1[Si](C)(C)C
Yield: 82 %

Procedure:
The compound of Example 41 (1.2 g, 4.1 mmol) and sodium borohydride (200 mg, 5.3 mmol) in ethanol (20 mL) were stirred at ambient temperature for 2 h. The solution was concentrated and partitioned between ether and 10% citric acid. The ether layer was washed with water and then brine, dried (MgSO4), concentrated, and recrystallized from cold hexanes to afford 1.0 g of the title compound, an 82% yield. m.p. 107°-108° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11][CH2:12][CH2:13]Br>C(O)C>[CH3:10][O:11][CH2:12][CH2:13][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CNCc1ccccc1
Reactant: COCCBr
Solvent: CCO
Product: COCCN(C)Cc1ccccc1
Yield: 58 %

Procedure:
The synthesis of BnMO was carried out in a manner similar to that of BnEO (process 2) using N-methylbenzylamine (15 mL, 0.116 mol), bromoethyl methyl ether (12 mL, 0.116×1.1 mmol), and ethanol (200 mL) as a solvent. BnMO (12.09 g, 67.46 mmol, yield 58%) was obtained as a pale yellow clear liquid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=2)[CH2:31][CH2:30]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:24]=[C:23]3[C:22](=[CH:17][CH:16]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:32]([CH:29]2[CH2:31][CH2:30]2)[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=2)=[O:28])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(CNC2CC2)cc1OC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: COc1ccc(CN(C(=O)CN(c2ccc3ncccc3c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc1OC

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>ClCCl>[CH2:13]([Cl:1])/[CH:14]=[C:15](\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])/[CH3:22]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCC/C(C)=C\CCl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of N-chlorosuccinimide (10.0 g) and dimethylsulfide (6.56 ml) in dichloromethane (200 ml) was added nerol (7.71 g) while being cooled with ice. The mixture was stirred at 0° C. for 4 hours. The reaction solution was washed with brine and dried over sodium sulfate anhydride. Then, the solvent was evaporated, thereby yielding a raw product of neryl chloride. In a manner similar to Reference Example 1, this raw product was reacted with methyl 4- hydroxybenzoate (7.61 g) and then hydrolyzed to yield 7.47 g (55%) of 4- neryloxybenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>ClCCl>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:1]=[C:15]=[S:16])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13])=[O:7]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1ccc(N=C=S)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A solution of the above synthesized methyl 4-amino-2-nitrobenzoate (50 mg, 0.25 mmol) and 1,1′-thiocarbonyldi-2(1H)-pyridone (59 mg, 0.25 mmol) in dichloromethane (4.2 ml) was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated, followed by purification with a silica gel column chromatography to obtain 42 mg of the desired product as a colorless oil (yield 69%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].I[C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[C:19]([N+:32]([O-:34])=[O:33])[CH:18]=1.O>C(O)C.O>[N+:32]([C:19]1[CH:18]=[C:17]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:22]=[CH:21][C:20]=1[S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])([O-:34])=[O:33]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1cc(I)ccc1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(-c2cccnc2)ccc1S(=O)(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Argon was passed through a mixture of 3-pyridineboronic acid (187 mg, 1.53 mmol) and Na2CO3 (408 mg, 3.84 mmol) in water ethanol (water 3.74 ml, ethanol 14.96 ml) at stirring at 90° C. for 30 min and cooled to 80° C. 4-Iodo-2-nitro-1-(phenylsulfonyl)-benzene 4(3) (734 mg, 1.9 mmol) was added to the reaction mixture in argon current, inert gas was passed for another 10 min, then bis-triphenylphosphinepalladium dichloride (34 mg) was added and argon was passed for additional 5 min. The reaction mixture was stirred for 2 h at 85° C. in argon atmosphere, then, cooled, water was added, and precipitated solid was filtered off. The reaction product was extracted from mother liquor with CH2Cl2, organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was suspended in CH2Cl2, filtered off, mother liquor was evaporated, the residue washed with diethyl ether, it gave 460 mg (70.5%) of 3-(3-nitro-4-(phenylsulfonyl)phenyl)pyridine 5(1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](=[O:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>CCCCCC>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([OH:20])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCCc1ccccc1)CCCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OC(CCCc1ccccc1)CCCc1ccccc1
Yield: 30 %

Procedure:
Using the procedure of Example 42 with the resultant compound of Example 52 gave, after silica gel chromatography using 15% ethyl acetate in hexane, the desired compound (Rf 0.23, 30% ethyl acetate in hexane) as an oil. 1H NMR (CDCl3) δ 1.4-1.8 (m, 8H), 2.62 (br t, 4 H), 3.63 (m, 1H), 7.15-7.3 (m, 10H). Mass spectrum (M+NH4)+ =286.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[I-].[Na+].[CH3:32][NH:33][CH3:34].O1CCCC1>CN(C)C=O>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
A solution of 7-(3-chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (54 mg, 0.13 mmol), sodium iodide (5 mg, 0.03 mmol), and 2 N dimethylamine in tetrahydrofuran (3 mL, 6 mmol) in N,N-dimethylformamide (5 mL) is heated at 100° C. for 48 h. The mixture is cooled and concentrated in vacuo. The residue is chromatographed on SiO2 (100% ethyl acetate to 10% methanol in ethyl acetate) to yield the title compound, 41 mg (74%), as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:27][N:26]=2)=[CH:33][CH:32]=1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)nc1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(Cl)cc3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 18 mg (0.44 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 5-Chloromethyl-2-(4-chloro-phenyl)-pyridine (GB 1147068) were added and stirred continued over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 133 mg (73%) of the title compound as light brown powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: O=C(Cl)OCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)OCCCl)C1O
Reaction time: 21 h
Yield: 87.3 %

Procedure:
400 mg (1.70 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole, 260 μl (1.87 mmol) of triethylamine and 40 mg of dichloromethane were stirred at room temperature, and 193 μl (1.87 mmol) of 2-chloroethyl chloroformate were added thereto and stirred for 21 hours. The reaction liquid was washed thrice with water and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from chloroform to obtain 507 mg of the intended compound as pale yellow crystals. (yield: 87%)
Reaction SMILES: [Br:1][C:2]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:5]2[C:6]3[C:7](=[O:21])[NH:8][C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.BrN1C(=O)CCC1=O.N1C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:5]2[C:6]3[C:7](=[O:21])[NH:8][C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])=[N:10][C:11]=3[CH:12]=[CH:13][C:4]=2[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(=O)[nH]1)-c1cc([N+](=O)[O-])c(Br)cc1CC2
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2ccc3cc(Br)c([N+](=O)[O-])cc3c2c(=O)[nH]1

Procedure:
N-(8-Bromo-1,2,5,6-tetrahydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.23 g, 0.5 mmole) was reacted with N-bromosuccinimide (0.12 g, 0.7 mmole) and pyridine (0.06 ml, 0.8 mmole) in dry benzene (150 ml) in the same manner as in example 2. The crude product was purified by trituration with methanol:water (1:9), followed by filtration and washing (water and methanol) to give, after drying, N-(8-bromo-1,2-dihydro-9-nitro-1-oxobenzo[f]quinazolin-3-yl)pivalamide as a pale yellow solid. (0.20 g, 94%) 1H NMR(DMSO-d6, 200 MHz) δ: 1.27(s, 9H, t-butyl); 7.76(d, J=9.0 Hz, 1H, Ar); 8.32(d, J=9.0 Hz, 1H, Ar); 8.65(s, 1H, Ar); 10.21(s, 1H, Ar); 11.40(s, 1H, NH); 12.45(br s, 1H, NH).
Reaction SMILES: CO.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:13]([N+:24]([O-])=O)[CH:12]=1>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:13]1[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])[CH:23]=[CH:22][C:14]=1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1N
Temperature: 25 °C

Procedure:
0.27 g of 10% palladium-carbon was added to a mixed solution of 9.0 mL of methanol and 9.0 mL of ethyl acetate containing 0.90 g of tert-butyl 4-(2,4-difluorophenyl)-2-nitrobenzoate and stirred under hydrogen atmosphere at room temperature for 30 minuses. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure to obtain 0.80 g of tert-butyl 2-amino-4-(2,4-difluorophenyl)benzoate as white solid.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@H:6]1[CH2:11][NH:10][C@H:9]([C:12]([NH2:14])=[O:13])[C:8]([CH3:15])=[CH:7]1)[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.[C:25](=O)(OC(Cl)(Cl)Cl)[O:26]C(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:25](=[O:26])[N:10]2[CH2:11][C@H:6]1[CH:7]=[C:8]([CH3:15])[C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCON[C@@H]1C=C(C)[C@@H](C(N)=O)NC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 204.9 %

Procedure:
A solution of (2S,5R)-5-(allyloxyamino)-3-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 85, 0.758 g, 3.59 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.507 mL, 14.35 mmol) in acetonitrile (350 mL) was cooled to below 0° C. in an ice-salt bath and added a solution of bis(trichloromethyl) carbonate (0.426 g, 1.44 mmol) in ACN (15 mL) at a rate of 0.1 mL/min. The reaction mixture was stirred at rt overnight. The solvents were evaporated at 30° C., and the crude mixture was redissolved in EtOAc. The crude organic solution was washed with sat. NaHCO3, brine, dried over MgSO4, and filtered. The organics were evaporated and the crude product was loaded onto silica gel at 30° C. and Purified via flash chromatography (80 g, 0-100% EtOAc/Hexanes), to obtain the desired product (0.700 g, 82%) as pale yellow oil.
Reaction SMILES: Cl[CH:2]([C:4]1[NH:5][C:6](=[O:14])[C:7]2[CH2:13][O:12][CH2:11][CH2:10][C:8]=2[N:9]=1)[CH3:3].[CH3:15][NH2:16].O>CO>[CH3:15][NH:16][CH:2]([C:4]1[NH:5][C:6](=[O:14])[C:7]2[CH2:13][O:12][CH2:11][CH2:10][C:8]=2[N:9]=1)[CH3:3]
Reactant: CC(Cl)c1nc2c(c(=O)[nH]1)COCC2
Reactant: CN
Solvent: O
Solvent: CO
Product: CNC(C)c1nc2c(c(=O)[nH]1)COCC2
Temperature: 110 °C

Procedure:
To a solution of 2-(1-chloroethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (270 mg, 1.3 mmol) in methanol (1 mL) was added methylamine in water (1.1 mL, 13 mmol, 40%). The mixture was heated via microwave at 110° C. for 10 min., concentrated in vacuo and purified via reverse phase chromatography (Acetonitrile:water) to provide the title compound (260 mg). MS m/z 210.3 (M+1), retention time=0.54 min.
Reaction SMILES: Cl.[NH2:2][OH:3].[NH:4]1[C:8]([CH2:9][C:10]2[S:14][C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[N:7][N:6]=[N:5]1>C(O)C>[NH:4]1[C:8]([CH2:9][C:10]2[S:14][C:13]([C:15](=[N:2][OH:3])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[N:7][N:6]=[N:5]1
Reactant: CCOC(=O)C(=O)c1ccc(Cc2nnn[nH]2)s1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=NO)c1ccc(Cc2nnn[nH]2)s1
Reaction time: 72 h
Yield: 90.3 %

Procedure:
Hydroxylamine hydrochloride (205 mg) was added to a stirred mixture of ethyl 2-[5-(1-tetrazolylmethyl)thien-2-yl]-2-oxoacetate (Description 50) (394 mg) and ethanol (10 ml). The mixture was left at room temperature for 3 days, then the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine and dried over magnesium sulphate. The solution was evaporated to give the product (376 mg) as a mixture of isomers. νmax (nujol) 3131, 1746, 1724 cm-1. δ (CD3COCD3), 1.31-1.39 (3H, m), 4.36 and 4.42 (2H, two q's, J 7.22 Hz), 6.02 and 6.08 (2H, two s's), 7.10 and 7.25 (1H, two d's, J 3.73 Hz), 7.31 and 7.78 (1H, two d's, J 3.98 Hz), 9.26 and 9.30 (1H, two s's), 11.14 and 12.25 (1H, two broad s's). m/z 280 (M-H)-. [Found: m/z 281.0584. Calc. for C10H11N5O3S; 281.0583].
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]([CH2:11]Br)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[OH:1][N:2]=[C:3]([C:9]1[N:13]=[C:14]([NH2:16])[S:15][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)C(=NO)c1csc(N)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (2.4 g) and thiourea (0.76 g) in ethanol (15 ml) was stirred for 1 hour at 60° C. Ethanol was distilled off under reduced pressure and water was added to the residue. The resultant mixture was adjusted to pH 1.0 and washed with ethyl acetate. The aqueous layer was adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and benzene (1:3) as developing solvent. The eluates containing syn isomer were collected and concentrated to give ethyl 2-hydroxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (0.3 g).
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[C:10]([CH3:26])=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:12](N)=[N:13][CH:14]=1.[ClH:27]>CC#N.[Cu](Cl)Cl>[Br:8][C:9]1[C:10]([CH3:26])=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:12]([Cl:27])=[N:13][CH:14]=1
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1c(Br)cnc(Cl)c1-c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
To a suspension of copper (II) chloride (421 mg, 3.92 mmol) and t-butyl nitrite (466 μL, 3.92 mmol) in dry MeCN (12 mL) at 70° C. was added 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 864 mg, 2.61 mmol) dropwise as a solution in MeCN (3 mL) over 5 mins. The reaction mixture was stirred at 70° C. for 3.5 hrs then poured onto 5 N aqueous HCl (20 mL). The reaction mixture was extracted with EtOAc (4×20 mL) then the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound as an orange solid (184 mg).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][C:13](=O)[C:10]3([CH2:12][CH2:11]3)[C:9]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[CH3:23][O:24][NH2:25]>CO.C(Cl)Cl>[CH3:23][O:24]/[N:25]=[C:13]1\[CH2:14][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9](=[O:16])[C:10]2\1[CH2:12][CH2:11]2
Reactant: CON
Reactant: O=C1CN(Cc2ccccc2)C(=O)C12CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CO/N=C1\CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
5-(Phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione (Example 128) (2.8619 g, 13.29 mmol), sodium acetate (2.23 g, 26.59 mmol), and O-methylhydroxylamine hydrochloride (2.22 g, 26.59) was dissolved in 65 mL of MeOH. The mixture was stirred at room temperature overnight and then diluted with 300 mL of DCM. The mixture was washed with sat. aq. NaHCO3 (200 mL), and the organics were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide (7Z)-5-(phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione 7-(O-methyloxime) (3.0864 g, 95%). LCMS: (M+H)+: 245.1.