Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Si:7]([O:14][C:15]1[CH:20]=[C:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=1C1CCC(=O)CC1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].O1C[CH2:39][CH2:38][CH2:37]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([Si:7]([O:14][C:15]1[CH:20]=[C:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=1[CH:38]1[CH2:39][CH2:3][C:2](=[CH2:5])[CH2:1][CH2:37]1)([CH3:8])[CH3:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: C=C1CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a round bottomed flask was added methyltriphenylphosphonium bromide (0.99 g) and tetrahydrofuran (30 ml). The resulting suspension was cooled to 0° C. and potassium tert-butoxide (0.31 g) was added in one portion. The resulting solution was stirred at 0° C. for 0.5 hr, then 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (0.60 g) added as a solution in tetrahydrofuran (10 ml). The solution was stirred for 1 hr at 0° C., then allowed to warm to room temperature and stirred for 15 hr. The reaction mixture was partitioned between ethyl acetate (20 ml) and saturated ammonium chloride solution (20 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (2×20ml). The combined organic phases were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, 1:9 v/v) furnished the title compound (0.56 g, 93%) as a colourless oil. δH (CDCl3): 0.17 (6H, s), 0.24 (6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.34-1.47 (2H, m), 1.86-1.94 (2H, m), 2.10-2.20 (2H, m), 2.35-2.43 (2H, m), 3.00 (1H, tt), 4.64 (2H, m), 6.29 (1H, d), 6.39 (1H, dd), 6.94 (1H, d).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[CH:27]=[CH:26][C:13]([CH2:14][NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=3[CH3:25])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:4][C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=3[CH3:25])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Reactant: BrCc1ccccc1
Product: C=CCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 60C and benzyl bromide was processed as described in Example 6B to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[I:21]N1C(=O)CCC1=O>ClCCl.C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:6][C:7]=1[I:21]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cccc(-c2ccc(O)cc2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc(O)c(I)c2)c1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
4′-Hydroxybiphenyl-3-carbonitrile (Preparation 121, 570 mg, 2.92 mmol) was dissolved in dichloromethane (10 mL) and acetic acid (10 mL). Then concentrated sulfuric acid (0.30 mL) and N-iodosuccinimide (657 mg, 2.92 mmol) were added at 0° C. (ice-bath cooling) and the reaction was allowed to warm to room temperature over 2 hours. The mixture was partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and dried over anhydrous MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in heptane to give the title compound (720 mg, 77%).
Reaction SMILES: C(OC(NCCCCCC(O)=O)=O)(C)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][N:47]=[C:48]=[O:49])=[O:40])([CH3:37])([CH3:36])[CH3:35].[F:50][C:51]1[C:52](=[O:58])[NH:53][C:54](=[O:57])[NH:55][CH:56]=1>C1C=CC=CC=1.C(N(CC)CC)C>[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([N:55]1[CH:56]=[C:51]([F:50])[C:52](=[O:58])[NH:53][C:54]1=[O:57])=[O:49])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCCCCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCNC(=O)n1cc(F)c(=O)[nH]c1=O

Procedure:
The reaction of 6-t-butoxycarbonylaminohexanoic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 5-t-butoxycarbonylaminopentyl isocyanate, which was reacted with 5-fluorouracil to provide 1-[N-(5-t-butoxycarbonylaminopentyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 20.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[C:7](=[O:13])[CH:8]=1
Reactant: NN
Reactant: CCOC(=O)Cn1ccc(C)cc1=O
Solvent: CCO
Solvent: O
Product: Cc1ccn(CC(=O)NN)c(=O)c1
Yield: 94 %

Procedure:
As described for example 112a, (4-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 94%). MS: m/e=204.3 [M+Na]+.
Reaction SMILES: [CH:1]([N:14]1[C:18]2[CH:19]=[C:20]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[O:30]CC3C=CC=CC=3)[CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:38])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C.CO>[CH:1]([N:14]1[C:18]2[CH:19]=[C:20]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[OH:30])[CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:38])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c(-c2ccc3oc(=O)n(C(c4ccccc4)c4ccccc4)c3c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c(-c2ccc3oc(=O)n(C(c4ccccc4)c4ccccc4)c3c2)c1
Reaction time: 16 h
Yield: 98 %

Procedure:
A mixture of 3-benzhydryl-5-(2-(benzyloxy)-5-methylphenyl)benzo[d]oxazol-2(3H)-one (1.0 g, 2.0 mmol) and palladium on activated charcoal (10% w/w, 0.20 g) in ethyl acetate/methanol (1:1 v/v, 20 mL) was stirred under an atmosphere of hydrogen (1 atm) for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate/methanol (1:1 v/v, 20 mL). The filtrate and washes were combined and concentrated in vacuo. The residue was purified by column chromatography eluting with a 20-65% gradient of ethyl acetate in hexanes to afford 3-benzhydryl-5-(2-hydroxy-5-methylphenyl)benzo[d]oxazol-2(3H)-one as a colorless solid in 98% yield (0.80 g): 1H NMR (300 MHz, CDCl3) δ 7.38-7.32 (m, 6H), 7.30-7.24 (m, 5H), 7.17-7.12 (m, 1H), 6.99 (dd, J=8.2, 1.6 Hz, 1H), 6.84 (s, 1H), 6.79-6.73 (m, 2H), 6.51 (s, 1H), 4.68 (s, 1H), 2.24 (s, 3H); MS (ES+) m/z 407.8 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)=[CH:11][N:10]=[C:9]1SC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)=[CH:11][N:10]=[C:9]1[NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(SC)n(Cc3ccccc3)c2=O)cc1F
Reactant: Nc1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc(Nc3ccc(F)cc3)n(Cc3ccccc3)c2=O)cc1F
Temperature: 25 °C
Yield: 71 %

Procedure:
3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(methylthio)pyrimidin-4(3H)-one (697.4 mg, 1.957 mmol) was dissolved in 1,4-dioxane (10 ml) and 4-fluoroaniline (1.50 ml, 15.6 mmol) and concentrated hydrochloric acid (0.040 ml, 1.1 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (125 C) and stirred under nitrogen. After stirring for 70 hours, the reaction was cooled to room temperature and concentrated. It was then treated with Et2O, and filtered, and the solid was washed with Et2O and dried in vacuo to afford the desired 3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one (582.7 mg, 1.39 mmol, 96% purity, 67% yield over two steps). MS (ESI pos. ion) m/z: 420 (MH+). Calc'd exact mass for C24H19F2N3O2: 419. 1HNMR (400 MHz, CDCl3): 7.89 (br s, 1H), 7.53-7.37 (m, 8H), 7.13 dd, J=9.2 Hz, 4.0 Hz, 2H), 7.01 (t, J=8.0 Hz, 3H), 5.47 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:14][CH2:13]1)[CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH:12]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:11][CH:10]=3)[C:5]([CH3:16])([CH3:15])[CH2:6][CH2:7]2)[CH2:14][CH2:13]1
Reactant: CC1(C)CCN(C2CC2)c2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C)CCN(C2CC2)c2ccc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and using 6-bromo-1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro quinoline (Intermediate 51, 0.8 g, 2.86 mmol), (trimethylsilyl)acetylene (5 mL, 35 mmol), triethyl amine (10 mL), anhydrous tetrahydrofuiran, copper(I)iodide (0.080 g, 0.42 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.240 g, 0.34 mmol), the title compound was obtained as an oil (0.67 g, 79%).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:24]1([C:22]([NH:21][NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: [H][H]
Reactant: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C1CCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)C1CCCC1
Yield: 94.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N′-(cyclopentylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 191 (0.33 g, 0.84 ml) in methanol (20 mL) was added 10% Pd/C (0.30 g). The mixture was hydrogenated under 15 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered through Celite, and the filtrate was evaporated to give (2S,5R)—N′-(cyclopentylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 192 (0.24 g, 98%) as a colorless foam.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:23])[CH2:7][O:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10])=[CH:4][CH:3]2[S:24][CH:25]=[CH:26][CH:2]12.[Br:27]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[C:19]([O:18][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[C:9]([O:8][CH2:7][C:6]([C:5]1[S:1][CH:2]2[CH:26]=[C:25]([Br:27])[S:24][CH:3]2[CH:4]=1)=[O:23])=[O:10])=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)C1=CC2SC=CC2S1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)C1=CC2SC(Br)=CC2S1
Yield: 65.6 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-[2-(3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-2-oxo-ethyl]ester (595 mg, 1.5 mmol) was dissolved in DMF (7.5 mL) and treated with N-bromosuccinimide (295 mg, 1.65 mmol). The reaction mixture was stirred for 4d at RT then diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/Hex) to afford the title compound (469 mg, 66%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[C:27]#[C:28][C:29]2([OH:39])[CH2:38][CH2:37][C:32]3([O:36][CH2:35][CH2:34][O:33]3)[CH2:31][CH2:30]2)=[CH:22][CH:21]=1>C(O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:28]([C:29]3([OH:39])[CH2:30][CH2:31][C:32]4([O:33][CH2:34][CH2:35][O:36]4)[CH2:37][CH2:38]3)[CH:27]=2)=[CH:22][CH:21]=1
Reactant: O=C(C#CC1(O)CCC2(CC1)OCCO2)c1ccc(Cl)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (457 mg, 2.62 mmol) in ethanol (4.4 mL), triethylamine (0.730 mL, 5.24 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 1-(4-chlorophenyl)-3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-2-propyn-1-one (Reference Example 18) (700 mg, 2.18 mmol) in ethanol (4.4 mL) was added dropwise, and the obtained solution was stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (756 mg, 1.71 mmol, 79%) as an amorphous product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Br-:32].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[C:11]([Br:32])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)ccn2CCN1Cc1ccc(Cl)c(Cl)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 62.3 %

Procedure:
To a solution of 9-benzyloxy-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (3.8 g) obtained in Example 1, Step 3 in chloroform (90 ml)-methanol (60 ml) was added phenyltrimethylammonium tribromide (5.0 g) and the mixture was stirred at room temperature for 13 hr. An aqueous sodium sulfite solution was added to the reaction mixture and the mixture was extracted twice with chloroform. The combined extract was washed with brine and purified as it was by silica gel column chromatography (chloroform-methanol=19:1–10:1) to give 9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (2.44 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][N:9]=[C:4]2[C:3]=1[CH3:12].[BH4-].[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[N:10][C:5]2[NH:6][CH2:7][CH2:8][NH:9][C:4]=2[C:3]=1[CH3:12]
Reactant: Cc1c(Br)cnc2nccnc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c(Br)cnc2c1NCCN2
Reaction time: 0.75 h
Yield: 56.1 %

Procedure:
7-bromo-8-methylpyrido[2,3-b]pyrazine (0.21 g) and NaBH4 (0.21 g) in THF (1.4 ml) was treated with trifluoroacetic acid (1.4 ml) at room temperature over a period of 15 min. Stirring continued for additional 45 min then water was added followed by 50% sodium hydroxide. The residue was extracted into CH2Cl2, filtered, dried, and concentrated to furnish the desired product (0.12 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH:17]1([C:20]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:16])[C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH2:5][CH2:6]2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)C2CC2)CC1)c1ccc(F)cc1
Reaction time: 21 h

Procedure:
To a suspension of N-(piperidin-4-yl)-4-fluorobenzamide (556 mg) in dichloromethane (6 ml) were added cyclopropanecarboxylic acid (0.20 ml), 1-hydroxybenzotriazole (338 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (480 mg) at ambient temperature. After stirring for 21 hours, the mixture was diluted with dichloromethane, and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. After crystallization from diisopropyl ether, N-(1-cyclopropylcarbonylpiperidin-4-yl)-4-fluorobenzamide (627 mg) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:2][O:3][N:4]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Br:5])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(=O)c1ccccc1Br
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccccc1Br

Procedure:
5.2 g (62 mmol) of O-methylhydroxylamine hydrochloride is added to a solution of 10 g (41 mmol) of methyl 2-bromophenylglyoxylate in 30 ml of methanol, and the mixture is refluxed for 2 hours. The mixture is evaporated down, and the residue is taken up in ethyl acetate and washed with water. After drying and evaporating down, there remains 6.9 g (62%) of compound E.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].[OH:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-:46].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][C:8](=[O:46])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:30][C:31]2[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[CH2:42][CH2:43][CH3:44])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCCc1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)CCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 1.69 g (3.58 mmol) of 4-(5-bromopentyloxy)-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester from the preceding example, 0.738 g (3.58 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 2.07 g (14.98 mmol) of anhydrous potassium carbonate, and 37.5 mL of 2-butanone was stirred and refluxed for 18.5 hr. After being cooled to room temperature, the mixture was filtered through anhydrous magnesium sulfate and the solids were washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the crude product was purified by flash chromatography on 250 g of silica gel, eluting with hexane-ethyl acetate (4:1). There was obtained 1.93 g (90.1%) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.BrCC1C=CC=C(F)C=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Fc1cccc(CBr)c1
Product: Nc1cccc(OCc2ccc(F)cc2)c1

Procedure:
3-Nitro-phenol was reacted with 1-bromomethyl-4-fluoro-benzene according to the procedure from Example 199A substituting 1-bromomethyl-4-fluoro-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([C:15]([O:17]CC)=O)[C:11]([CH3:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]([C:15](=[O:17])[NH:25][C:24]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=3)[C:11]([CH3:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C1C(=O)N(c2ccc(Cl)c(Cl)c2)N=C1C
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1C
Product: CC1=NN(c2ccc(Cl)c(Cl)c2)C(=O)C1C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
The mixture of 0.6 g of 1-(3,4-dichlorophenyl)-3-methyl-4-carbethoxy-2-pyrazolin-5-one, 0.31 g of 3,4-dichloroaniline and 40 ml of xylene is distilled for a few minutes, refluxed 20 minutes and distilled again a few minutes. The cooled solution deposits crystals, which are collected, washed with benzene and recrystallized from ethyl acetate to yield the 1-(3,4-dichlorophenyl)-3-methyl-4-(3,4-dichlorophenylcarbamoyl)-2-pyrazolin-5-one, melting at 255°-257° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Cl:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH:31][C:13](=[O:15])/[C:12](/[C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=3)=[N:16]/[O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[S:30][C:26]=2[CH:25]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2nc3ccc(Cl)cc3s2)cc1Cl
Reaction time: 2 h
Yield: 53.7 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 84 mg, 0.24 mmol), 6-chloro-2-aminobenzothiazole (45 mg, 0.24 mmol) and N,N-diisopropylethylamine (127 μL, 0.73 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% ethyl acetate/hexanes) to afford (E)-N-(6-chloro-benzothiazol-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetamide (66 mg, 53%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C21H19Cl2N3O4S2 [M+] 511.02, found 512 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.68 (m, 4 H, 2×CH2), 1.91 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 4.97 (m, 1 H, OCH), 7.43 (dd, Jo=8.6, Jm=2.1 Hz, 1 H, Ar), 7.60 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.71 (m, 2 H, Ar), 7.81 (m, 1 H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.18 (s, 1 H, NH).