Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([C:15]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)=[O:16])[CH2:12]1)=O)C1C=CC=CC=1.N#N>CCO.[Pd]>[NH:11]1[CH2:14][CH:13]([C:15]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)=[O:16])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CNC2)CC1
Reaction time: 24 h
Yield: 97.5 %

Procedure:
A stirred solution of tert-butyl 4-({1-[(benzyloxy)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane-1-carboxylate (1.54 g, 3.69 mmol) in EtOH (10 mL) was purged with N2 and charged with 10% Pd/C (154 mg, 10% wt/wt). The flask was purged with N2 (N2/vacuum cycle×3) and then H2 (H2/vacuum cycle×3). After 24 hours the reaction was incomplete by NMR analysis. The mixture was filtered through Celite®, fresh catalyst charged (154 mg, 10% wt/wt) and the hydrogenation resumed and after a further 24 and 48 hours this process was repeated. NMR analysis confirmed consumption of starting material and the reaction was filtered through Celite® and concentrated at reduced pressure to give the title compound (1.02 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:28].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:28])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CCO)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(CCO)cc3)cc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 22.2 %

Procedure:
To a mixture of 6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carbaldehyde (150 mg, 0.50 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) was added 2-methyl-2-butene (5 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (900 mg, 10.0 mmol) and sodium phosphate monobasic hydrate (1.4 g, 10 mmol) in water (5 mL) dropwise via additional funnel. Then ice bath was removed, and the reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo to give a residue, which was purified by pre-HPLC (Kromasil Eternity-5-C18 150×30 mm×5 μm Mobile phase: from 26% MeCN in water (0.1% TFA) to 41% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carboxylic acid (35 mg, 25% yield) as a white solid. MS (ES+) 337.9 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.01-7.99 (m, 2 H), 7.57 (s, 1 H), 7.37 (d, 2 H), 7.30 (d, 2 H), 3.80 (t, 2 H), 2.91 (t, 2 H).
Reaction SMILES: O1CCCC1.[Si]([O:13][CH2:14][C:15]1[CH:20]=[C:19]([CH:21]([S:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:18]([CH3:38])=[CH:17][N:16]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>CCCCCC>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:30][CH:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:19]2[C:18]([CH3:38])=[CH:17][N:16]=[C:15]([CH2:14][OH:13])[CH:20]=2)=[CH:32][CH:33]=1
Reactant: Cc1cnc(CO[Si](C)(C)C(C)(C)C)cc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1cnc(CO)cc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a tetrahydrofuran solution (3 ml) of 2-[(t-butyldimethylsilyloxy)methyl]-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-5-methylpyridine (200 mg, 0.395 mmol) was added tetrabutylammonium fluoride (a 1.0M tetrahydrofuran solution, 593 μl, 0.593 mmol). The resulting mixture was stirred for 20 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (150 mg, 0.384 mmol, 97%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH:16]1([NH:24][C:25](=[O:28])[CH2:26]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:26][C:25]([NH:24][CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:28])=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CBr)NC1CCCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC(=O)NC2CCCCCCC2)cc1
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
Bromoacetyl chloride (0.25 mL) was added slowly to a chilled (ice-water-bath) solution of cyclooctylamine (0.763g) in dichloromethane (15 mL) and the mixture was stirred with cooling for 45 minutes, then at room temperature overnight. After water (20 mL) was added, the layers were separated and the dried organic layer (MgSO4) was evaporated to provide 0.7 g of N-cycloocyl-bromoacetamide. A solution of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.605 g) in dimethylformamide (8 mL) under argon was treated with 55% sodium hydride (0.147 g), stirred for 30 minutes and then N-cyclooctyl-bromoacetamide (0.7 g) in dimethylformamide (5 mL) was added. The solution was stirred at room temperature for 18 hours and worked up as in Example 20. The crude material was purified by flash chromatography (ethyl acetate-hexane; 3:7) to yield 0.4 g of 4-[2-(cyclooctylamino)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[CH3:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:27][C:28](OCC)=[O:29])=O)=[CH:21][N:20]=2)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1>>[CH3:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:27][C:28](=[O:29])[NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=3)=[CH:21][N:20]=2)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1
Reactant: CCOC(=O)CC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1
Reactant: Nc1ccccc1N
Product: Cc1nc2cnccc2n1-c1ccc(C2=Nc3ccccc3NC(=O)C2)cn1
Yield: 14.3 %

Procedure:
The procedure of Example 1 was followed using 1,2-diaminobenzene (86 mg, 0.76 mmol) and ethyl 2-(2-methylimidazo[4,5-c]pyrid-1-yl)pyrid-5-oylacetate (260 mg, 0.80 mmol). The crude product was purified by flash chromatography (eluting with ethyl acetate/methanol =6:1), followed by recrystallisation from acetone to give the title compound (40 mg, 14%) as a buff solid, m.p. 208°-210° C..
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]([F:18])([F:17])[C:7]1[N:11]2[N:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1>N1C=CC=CC=1.C1COCC1>[N:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:7]([C:6]([F:18])([F:17])[F:5])=[N:8][N:9]=2)[N:12]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2nnc(C(F)(F)F)n2n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: FC(F)(F)c1nnc2ccc(N=C=S)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
Thiophosgene (1 mL, 12.7 mmol) was added to a solution of 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (860 mg, 4.23 mmol) in pyridine (10 mL) and THF (15 mL) and the resulting dark mixture was stirred at room temperature for 2 h. The dark mixture was partitioned between EtOAc and 1M HCl. The organic layer was washed with 1M HCl (2×), dried over sodium sulfate, and evaporated to dryness to afford 545 mg (60% pure) of 6-isothiocyanato-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine as a dark purple solid. LCMS [M+1]+ 278.5 (OMe adduct).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH2:11]([O:13][C:14](=[O:58])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([C:40]3[CH:44]=[C:43]([C:45]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[NH:46])[S:42][C:41]=3[S:55][CH3:56])(=[O:39])=[O:38])[CH:32]=2)=[C:26]([NH2:57])[CH:25]=1)=[O:22])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH2:11]([O:13][C:14](=[O:58])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([C:40]3[CH:44]=[C:43]([C:45]([NH:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[NH:46])[S:42][C:41]=3[S:55][CH3:56])(=[O:39])=[O:38])[CH:32]=2)=[C:26]([NH:57][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:10])[CH:25]=1)=[O:22])[CH3:12]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(N)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(NC(=O)CCCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
4-Chlorocarbonyl-butyric acid methyl ester (20.4 μL, 0.148 mmol) was added to a solution of 6-(3-{2-amino-3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-4-yl}-ureido)-hexanoic acid ethyl ester (70.8 mg, 96.4 μmol, Example 278: step c) and triethylamine (41.2 μL, 0.296 mmol) in CH2Cl2 (5 mL, anhydrous) at rt. The reaction mixture was stirred overnight at rt, then diluted in EtOAc, washed with water and brine, and dried over magnesium sulfate. Removal of solvents in vacuo followed by flash chromatography (75–100% EtOAc/hexanes) yielded the title compound as a brown oil (45.5 mg, 54.5%). ESI-MS (m/z): Calcd. for C39H51N5O10S3: 846.3 (M+1); found: 845.9.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:17]#[N:18])#[N:2].[ClH:19]>C(O)(=O)C>[ClH:19].[ClH:19].[ClH:19].[ClH:19].[NH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: N#CCCNCCCCCCCCNCCC#N
Agent: Cl
Solvent: CC(=O)O
Product: NCCCNCCCCCCCCNCCCN

Procedure:
Combine 14.4 g (0.057 mol) of the product of Step A, 200 ml of acetic acid, 30 ml of conc. HCl, and 1.2 g PtO 2 and treat the mixture with H2 at 45 lbs/in2 in a shaker flask until H2 is no longer being reacted. Filter the mixture and remove the solvent at reduced pressure. 22.5 g of the title compound is obtained after purification. (Rf is 0.17 for TLC on silica gel developed with 40% conc. ammonia/methanol).
Reaction SMILES: [BrH:1].P(Br)(Br)Br.[O:6]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:23])[CH2:21]O)[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[O:6]([C:13]1[CH:14]=[C:15]([CH2:19][C:20]([CH3:23])=[CH:21][Br:1])[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=Cc1cccc(Oc2ccccc2)c1)CO
Reactant: Br
Agent: BrP(Br)Br
Solvent: CCO
Product: CC(=CBr)Cc1cccc(Oc2ccccc2)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 53.4 %

Procedure:
A mixture of 47% hydrobromic acid (3.0 g) and phosphorus tribromide (15.7 ml) was stirred at 40° C. for 3 hours, and a solution of 3-(m-phenoxyphenyl)-2-methyl-2-propenyl alcohol (9.5 g) in ethanol (20 ml) was dropwise added thereto at 10° C. The resultant mixture was aged at the same temperature for 5 hours, poured into ice-water (200 ml) and extracted with diethyl ether (100 ml×2). The ethereal layer was combined, washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 3-(m-phenoxyphenyl)-2-methyl-propenylbromide (6 g).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1.C1C=CC=CC=1>O>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[CH2:11]([O:9][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])[NH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: NCCCC[C@H](N)C(=O)OCc1ccccc1
Yield: 84 %

Procedure:
30 g of L-lysine (20.5·10-2 mole) and 70 ml of distilled benzyl alcohol (67.6·10-2 mole) are introduced into an extractor of the Dean-Stark type; 88.5 g of paratoluene sulfonic acid monohydrate (46.5·10-2 mole) and 300 ml of benzene are added. The mixture is heated at reflux until all of the water formed in the reaction has been removed. The solution is transferred to a beaker to which 100 ml of methanol are added. The salt is precipitated by the addition of 500 ml of ethyl ether at room temperature. The precipitate is taken up by warming in 300 ml of methanol and reprecipitated by ethyl ether. 100 g of the N,N'-ditosylate of L-lysine benzyl ester are recovered; yield=84%, M.P.=163° C.
Reaction SMILES: IP(I)I.[Br:5][C:6]1[CH:7]=[C:8]2[C:18](=[CH:19][CH:20]=1)[O:17][C:11]1[CH:12]=[N:13][C:14]([Cl:16])=[CH:15][C:10]=1[C:9]2([CH2:22][O:23][CH:24]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:25][N+:26]([O-])=O)[NH2:21]>C(Cl)Cl>[NH2:21][C:9]1([CH2:22][O:23][CH:24]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:25]#[N:26])[C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[CH:12][C:11]=2[O:17][C:18]2[C:8]1=[CH:7][C:6]([Br:5])=[CH:20][CH:19]=2
Reactant: NC1(COC(C[N+](=O)[O-])C2CCCCC2)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: IP(I)I
Solvent: ClCCl
Product: N#CC(OCC1(N)c2cc(Br)ccc2Oc2cnc(Cl)cc21)C1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
TEA (1.263 ml, 9.06 mmol) and triiodophosphine (1.243 g, 3.02 mmol) were added to 7-bromo-3-chloro-5-((1-cyclohexyl-2-nitroethoxy)methyl)-5H-chromeno[2,3-c]pyridin-5-amine (1.5 g, 3.02 mmol) in DCM (30.2 ml) at 0° C. The reaction was stirred 10 minutes before the ice water bath was removed and the reaction was allowed to come to RT. After 1.5 hours, the solution is cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate, diluted with water, and extracted with DCM. The combined organic extracts were washed with 1N NaOH, water, saturated aqueous NaCl, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:4 EtOAc in hexane, to provide 2-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)-2-cyclohexylacetonitrile, [M+H]=462.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([OH:19])=[C:6]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C.O>[CH2:27]([O:19][C:5]1[CH:4]=[C:3]([O:20][CH2:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC(=O)c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
1-(5-Chloro-2,4-dihydroxy-phenyl)-2-(4-methoxy-phenyl)-ethanone (1 eq) was dissolved in acetonitrile and potassium carbonate (4 eq) was added portion wise. The suspension was stirred for five minutes, before the addition of benzyl bromide (2.4 eq), and after which, the reaction mixture was stirred under nitrogen at reflux for 3 hours. The reaction was allowed to cool to room temperature and diluted with water. This was extracted into ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a syrup. This was triturated with 1:1 diethyl ether:hexane to give 1-(2,4-bis-benzyloxy-5-chloro-phenyl)-2-(4-methoxy-phenyl)-ethanone as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16]C3C=CC=C4C(NC(=O)C=34)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:29]N>C(O)C>[NH2:29][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: O=C1NC(=O)c2c(CCCCN3CCC(c4ccccc4)CC3)cccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: NCCCCN1CCC(c2ccccc2)CC1

Procedure:
To a solution of 10.38 g (28.64 mM) of 4-(4-phenylpiperidin-1-yl)butan-1-ylphthalimide in ethanol (160 ml) was added 4.2 ml (86.58 mM) of hydrazine monohydrate at room temperature and the mixture was refluxed for 1.5 hours. The white solid that formed was filtered off and the solvent was distilled off under reduced pressure. The residue was diluted with aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[C:10]([Cl:15])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([O-])=O.O.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[C:10]([Cl:15])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1C(=O)Nc1cccnc1Cl

Procedure:
Stannous chloride (60.0 g, 320 mmol) was added in the solution of 2-nitro-N-(2-chloro-pyridin-3-yl)-benzamide (14.0 g) in absolute ethanol (200 mL). After being refluxed for 4 hours the solution was diluted with 160 ml conc. HCI and left in the refrigerator to crystallize. Obtained product was isolated by filtration. Isolated substance was dissolved in 100 ml boiling water and made alkaline with 30% NaOH (pH 8.5). Obtained precipitate was isolated by filtration and dried. Yield 7.0 g, mp 172-175° C.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1([F:34])[O:8][C:7]2[CH:9]=[C:10]([N+:31]([O-])=O)[CH:11]=[C:12]([C@@:13]34[N:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[S:20][CH2:19][C@@H:18]3[CH2:17][CH2:16][O:15][CH2:14]4)[C:6]=2[O:5]1>C(O)C.[Fe]>[NH2:31][C:10]1[CH:11]=[C:12]([C@@:13]23[N:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[S:20][CH2:19][C@@H:18]2[CH2:17][CH2:16][O:15][CH2:14]3)[C:6]2[O:5][C:4]([F:3])([F:34])[O:8][C:7]=2[CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])cc4c3OC(F)(F)O4)COCC[C@H]2CS1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc4c3OC(F)(F)O4)COCC[C@H]2CS1
Yield: 89 %

Procedure:
Iron powder (7.09 mg) and a saturated ammonium chloride solution (1.0 ml) were added to a solution of tert-butyl (±)-[(4aR*,8aS*)-8a-(2,2-difluoro-6-nitrobenzo[1,3]dioxol-4-yl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]carbamate (60.0 mg) in ethanol (20 ml), and the mixture was heated under reflux for 30 minutes. The reaction solution was returned to room temperature and the insoluble matter was removed by filtration through celite. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (50.0 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH2:1][Br:17])=[CH:7][CH:6]=1)([O-:16])=[O:15]
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
4-Methyl-2'-nitrobiphenyl (from Step A) (2.173 g, 10.2 mmol) was dissolved in CCl4 (100 mL) and heated to reflux with stirring. To this was added a bromine solution [prepared by diluting 11.2 ml (11.2 mmole) of commercial 1.0M solution in CCl14 to a final volume of 40 mL with CCl4 ] dropwise while a 100 W lamp was used to irradiate the refluxing reaction mixture. After completion of addition, the solution was cooled to room temperature, volatiles were removed, and the residue was flash chromatographed over 700 mL SiO2, eluting with 1.5-4.0-10.0% EtOAc/hexane, to afford 2.68 g (90%) of the title compound, 85% pure as indicated by NMR (the remainder being the dibrominated material), but homogeneous on TLC (4/1 hex-EtOAc).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1>>[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:32]=[CH:33][C:34]([NH:37][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:13][C:12]=2[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:35][CH:36]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCCc1nc(-c2ccccc2Br)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2Br)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H25BrN4O3 (m/e) 473, obsd 474 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([Cl:28])[C:18]=1[NH2:19].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:16][C:17]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[C:20]([Cl:28])[C:18]=1[NH:19][C:2]1[C:3]([C:8]2[CH:13]=[C:12]([S:14][CH3:15])[N:11]=[CH:10][N:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Reactant: CSc1cc(-c2nccnc2Cl)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(Nc2nccnc2-c2cc(SC)ncn2)c1Cl

Procedure:
A suspension of 4-(3-chloro-pyrazin-2-yl)-6-methylsulfanyl-pyrimidine (37) (200 mg, 0.838 mmol), 2,6-dichloro-3,5-dimethoxyaniline (280 mg, 1.26 mmol), DPEphos (90 mg, 0.167 mmol), palladium (II) acetate (19 mg, 0.085 mmol) and cesium carbonate (546 mg, 1.68 mmol) in dioxane (8 mL) is degassed. After purging with Ar, the vial is sealed by the cap and irradiated at 150° C. for 30 minutes in Smith Synthesizer. The reaction mixture is evaporated and purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 30% to afford the desired product (2,6-dichloro-3,5-dimethoxy-phenyl)-[3-(6-methylsulfanyl-pyrimidin-4-yl)-pyrazin-2-yl]-amine (38).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH3:32])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][CH3:32])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3CCCCO3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3CCCCO3)CS[C@H]12)c1csc(N)n1
Yield: 53.1 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydropyran-2-yl)methylthio-3-cephem-4-carboxylate (80 mg) was reacted with iodomethyl pivalate (72 mg), followed by purifying the reaction product in accordance with the procedure of Example 2, giving the titled compound (50 mg; 53%)