Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N+]([O-:5])(C)C.Br[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[CH:18]=1>CS(C)=O.O.[Cl-].[Na+].O>[CH:7]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[CH:18]=1)=[O:5]
Reactant: N#Cc1cc2cc(CBr)ccc2o1
Reactant: C[N+](C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc2cc(C=O)ccc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
Trimethlamine-N-oxide (6.75 g, 90 mmol) was added to a solution of 5-(bromomethyl)benzofuran-2-carbonitrile (4.46 g, 18.89 mmol) in 57 mL of DMSO and 6 mL of H2O. The mixture was stirred at 70° C. for 3 hr. After the reaction was cooled to room temperature, the mixture was diluted with 72 mL of brine, and extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (2×20 mL), brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography, 100% Heptane-30% Ethyl Acetate/70% Heptane, to give 5-formylbenzofuran-2-carbonitrile (1.5 g). 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=8.7 Hz, 1H), 8.12 (dd, J=8.7, 1.7 Hz, 1H), 8.30 (d, J=0.9 Hz, 1H), 8.46 (dd, J=1.6, 0.6 Hz, 1H), 10.11 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([N:9]=[C:10]=[O:11])=[C:6]([F:8])[CH:7]=1.[CH:13]1([C:16]([N:18]2[CH2:22][CH2:21][C@@H:20]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[CH2:19]2)=[O:17])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([NH:9][C:10]([NH:27][NH:26][C:24](=[O:25])[CH2:23][C@@H:20]2[CH2:21][CH2:22][N:18]([C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[CH2:19]2)=[O:11])=[C:6]([F:8])[CH:7]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C=Nc1c(F)cc(Br)cc1F
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1c(F)cc(Br)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a round-bottom flask, 5-bromo-1,3-difluoro-2-isocyanatobenzene (1550 mg, 6.62 mmol) was dissolved in dichloromethane (10 mL) under nitrogen and cooled to −78° C. In a separate vial, 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (1357 mg, 6.42 mmol) was dissolved in 10 mL of dichloromethane and then added to the cooled solution. The resultant reaction mixture was allowed to warm to room temperature and stirred for 1 h. A precipitate began to form and analysis by LCMS indicated formation of the desired product. The precipitated product was collected under vacuum filtration and washed with dichloromethane to afford the title product as a white solid (2850 mg, 99%). MS(ES)+ m/e 445.2, 447.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O.O(CCCC)CCCC>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CCCCOCCCC
Solvent: CC(=O)O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCc1ccccc1
Yield: 61.1 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8-nitro-5-(8-phenyloctoxy) quinoline (2.1 g, 0.005 mol), degreased 40 mesh Fe filings (5 g), H2O (20 ml), HOAc (4 ml) and n-Bu2O (4 ml) was heated at 80° C. to 1.5 h, cooled and filtered. The solid was thoroughly extracted with Et2O and the filtered extract was dried (Na2SO4), treated with carbon and concentrated to an oil. Trituration with pet ether gave 1.2 g (61%) of 8-amino-6-methoxy-4-methyl-5-(8-phenyloctoxy) quinoline as yellow-green solid, mp 33°-34° C. Crystallization from pet ether (Darco) gave the analytical sample as yellow green crystals, mp 39°-40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To an ice-cold solution of 2.0 g (5.12 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclopentyl-acetic acid in 55 ml tetrahydrofuran were added in portions 0.29 g (7.64 mmol) lithium aluminium hydride. After removal of the cooling bath the reaction mixture was stirred for 2.5 h at room temperature and then poured onto 200 ml saturated aqueous tartrate solution. The phases were separated and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50). Yellow solid (68%). MS (Turbo Spray): m/z=377.2 [M+H].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:11]([CH2:22][CH:23]([CH3:25])[CH3:24])([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[CH:8]([CH3:10])[CH3:9].Cl>C(OCC)C>[CH2:7]([C:11]([CH2:22][CH:23]([CH3:25])[CH3:24])([CH2:12][OH:13])[CH2:17][OH:18])[CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C(CC(C)C)(CC(C)C)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)CC(CO)(CO)CC(C)C
Temperature: 0 °C
Yield: 78 %

Procedure:
To 3 g (0.079 mol) LiAlH4 was added 100 ml ethyl ether, then added 15.5 g (0.057 mol) diethyl 2,2-diisobutylmalonate dropwise with intensely stirring. The reaction mixture was heated refluxing for 5 hours, then poured into 100 g ice that was acidified with dilute hydrochloric acid. The mixture was extracted with ethyl ether. After remove ethyl ether from the extract, 2,2-diisobutyl-1,3-propandiol as a white solid was recrystallized from hexane, and the yield was 78%. m.p. 75-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=O)[C:14]([NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2C(C3CCCCC3)=[C:31]3[N:25]([CH2:26][CH2:27][O:28][C:29]4[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:30]=43)[C:24]=2[CH:45]=1)=[O:19])([CH3:16])[CH3:15].[C:47]1([CH3:53])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(O)(=O)C>[CH:47]1([C:53]2[C:23]3[CH:22]=[CH:21][C:20]([C:18]([NH:17][C:14]([C:13]4[NH:12][C:3]5[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=5[N:1]=4)([CH3:16])[CH3:15])=[O:19])=[CH:45][C:24]=3[N:25]3[C:31]=2[C:30]2[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:29]=2[O:28][CH2:27][CH2:26]3)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: COC(=O)c1ccc(N)c(NC(=O)C(C)(C)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CCOc2cc(OC)ccc2-4)c1
Reactant: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(C(C)(C)NC(=O)c3ccc4c(C5CCCCC5)c5n(c4c3)CCOc3cc(OC)ccc3-5)[nH]c2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Methyl 4-amino-3-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate (0.73 g, 1.16 mmol) was dissolved in acetic acid (14.0 ml), and the mixture was stirred at 100° C. for 2 hr. The mixture was allowed to cool to room temperature, toluene was added, and the solvent was evaporated under reduced pressure. To the obtained residue were added methanol and water. The precipitate was collected by filtration, washed with water, and dried in vacuo to give methyl 2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylate (0.67 g, yield 95%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:18][NH:19][C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)=[O:21])[C:12]=2[OH:38])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:18][NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)=[O:21])[C:12]=2[OH:38])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)NN=C(c2ccccc2)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(C(=NNC(=O)c2ccc(C(=O)O)cc2)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To methyl 4-({2-[[5-(4-t-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl)methylene]hydrazino}carbonyl)benzoate (0.196 mmol, 100 mg), methanol (4 mL) was added, and 1 M aqueous sodium hydroxide (0.981 mmol, 0.981 mL) was added at room temperature. After 15 minutes of stirring at room temperature and 1 hour of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (0.981 mmol, 0.981 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (93 mg, yield 95%).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+].Br[C:54]1[CH:55]=[C:56]([O:62][CH3:63])[C:57]([F:61])=[C:58]([F:60])[CH:59]=1.[CH3:64][O:65][C:66]1[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][C:67]=1[C:74](=[O:76])[CH3:75]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:60][C:58]1[CH:59]=[C:54]([CH2:75][C:74]([C:67]2[CH:68]=[C:69]([O:72][CH3:73])[CH:70]=[CH:71][C:66]=2[O:65][CH3:64])=[O:76])[CH:55]=[C:56]([O:62][CH3:63])[C:57]=1[F:61]
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: COc1cc(Br)cc(F)c1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC)c(C(=O)Cc2cc(F)c(F)c(OC)c2)c1
Temperature: 70 °C
Yield: 24.8 %

Procedure:
A 100-mL round-bottom flask charged with Pd2dba3 (69 mg, 0.075 mmol), BINAP (112 mg, 0.18 mmol), and NaOt−Bu (650 mg, 6.5 mmol) was degassed and filled with N2. THF (20 mL) was added, followed by a solution 5-bromo-1,2-difluoro-3-methoxybenzene (1.1 g, 5 mmol) and 1-(2,5-dimethoxyphenyl)ethanone (1.08 g, 6 mmol) in THF (10 mL). The resulting mixture was heated at 70° C. for 16 h. Water (30 mL) was added, and the mixture was extracted with ether (3×50 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=80/1˜40/1) to give 2-(3,4-difluoro-5-methoxyphenyl)-1-(2,5-dimethoxyphenyl)ethanone (0.4 g) as a light yellow solid. 1H NMR (CDCl3): δ 7.24 (d, 1H), 7.04 (dd, 1H), 6.92 (d, 1H), 6.68-6.61 (m, 2H), 4.23 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H); LCMS: 323 (M+H)+.
Reaction SMILES: CC1C=CC(C[S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=CC=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:19][CH:20]=1)([CH3:26])[CH3:25]
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Reactant: CC(C)c1ccc(CBr)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1ccc(C(C)C)cc1

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 1-bromomethyl-4-isopropylbenzene (15 g), a 2M ethanolic solution of sodium ethylate (49 cc) and ethyl 2-mercaptoacetate (9.8 g) in ethanol (150 cc). Ethyl (4-isopropylbenzylthio)acetate (17.9 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Br[CH2:11][CH2:12][CH2:13][OH:14]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][CH2:11][CH2:12][CH2:13][OH:14])[CH:8]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: OCCCBr
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1NCCCO
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of 5-chloro-2-methylaniline (10.1 g) and 3-bromo-1-propanol (2.5 mL) were heated at 100° C. under nitrogen for 45 minutes. After cooling, a solid mass formed which was partitioned between dichloromethane and 1N sodium hydroxide. The organic phase was washed with brine, dried over anhydrous potassium carbonate, and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 20% ethyl acetate in hexane gave the title compound (5.6 g, 98.1%) as a brown oil, which was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:19](CC)CC)C.ClC(OCC)=O.N.[Cl-].[NH4+]>O1CCCC1>[C:14]([C@@H:9]1[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:16])[NH2:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
(2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid 13b (86.4 g, 0.374 mol) was dissolved in 1.2 L of tetrahydrofuran followed by addition of triethylamine (41 g, 0.411 mol) under argon atmosphere. The reaction mixture was cooled to −15° C., ethyl chlorformate (43.84 g, 0.411 mol) was added. After the mixture was stirred for 10 minutes, aqueous ammonia (236.8 mL) was added. The reaction mixture was slowly warmed up to 5° C. during 2 hours followed by addition of ammonium chloride (32 g). The reaction mixture was stirred for 30 minutes and separated. The separated organic phase was dried over anhydrous sodium sulfate, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The combined organic extracts were concentrated under reduced pressure to obtain the title compound (2S,4R)-tert-butyl 2-carbamoyl-4-hydroxypyrrolidine-1-carboxylate 13c (74 g, yield 86%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]([C:23]([N:25]([CH2:38][CH2:39][O:40][CH3:41])[C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][N:34]=[C:33]4[CH3:37])=[CH:28][CH:27]=3)=O)[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:12]([CH2:23][N:25]([CH2:38][CH2:39][O:40][CH3:41])[C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[CH:35][N:34]=[C:33]4[CH3:37])=[CH:28][CH:27]=3)[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N2CCN(Cc3ccccc3)C(C(=O)N(CCOC)c3ccc(-n4ccnc4C)cc3)C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCOc1ccc(N2CCN(Cc3ccccc3)C(CN(CCOC)c3ccc(-n4ccnc4C)cc3)C2)cc1

Procedure:
In a manner similar to Preparation 2, react 4-(4-ethoxyphenyl)-N-(2-methoxyethyl)-N-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-1-(phenylmethyl)-2-piperazinecarboxamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[C:28]([O:31][CH2:32][CH:33]([O:39][CH2:40]OC(=O)C)[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:30])[CH3:29]>>[C:36]([O:35][CH2:34][CH:33]([O:39][CH2:40][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2)[CH2:32][O:31][C:28](=[O:30])[CH3:29])(=[O:38])[CH3:37]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CC(=O)OCOC(COC(C)=O)COC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: CC(=O)OCC(COC(C)=O)OCn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 0.5 h

Procedure:
A mixture of 50.0 g (0.33 mole) of guanine, 33 g of ammonium sulfate, and 2.2 l of hexamethyldisilazane was stirred at reflux under N2 for 3 days, during which time all of the solid dissolved. The solvent was then removed by distillation under reduced pressure. To the very viscous, orange residual oil was added under N2 84 g (0.34 mole) of acetoxymethyl 1,3-diacetoxy-2-propyl ether, which formed in second liquid phase at the bottom of the flask. The flask was fitted with a distillation adapter, and the mixture was heated under low vacuum in an oil bath at approximately 135°. After an induction period lasting several minutes, boiling began and soon became quite vigorous. Distillation of trimethylsilyl acetate (along with any residual hexamethyldisilazane) proceeded rapidly at first but slowed after 30 minutes. After 2 hours the mixture was added to 1.3 l of 90% EtOH. The mixture was heated to boiling and maintained there until the separated gummy material was transformed to a tractable solid. The solid (8.2 g, consisting almost exclusively of guanine) was removed by filtration while hot. The filtrate was allowed to stand overnight, resulting in separation of an orange-brown gum. The supernatant was decanted away from the gum, filtered, and then concentrated to small volume. The solid which separated on concentration was collected on a filter and washed with H2O, then with some EtOH, to give 15.4 g of cream-colored crystals. By NMR, this material was solely the -alkylated isomer, although TLC indicated partial side chain deactylation. The material was suitable for deprotection without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C1COCC1>[Br:37][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)cc1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)cc1-c1ccccc1
Reaction time: 16 h

Procedure:
5-Hydroxymethyl-biphenyl-2-carbonitrile from step 3 (1.3 g, 6.2 mmol) was dissolved in THF (31 ml) and treated with Ph3P (2.4 g, 9.3 mmol) followed by CBr4 (3 g, 9.3 mmol). The reaction was mixture stirred at room temp. for 16 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product. FAB MS: 273 m/z (M+ +H)
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12.[Br:30][CH2:31][C:32]([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])[C:33](=[N:37][O:38][CH3:39])[C:34](Cl)=[O:35].O>C(OCC)(=O)C>[Br:30][CH2:31][C:32]([O:43][CH2:44][CH3:45])([O:40][CH2:41][CH3:42])[C:33](=[N:37][O:38][CH3:39])[C:34]([NH:2][CH:3]1[C:28](=[O:29])[N:5]2[C:6]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:7]([CH:10]=[CH2:11])[CH2:8][S:9][C@H:4]12)=[O:35]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)Cl
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Yield: 100.6 %

Procedure:
To a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (6.4 g) and timethylsilylacetamide (9.8 g) in ethyl acetate (80 ml) was added 4-bromo-3,3-diethoxy-2-methoxyiminobutyryl chloride (syn isomer) (5.0 g) at -20° C. with stirring, and the stirring was continued at -20° to 5° C. for an hour. To the reaction mixture were added ethyl acetate and water, and the separated ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (10.1 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:27])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12](C(OCC)=O)[C:11]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]2([CH3:27])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[CH:12][C:11]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(CCCC2CCCCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(CCCC2CCCCC2)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 29.7 %

Procedure:
A solution of Example 36F (2.14 g, 5.78 mmol) in 1,4-dioxane (20 mL) was treated with aqueous 1N hydrochloric acid solution (20 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (0.513 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:23]([C:24]4[CH:28]=[CH:27][O:26][N:25]=4)[CH:22]=[N:21][N:20]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:40][C:22]1[N:23]([C:24]2[CH:28]=[CH:27][O:26][N:25]=2)[C:19]([C:13]2[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:29]([F:32])([F:31])[F:30])[CH:4]=3)(=[O:9])=[O:10])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=2)=[N:20][N:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=S(=O)(Nc1cc(Cl)cnc1-c1nncn1-c1ccon1)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Cl)cnc1-c1nnc(Br)n1-c1ccon1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Chloro-N-[5-chloro-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide (80 mg) in CCl4/DCM (3 mL/1 mL) was charged with NBS (30 mg). The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with sat NaHCO3 and extracted EtOAc (50 mL×2), the combined organic layer was concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography (10% to 100% gradient of EtOAc-Hexane), and followed by preparative HPLC (10% to 90% gradient of MeCN-water) and dried (Lyophilizer) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 11.6 (br, 1H), 8.60 (d, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.19 (d, 1H), 7.98 (dd, 1H), 7.62 (d, 1H), 6.63 (d, 1H). MS (ES) [M+H]+ expected 584.0. found 584.0.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[CH3:19][O:20][C:21](=[O:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:19][O:20][C:21](=[O:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:17][CH2:16][CH2:15][CH2:14][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCCN1CCCCC1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
Triethylamine (250 mg, 2.5 mmol) and 3-piperidinopropylamine (284 mg, 2.0 mmol) are dissolved in CH2Cl2 (5 mL). Terephtalic acid monomethyl ester chloride (197 mg, 2.0 mmol) in 2.0 ml of CH2Cl2 is added to the mixture. The reaction mixture is stirred at room temperature for 2 h. The reaction is diluted with CH2Cl2 and washed with brine. The separated organic layer is dried over Na2SO4 and evaporated. The crude material is purified by silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH) to give 473 mg (78%) of the title compound. MS (APCI+) 305 (M+H)+.