Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (355 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (308 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (560 mg, 96%). MS (ISN) 581.1 [(M−H)−]; mp 132° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([NH:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])c2)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
To a solution of N-{3-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.42 mmol) produced in Example 37(ii) in pyridine (2 mL) was added acetyl chloride (39 μL, 0.548 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (20 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane/diethyl ether to give the title compound (112 mg, 52%) as a yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CO[CH2:24][Cl:25]>C(=S)=S.Cl[Ti](Cl)(Cl)Cl>[Cl:25][CH2:24][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=3)[CH2:9][C:8]=2[CH:7]=1
Reactant: COCCl
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: S=C=S
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)c(CCl)cc1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,6-di-t-butylfluorene (2.00 g, 7.19 mmol) and chloromethyl methyl ether (2.5 ml) in CS2 (15 ml) was added at 0° C. a solution of TiCl4 (0.4 ml) in CS2 (5 ml). The reaction mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and extracted with ether. The ether extract was dried over sodium sulfate and evaporated under vacuum to leave a residue, which was purified by column chromatography (hexane/CH2Cl2=10/1) and crystallization from hot heptanes. The product provided 2-chloromethyl-3,6-di-t-butylfluorene (yield 0.75 g). 1H NMR (CDCl3): δ 7.80 and 7.78 (each d, 1H, 4,5-H), 7.47 (d, 1H, J=8.1 Hz, H8), 7.34 (dd, 1H, J=8.1 Hz, J=1.5 Hz, H7), 7.31 (d, 1H, 1H, J=1.5 Hz, H1), 4.72 (s, 2H, CH2Cl), 3.87 (s, 2H, H9), 1.41 (s, 18H, t-Bu) and 2,7-dichloromethyl-3,6-di-t-butylfluorene (yield 0.63 g). 1H NMR (CDCl3): δ 7.87 (br s, 2H, 4,5-H), 7.34 (br s, 2H, 1,8-H), 4.75 (s, 4H, CH2Cl), 3.95 (s, 2H, H9), 1.42 (s, 18H, t-Bu) as indicated by the following reaction:
Reaction SMILES: OC(C1N=CC([C:11]2[S:15][C:14]([N+:16]([O-:18])=[O:17])=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=CC=1)(C)C.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:37]=[N:38][N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=3)=[CH:32][CH:31]=2)O1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:14]1[S:15][C:11]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[N:37]=[N:38][N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:47])[CH3:48])[CH:40]=3)=[CH:34][CH:35]=2)=[CH:12][C:13]=1[C:19]([NH2:21])=[O:20])([O-:18])=[O:17]
Reactant: CC1(C)OB(c2ccc(-c3cn(COCC[Si](C)(C)C)nn3)cc2)OC1(C)C
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(-c3cc(C(N)=O)c([N+](=O)[O-])s3)cc2)nn1
Temperature: 90 °C

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (470 mg, 1.87 mmol), 4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,3-triazole (751 mg, 1.87 mmol), and Pd(PPh3)4 (108 mg, 0.094 mmol) were combined in a vial and evacuated/backfilled with nitrogen. THF (4.4 mL) and 2 N Na2CO3 (1.9 mL) were added. The reaction mixture was heated to 90° C. overnight. The black reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, combined with silica, and evaporated. Flash chromatography (dry load, 50-100% EtOAc/hexanes) afforded a brown solid that was triturated with CH2Cl2 and filtered to isolate the title compound as a yellow solid. The mother liquor was concentrated, triturated again, and filtered to isolate an additional batch of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)[CH:7]=1.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:8]([O:12][CH3:13])[C:9]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:16]#[N:15])=[CH:18][CH:19]=2)=[O:11])[CH:7]=1
Reactant: COC(C(=O)O)c1cc(Br)ccc1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cc(Br)ccc1F

Procedure:
(RS)-(5-Bromo-2-fluoro-phenyl)-methoxy-acetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-(5-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Colorless solid. MS 377.2 ([M+H]+)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]4[CH:28]=[CH:29][S:30][C:26]=4[CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].CCOC(C)=O>CO>[ClH:32].[ClH:32].[ClH:32].[S:30]1[C:26]2[CH:25]=[CH:24][N:23]=[C:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[C:27]=2[CH:28]=[CH:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
{trans-4-[2-(4-Thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.2 g, 3 mmol) was treated with 1 N HCl in EtOAc (40 ml, 40 mmol) and MeOH (0.74 ml) and the resulting mixture was stirred 4 h at room temperature. A white precipitate was formed that was collected by filtration and washed with EtOAc. The solid was dried over night under high vacuum to yield trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride as a white powder (1.2 g, 94%), MS (ISP) m/z=345.1 [(M+H)+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Br:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:30]>C(OCC)(=O)C>[ClH:30].[Br:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the obtained 1-(tert-butoxycarbonyl)-4-(6-bromonaphthalene-2-sulfonyl)piperazine (2.80 g) were added methanol (10 ml) and 4 N hydrochloric acid in ethyl acetate solution (25 ml), and the solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated and the residue was treated with acetone to give amorphous powders. The powders were dried under reduced pressure to give the title compound (2.358 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>>[C:27]([C:29]1[CH:34]=[C:33]([CH:32]=[CH:31][CH:30]=1)[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:2])=[O:26])[CH2:6][O:7][C:8]=2[CH:13]=1)#[N:28]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: N#Cc1cccc(Oc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-cyano-phenylboronic acid following a procedure analogous to that described for Intermediate 6. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.10 min; Mass spectrum (ESI+): m/z=446 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:29]3[CH:28]=[C:27]([NH:30][C:31]([C:33]4[CH:37]=[CH:36][S:35][CH:34]=4)=[O:32])[CH:26]=[CH:25][C:24]=3[CH3:23])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Product: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2

Procedure:
The title compound was prepared from 5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one by following the procedures in Example 1d except using N-[4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-thiophenecarboxamide for the Suzuki cross-coupling reaction. LC-MS m/z 524 (M+H)+, 2.21 min (ret. time). xdb
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24](C(OC(C)(C)C)=O)[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[F:35][C:36]([F:43])([F:42])[C:37]1[N:38]=[CH:39][NH:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+].[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(#N)C>[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([N:40]3[CH:41]=[C:37]([C:36]([F:43])([F:42])[F:35])[N:38]=[CH:39]3)[C:19]3[C:23](=[O:33])[NH:24][CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N[C@H]1COCC[C@H]1Nc1nc(-n2cnc(C(F)(F)F)c2)c2c(c1F)CNC2=O
Yield: 8.8 %

Procedure:
In a 10 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 4-(trifluoromethyl)-1H-imidazole (48.9 mg, 0.359 mmol) and K2CO3 (66.2 mg, 0.479 mmol) were dissolved in ACN (2 mL). The cap was sealed and the mixture was reacted at 100° C. for 16 h. The reaction mixture was subsequently filtered through a Buchner funnel to remove un-dissolved K2CO3. The solids were washed with ACN (2×5 mL) and the filtrate was evaporated to give a residue, which was treated with TFA (2 mL) at RT for 20 min to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The product was reconstituted in DMSO (5 mL) and was then purified by preparative HPLC eluting with water (0.05% TFA) and ACN (15-45% gradient, 0.035% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a brown solid (4.2 mg, 8.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (m, 1H), 2.05 (td, J=12.88, 7.33 Hz, 1H), 3.30-3.90 (m, 4H), 3.78-3.99 (m, 2H), 4.44 (s, 2H), 6.49 (br s, 2H), 7.54 (d, J=5.56 Hz, 1H), 7.85 (br s, 2H), 8.67-8.80 (m, 2H). [M+H] calc'd for C16H16F4N6O2, 401. found, 401.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13](=[O:26])[N:8]2[C:9]=1[C:10]([O-:12])=[O:11].[Na+].[C:28]([O:34][CH2:35]Br)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13](=[O:26])[N:8]2[C:9]=1[C:10]([O:12][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:11]
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
1 g of sodium 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate was disssolved in 50 ml of dimethyl sulphoxide, and 975 mg of pivaloyloxymethyl bromide were added thereto, after which the mixture was stirred at room temperature for 15 minutes. The mixture was then diluted with 200 ml of ethyl acetate, washed in turn with 50 ml of a saturated aqueous solution of sodium bicarbonate and 50 ml of a saturated aqueous solution of potassium bisulphate, and then dried over anhydrous magnesium sulphate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure and the resulting residue was chromatographed through 100 g of silica gel eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to afford 750 mg of the desired pivaloyloxymethyl 3-methoxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate.
Reaction SMILES: [H-].[Na+].[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@H:12]([OH:24])[C@@H:11]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CO>CN(C=O)C>[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@H:12]([O:24][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:11]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5]
Reactant: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A suspension of sodium hydride (196 mg, 5.1 mmol) in dry DMF (10 mL) was cooled to 0° C., and a solution of methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D glucopyranoside (10) (2.53 g, 4.3 mmol) in dry DMF (20 mL) was added dropwise in 30 minutes. The resulting solution was stirred at room temperature for 30 minutes and benzyl bromide (880 mg, 5.1 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature overnight, cooled to 0° C. and dry methanol (1 mL) was added dropwise. The reaction mixture was concentrated under reduced pressure, then xylene (20 mL) was co-evaporated from the residue. The residue was taken up in CHCl3 (100 mL) washed with H2O (100 ml), saturated NaHCO2 solution (100 mL) dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography using EtOAc—Hexane 1:9 as the mobile phase to give methyl 2-azido-4-O-benzyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (32) (2.0 g, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[C:8]2[N:13]([C:14]=1[Br:15])[N:12]=[CH:11][N:10]=[C:9]2[NH2:16])=[O:5])[CH3:2].C(N(CC)CC)C.C1([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=2)C=CC=CC=1>C1COCC1>[NH2:16][C:9]1[C:8]2=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:38]([NH:39][C:40]4[CH:45]=[C:44]([C:46]([F:48])([F:47])[F:49])[CH:43]=[CH:42][N:41]=4)=[O:37])=[CH:21][CH:22]=3)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:14]([Br:15])[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)c1c(-c2ccc(N)cc2)c2c(N)ncnn2c1Br
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1Br
Temperature: 70 °C
Yield: 88.8 %

Procedure:
Ethyl-4-amino-5-(4-aminophenyl)-7-bromopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (1.5 g, 3.99 mmol) was suspended in THF (20 mL) and treated with triethylamine (0.56 mL, 3.99 mmol) and phenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (1.13 g, 3.99 mmol). The mixture was heated to 70° C. for 18 h. After cooling to rt, he mixture was concentrated then suspended in EtOAc. The product was collected by filtration to give 2.0 g of a tan solid (89%). 1H-NMR (DMSO-d6) δ 9.91 (s, 1H) 9.75 (s, 1H), 8.53 (d, J=5.4, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.60 (d, J=11, 2H), 7.37-7.31 (m, 3H), 5.15 (bs, 2H), 4.04 (q, J=7.1, 2H), 0.99 (t, J=7.2, 3H); MS [M+H]+=563.9, 565.9; LCMS RT=3.22.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:17]#[N:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])C.[H][H]>CO.[Ni]>[CH3:1][O:3][C:4]([C:6]1([CH2:17][NH2:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1(C#N)CN(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1(CN)CN(C(=O)OC(C)(C)C)C1

Procedure:
3-Cyano-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (7.75 g; 30.5 mmol) in methanol (1000 ml) is combined with wet RaNi (˜28 g) and hydrogenated at room temperature under 1 atm of hydrogen for 2 hours. The reaction mixture is filtered and evaporated to dryness to yield the title compound as light brown resin, which crystallizes slowly (6.8 g; 91%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=3)[NH:12][C:11]=2[C:20](O)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]1[CH:31]=[N:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25]1>>[CH3:23][N:24]1[CH:25]=[C:26]([CH2:27][CH2:28][NH:29][C:20]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[O:21])[N:30]=[CH:31]1
Reactant: Cn1cnc(CCN)c1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Product: Cn1cnc(CCNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1

Procedure:
Reaction of 3-phenylsulfonyl-5-chloroindole-2-carboxylic acid with 1-methylhistamine under the conditions of Example 37 provides the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12]O)[C:6]=2[CH:14]=1.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:12][CH2:11][CH2:10][CH:7]1[C:6]2[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: OCCCC1COc2ccc(F)cc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc2c(c1)C(CCCCl)CO2
Reaction time: 3 h

Procedure:
3-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-1-propanol, prepared as described in EXAMPLE 11, (51 g) was dissolved in 300 ml of dichloromethane and 0.5 ml of dimethyl formamide was added. During 20 min 50 ml of thionyl chloride was added dropwise followed by stirring for 3 h. Ice cold water was added, the organic phase separated, dried over magnesium sulfate and concentrated in vacuo giving 46 g of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran as an oil.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.Cl.[NH4+].[Cl-]>CO.C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: O=C(N[C@H](CO)c1ccc(Cl)c(F)c1)N1CCc2cnc(NC3CCOCC3)nc2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 70 (1.236 g, 2.191 mmol) in 15% MeOH/DCM (75 mL) was added slowly HCl (2.19 mL, 8.763 mmol) and the reaction was stirred at RT for 20 min. Saturated NH4Cl was added slowly and the resulting solution extracted with DCM. The organic layer was separated and concentrated. The crude residue was purified by SiO2 chromatography eluting with an MeOH/DCM gradient (4 to 5% MeOH) to afford 0.841 g (85.3%) of I-14: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.38 (t, 1H), 7.14 (dd, 1H), 7.08 (d, 1H), 5.28 (d, 1H), 4.97 (m, 1H), 4.89 (d, 1H), 4.39 (s, 2H), 4.06-3.90 (m, 4H), 3.86 (m, 1H), 3.76-3.60 (m, 2H), 3.55 (dt, 2H), 2.69 (t, 2H), 2.26 (t, 1H), 2.02 (d, 2H), 1.53 (m, 2H); LCMS (ACPI-pos) m/z 450.0 (M+H)+.