Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.[C:19]([O:23][C:24]([N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][C:29]([C:35]#[CH:36])([OH:34])[CH2:30]2)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[C:15]([C:9]1[N:8]=[C:7]2[C:6]3[CH:18]=[C:2]([C:36]#[C:35][C:29]4([OH:34])[CH2:30][CH:31]5[N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH:27]([CH2:33][CH2:32]5)[CH2:28]4)[CH:3]=[CH:4][C:5]=3[O:14][CH2:13][CH2:12][N:11]2[CH:10]=1)(=[O:16])[NH2:17]
Reactant: C#CC1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(C#Cc1ccc3c(c1)-c1nc(C(N)=O)cn1CCO3)C2
Yield: 104.5 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure E. In a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (300 mg, 1.0 mmol) in acetonitrile (6 mL) and triethylamine (3 mL) were added Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), 3-Ethynyl-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.5 g, 2 mmol) and CuI (19 mg, 0.1 mmol). Then the solution was bubbled N2 for 5 min and microwaved for 2 h at 120° C. under nitrogen. The reaction mixture was filtered and the filtrate was purified by column (EtOAc/hexanes 2:1) to afford crude product (0.5 g, 99%). LCMS=479.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C>[Br:31][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1nccn2cnc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CN(C)C=O
Product: Clc1nccn2c(Br)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 2 h

Procedure:
To a solution of 8-chloro-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazine (2.10 g, 6.5 mmol) in DMF (12 mL) at 0° C. was added NBS (1.40 g, 7.84 mmol) and stirred for 2 h. DMF was removed under pressure and added water (75 mL). Solid formed was extracted with EtOAc (3×50 mL), washed with water (40 mL) and dried (Na2SO4). Evaporation of solvent gave crude material, which was purified by column chromatography on silica gel using CH2Cl2/MeOH (98:2). Yield: 2.05 g (77%); 1H NMR (CDCl3, 300 MHz) δ 7.11-7.21 (m, 5H), 7.28-7.32 (m, 3H), 7.61-7.64 (m, 2H), 7.70 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=O)[CH3:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:12][NH2:13]>CCOC(C)=O.O>[Cl:1][C:2]1[C:7]2[C:8]([CH3:9])=[N:12][NH:13][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1c(Cl)ccnc1Cl
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]c2ccnc(Cl)c12
Yield: 64 %

Procedure:
1-(2,4-Dichloro-pyridin-3-yl)-ethanone (6.2 g, 32.6 mmol) in 65% aqueous hydrazine (45 ml) was stirred at rt overnight. The mixture was diluted with EtOAc and water. The organic extract was washed with brine, dried and concentrated to give a white solid. The crude product was purified by flash column chromatography over silica gel (200 g) eluting with 1:1 petroleum ether:EtOAc to give an off-white solid (3.5 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s, 3 H), 7.47 (d, J=5.95 Hz, 1 H), 8.06 (d, J=5.95 Hz, 1 H). m/z (ES+APCI)+: 168/170 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:37])([F:36])[C:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])([OH:27])[CH2:21][N:22]2[CH:26]=[N:25][N:24]=[N:23]2)=[N:17][CH:18]=1>[Cu]>[N:1]1[N:2]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:36])([F:37])[C:20]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])([OH:27])[CH2:21][N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[N:17][CH:18]=2)[N:3]=[CH:4][CH:5]=1
Reactant: c1c[nH]nn1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(-n2nccn2)cn1
Temperature: 140 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
To a stirred solution of 1H-1,2,3-triazole (410 mg, 5.93 mmol) were added copper (Cu) powder (93 mg, 1.45 mmol), K2CO3 (160 mg, 1.15 mmol) and 1 (300 mg, 0.694 mmol) under N2 atmosphere. The reaction mixture was gradually heated to 140° C. and stirred for 4 h. The reaction mixture was cooled to 100° C., quenched with ethylenediaminetetraacetic acid (EDTA) sodiuim (Na) salt solution, and made basic with sodium carbonate (Na2CO3) solution. The aqueous layer was extracted with CH2Cl2 (3×50 mL); the combined organic phases were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluting with 45% EtOAc/hexane) to afford 9 (0.12 g, 0.297 mmol, 42%) as a solid. 1H NMR (500 MHz, CDCl3): δ 9.33 (s, 1H), 8.77 (s, 1H), 8.47 (dd, J=8.5, 2.0 Hz, 1H), 7.90 (s, 2H), 7.70 (d, J=9.0 Hz, 1H), 7.34-7.29 (m, 1H), 6.78-6.73 (m, 1H), 6.67-6.64 (m, 1H), 5.64 (d, J=14.0 Hz, 1H), 5.14 (d, J=14.0 Hz, 1H). MS (ESI): m/z 420.9 [M++1]. HPLC: 99.9%.
Reaction SMILES: [NH2:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:4][OH:5].[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([F:19])=[C:13](Cl)[N:12]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([F:19])=[C:13]([NH:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:4][OH:5])[N:12]=1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)(C)C(N)CCO
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(CCO)Nc1nc(Cl)c(C#N)cc1F
Temperature: 75 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
To a solution of 3-amino-4,4-dimethylpentan-1-ol (2.00 g, 8.64 mmol) in ethanol (20 mL) was added racemic 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (1.65 g, 8.64 mmol) and 5 mL of N,N,-diisopropylethylamine. The solution was stirred at 75° C. for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromatography (methylene chloride), yielding 2.2 g of 2-chloro-5-fluoro-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile, 95a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.02 minutes (M+H) 286.16
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[CH2:12]([O:19][CH2:20][CH:21]1[CH2:25][N:24]([C:26]2[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=2)[C:23](=[O:32])[CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH2:12]([O:19][CH2:20][CH:21]1[CH2:25][N:24]([C:26]2[C:30]([N+:1]([O-:4])=[O:2])=[CH:29][N:28]([CH3:31])[N:27]=2)[C:23](=[O:32])[CH2:22]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1ccc(N2CC(COCc3ccccc3)CC2=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CC(COCc3ccccc3)CC2=O)n1

Procedure:
To a mixture of fuming nitric acid (0.32 mL) and acetic anhydride (5.0 mL) was added 4-((benzyloxy)methyl)-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (1.1 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, water was added thereto, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.1 g).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]([F:34])([F:33])[C:17]([C:19]1[S:23][C:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[CH:21][CH:20]=1)=[O:18]>C(O)=O>[F:34][C:16]([F:15])([F:33])[C:17]([C:19]1[S:23][C:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)[CH2:6][CH2:5]2)=[O:28])=[CH:21][CH:20]=1)=[O:18]
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Solvent: O=CO
Product: N#Cc1ccc(N2CCN(C(=O)c3cccc(-c4ccc(C(=O)C(F)(F)F)s4)c3)CC2)nc1
Yield: 32 %

Procedure:
This compound was synthesized from 6-(piperazin-1-yl)nicotinonitrile and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described for example 37 step 3 (60 mg, yield 32%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=2.1 Hz, 1H), 8.19-8.17 (dd, J=4.0 Hz, J=1.5 Hz, 1H), 8.00-7.89 (m, 4H), 7.64-7.61 (m, 1H), 7.57-7.55 (m, 1H), 6.96-6.94 (t, J=9.2 Hz, 1H), 3.82-3.74 (m, 6H), 3.47 (m, 2H). MS (ESI) m/z: Calculated for C23H17F3N4O2S: 470.10. found: 515.6 (M+HCOOH)−
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:21])[CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:24](OC)[CH2:25][Br:26].B(F)(F)F.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:11][C:12]2[C:13]([O:19][CH3:20])=[CH:14][CH:15]=[C:16]([CH3:18])[C:17]=2[C@H:24]([CH2:25][Br:26])[O:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C)cc1CC(O)COCc1ccccc1
Reactant: COC(CBr)OC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C)c2c1C[C@@H](COCc1ccccc1)O[C@H]2CBr
Reaction time: 1.5 h

Procedure:
A solution of 1-benzyloxy-3-(2'-methoxy-5'-methylphenyl)-2-propanol (3.4 g, 12 mmol), from Step 1, and bromoacetaldehyde dimethyl acetal (1.7 mL, 14 mmol) in 25 mL of methylene chloride is cooled to 0° C. Boron trifluoride etherate (3.6 mL, 29 mmol) is added dropwise and the reaction mixture is stirred for 1.5 h. The resultant dark brown solution is poured into 50 mL of 10% aqueous sodium carbonate solution and the aqueous solution is extracted with 3×50 mL of diethyl ether. The combined ether extracts are washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH3:19])[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)nc3ccccc23)[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,4-dichloroquinazoline (12.69 g, 63 mmol) and 3-amino-5-methylpyrazole (6.18 g, 63 mmol) in ethanol (220 mL) is added triethylamine (8.13 mL, 63 mmol) and the reaction mixture is stirred for 3 hours at room temperature. The pale yellow precipitate is then collected by filtration, washed with cold ethanol and dried under vacuum to give (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:7]=[N:8][CH:9]=1.I[CH3:24]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[N:16]([CH3:24])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:7]=[N:8][CH:9]=1
Reactant: Cc1cc(C(=O)c2cncc(Br)c2)cc2oc(=O)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cncc(Br)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.18 g (4.00 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 1.27 g (3.80 mmol) 6-(5-bromo-pyridin-3-carbonyl)-4-methyl-3H-benzoxazol-2-one in 5 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.32 mL (5.00 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto ice water and the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [NH3:1].O.[C@@H:3]1([N:12]2[C:22]3[N:21]=[C:19]([NH2:20])[NH:18][C:16](=O)[C:15]=3[N:14]=[CH:13]2)[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1[OH:5].Cl[Si](C)(C)C>O>[NH2:20][C:19]1[N:21]=[C:22]2[C:15]([N:14]=[CH:13][N:12]2[C@@H:3]2[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]2[OH:5])=[C:16]([NH2:1])[N:18]=1
Reactant: N
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Solvent: O
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
This variation of the procedures of Robins, et al. supra, eliminated the need to utilize liquid ammonia in the reaction mixture since the ammonia molecule is generation in situ from the silazane reagent and the water of hydration of the guanosine hydrate starting material. Further, the use of chlorotrimethylsilane was not necessary nor was it necessary to conduct the reaction under anhydrous conditions, do a preliminary evaportaion, or open and re-seal the Parr bomb under a dry nitrogen atmosphere.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]([C:13]2[S:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH3:28])[CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]([C:13]2[S:17][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)=[N:15][C:14]=2[CH3:28])[CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1
Reactant: CCC(Oc1ccc(-c2noc(=O)[nH]2)c(OC)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCC(Oc1ccc(-c2noc(=O)[nH]2)c(O)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
To a stirred solution of 136 mg of 3-(2-methoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-4H-1,2,4-oxadiazol-5-one in 5 mL of dichloromethane at −70° C. was added 0.6 mL of a 1 M solution of boron tribromide in dichloromethane. After 1 h at −60° C., the reaction mixture was poured into methanol and a saturated aqueous solution of NaHCO3 then extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 90/10) to give 22 mg of 3-(2-hydroxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][CH:20]=[O:21])[CH:6]=1)[OH:4].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O.C(OC(C)C)(=O)C>[Br:1][CH2:2][C@H:3]([O:4][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:7]([NH:19][CH:20]=[O:21])[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reaction time: 72 h
Yield: 67.9 %

Procedure:
(R)-2-Bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol (intermediate 3) (9.9 g, 28 mmol) was dissolved in 36 mL dimethylformamide. Imidazole (2.3 g, 34 mmol) and t-butyldimethylsilylchloride (4.7 g, 31 mmol) were added. The solution was stirred under nitrogen atmosphere for 72 h. Additional imidazole (0.39 g, 5.7 mmol) and t-butyldimethylsilylchloride (0.64 g, 4.3 mmol) were added and the reaction was stirred for an additional 20 h. The reaction was diluted with a mixture of isopropyl acetate (53 mL) and hexanes (27 mL) and transferred to a separatory funnel. The organic layer was twice washed with a mixture of water (27 mL) and saturated aqueous sodium chloride (27 mL) followed by a final wash with saturated aqueous sodium chloride (27 mL). The organic layer was dried over sodium sulfate. Silica gel (23.6 g) and hexanes (27 mL) were added and the suspension was stirred for 10 minutes. The solids were removed by filtration and the filtrate concentrated under vacuum. The residue was crystallized from hexanes (45 mL) to afford 8.85 g (19 mmol, 68%) of intermediate 4 as a white solid. m/z: [M+H+] calcd for C22H30NO3SiBr 464.1, 466.1; found 464.2, 466.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[CH3:14][N:15]([C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:25]3[CH2:26][CH2:27][C@@H:23]([N:15]([CH3:14])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:24]3)=[O:13])[S:10][C:3]=12
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 37 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (1.05 g, 4.94 mmole), SOCl2 (10 ml), tert-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate 34b (0.989 g, 4.94 mmole) and Et3N (0.689 ml, 4.94 mmole) in a manner as previously described for example 9d to give a brown oil (0.723 g, 0.30%). 1H NMR (300 MHz, CDCl3) δ 8.62 (1H, d, J=5.1 Hz), 7.85 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.82 (1H, m), 3.93 (3H, m), 3.63 (1H, m), 2.82 (3H, s), 2.12 (2H, m), 1.47 (9H, s); ESIMS (MH+): 396.05.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([C:19](OCC)=[O:20])[NH:11][C:10]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO>C(O)(C)(C)C>[C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([CH2:19][OH:20])[NH:11][C:10]1=[O:24])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CCCCCCC(CC(=O)OC(C)(C)C)C(=O)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CC1CCCCCCC(CO)NC1=O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
The major isomer of ethyl 3-t-butoxycarbonylmethyl-2-oxo-1-azacyclodecane-10-carboxylate (0.68 g, 2.0 mmol) is dissolved in t-butanol (10 mL). Sodium borohydride (0.23 g, 6.0 mmol) is added and the reaction is warmed to 55° C. Methanol (2.0 mL) is added over a twenty minute period, and the reaction is kept at 55° C. for an additional 1 hour. The reaction is then partitioned between ethyl acetate and water, and the aqueous phase is extracted several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (50% ethyl acetate/hexane) to give 3-t-butoxycarbonylmethyl-10-hydroxymethyl-2-oxo-1-azacyclodecane, MS: M+1=300.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:21])[CH:19]([NH2:20])[C@H:16]3[S:15][CH2:14][C:13]=2[OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25]([CH2:27][CH2:28][C:29](Cl)=[S:30])#[N:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:21])[CH:19]([NH:20][C:29](=[S:30])[CH2:28][CH2:27][C:25]#[N:26])[C@H:16]3[S:15][CH2:14][C:13]=2[OH:22])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: N#CCCC(=S)Cl
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
7-Amino-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester [J. Am. Chem. Soc. 96, 4986 (1974)]is acylated with cyanomethylthioacetyl chloride by the procedure described in Example 1 to obtain 7-cyanomethylthioacetamido-3-cephem-3-ol-4-carboxylic acid p-nitrobenzyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:35]5[CH:36]=[CH:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=5)[CH:3]=4)[N:8]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:21])=[O:22])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)cc4)cnc32)cc1
Yield: 88.5 %

Procedure:
Intermediate B (4.04 g) and 4-formylphenylboronic acid (1.56 g) were suspended in 150 mL of acetonitrile and treated with 150 mL of 1 M sodium carbonate solution. To this was added dichloro-bis-(triphenylphosphine)-palladium(II) (608 mg) and the mixture was heated at reflux for 2.5 hours. The reaction mixture was filtered and the residue washed with EtOAc, the filtrates were combined and washed with water, and brine, dried over MgSO4, and concentrated. MPLC silica gel chromatography eluting with 0-30% EtOAc in hexane, produced 3.77 g of the title compound (M+H 492).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[C:20]1([N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:15]3[C:10]([C:11]([C:16]([F:18])([F:19])[F:17])=[CH:12][CH:13]=[CH:14]3)=[N:9]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1cccc2c(-c3ccccc3)n[nH]c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: FC(F)(F)c1cccc2c(-c3ccccc3)n(-c3ccccc3)nc12
Yield: 15.6 %

Procedure:
3-Phenyl-7-trifluoromethylindazole (0.2 g, 0.76 mmol), phenyl boronic acid (186 mg, 1.53 mmol), copper II acetate (208 mg, 1.14 mmol), and pyridine (93 uL, 1.14 mmol) in 6 mL methylene chloride were stirred at room temperature for 72 hours. The reaction mixture was filtered through Celite®, poured into NH4Cl (sat. soln.) and extracted with EtOAc. The combined organic layers were dried with Na2SO4, concentrated and the resulting residue was purified by HPLC (10-100% CH3CN—H2O) to provide the desired compound as a white solid (40 mg).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8]1([C:14]([CH3:24])([CH3:23])[CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH:16]2O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:21][C@H:18]1[CH2:17][C@@H:16]([O:4][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH3:7])[C@H:15]([C:14]([CH3:24])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:23])[CH2:20][CH2:19]1
Reactant: CCC(=O)C(=O)O
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 2.28 g 2-oxobutyric acid (2, 22.11 mmol, 1.3 eq), 4.04 g (−)-8-phenylmenthol (18, 17.02 mmol, 1.0 eq) and 169.9 mg para-toluenesulfonic acid monohydrate (0.884 mmol, 0.52 eq) in 48 mL benzene was heated to reflux for 20 h 35 min. After cooling down to room temperature, the solution was washed twice with 50 mL saturated aqueous sodium hydrogencarbonate solution, and subsequently with 50 mL water and 50 mL brine. The organic phase was dried over 5 g sodium sulfate and was filtered. The filter cake was washed with 10 mL benzene. The organic phase was evaporated to dryness in a rotary evaporator (40° C., 20 mbar) yielding the title compound (4.98 g, 92% by weight) as colorless solid.