Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C@H:11]([CH2:16][CH:17]=[CH2:18])[C:12](OC)=[O:13])([O-])=O.Cl[Sn]Cl.O>CO>[CH2:16]([C@H:11]1[NH:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][C:12]1=[O:13])[CH:17]=[CH2:18]
Reactant: C=CC[C@@H](Nc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: C=CC[C@H]1Nc2ccccc2NC1=O
Yield: 47 %

Procedure:
To a solution of 2-fluroronitrobenzene (3.70 g, 26.06 mmol) and (2R)-2-aminopent-4-enoic acid (3.00 g, 26.06 mmol) in MeOH (30 mL), was added NaHCO3 (4.82 g, 57.33 mmol), and the reaction mixture was refluxed overnight. After cooling, concentrating, and chasing with benzene (3×30 mL), the crude product was dried on high vacuum pump overnight to give (2R)-2-[(2-nitrophenyl)amino]-pent-4-enoic acid, which was then dissolved in MeOH, cooled to 0° C. and saturated with HCl(g). The reaction was capped and the reaction mixture was stirred at room temperature overnight, concentrated, and then subjected to silica gel chromatography eluting with 40%-60% CH2Cl2 in hexanes to give methyl (2R)-2-[(2-nitrophenyl)amino]pent-4-enoate (3.75 g, 57% overall yield for 2 steps). Methyl (2R)-2-[(2-nitrophenyl)amino]pent-4-enoate was dissolved in MeOH (70 mL) and SnCl2.H2O (16.84 g, 74.63 mmol) was added After refluxing overnight, the reaction mixture was cooled and concentrated under reduced pressure. The crude material was poured into EtOAc and saturated NaHCO3 and extracted with EtOAc (3×100 mL). The combined organics were then washed with NaHCO3 (1×50 mL) and brine (1×50 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 25%-40% EtoAc in Hexanes to give 1.31 g (47%) of (3R)-3-allyl-3,4-dihydroquinoxalin-2(1H)-one. LCMS (ES) m/z 189.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CN1Cc2cccc(N)c2C1=O
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1Cc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Temperature: 100 °C
Yield: 71.1 %

Procedure:
A mixture of 2,5-dichloro-4-iodopyridine (0.2 g, 0.73 mmol), 7-amino-2-methyl-3H-isoindol-1-one (0.118 g, 0.73 mmol), palladium(II) acetate (6.56 mg, 0.03 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.025 g, 0.04 mmol) and cesium carbonate (0.476 g, 1.46 mmol) were suspended in dioxane (5 mL). The mixture was heated at 100° C. for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated. A solid recovered from the top of the column was washed with water, dried in vacuo, and combined with the evaporated residue to afford 7-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3H-isoindol-1-one (0.160 g, 71% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.07 (3H, s), 4.50 (2H, s), 7.25-7.28 (1H, m), 7.48 (1H, s), 7.56-7.63 (2H, m), 8.36 (1H, s), 9.80 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=308.01 and 309.97 and 311.99.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:21][C@H:22]([C:33]1[NH:34][CH:35]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:37]=1)[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:21][C@H:22]([C:33]1[NH:34][CH:35]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:37]=1)[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:8]
Reactant: O=C(O)c1ccco1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1)c1ccco1
Temperature: 22 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
2-Furancarboxylic acid (12.6 mg, 0.11 mmol) was activated overnight at about 22° C. with carbonyldiimidazole (0.11 mmol, 0.2M in chloroform). 2-{(1S)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (0.1 mmol, 0.5M in chloroform) was added to the media and the mixture was stirred for about 12 hours at about 22° C. Aminomethylated resin was then added (50-60 mg, 1.2 mmol/g, Novabiochem) in order to quench the excess of acylating agent for about 12 hours. Purification on silica gel pad (200 mg, Alltech) with ethyl acetate as eluent gave the expected product (37.2 mg, 94%). 1H-NMR (CDCl3, 100 MHz) δ: 8.36 (br s, 1H); 7.67-6.4 (m, 16H); 5.48 (qd, J=7.1 Hz, 1H); 3.6 (ABX system, 2H). LC/MS: m/z=397 (M+H).
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].[C:6]([CH2:9][C:10](=O)[CH3:11])(=O)[CH3:7].[ClH:13]>>[ClH:13].[CH3:7][C:6]1[N:5]=[C:3]([OH:4])[N+:2]([O-:1])=[C:10]([CH3:11])[CH:9]=1
Reactant: NC(=O)NO
Reactant: CC(=O)CC(C)=O
Agent: Cl
Product: Cc1cc(C)[n+]([O-])c(O)n1
Temperature: 2 °C

Procedure:
0.40 mol (30.6 g) hydroxy urea was dissolved in 600 ml of 1 M HCl and 0.50 mol (50.06 g) acetyl acetone were added dropwise under ice cooling, maintaining the internal temperature at 1-3° C. The solution was thawed to room temperature in an ice bath and stirred over night, then filtered off and evaporated to dryness. The residue was suspended with 400 ml of acetone, the mixture was cooled to −18° C., the solid filtered off and washed with a little ice-cold acetone. After drying, 45.5 g of crude product were obtained. The crude product was recrystallized with 4.0 l ethanol from the boiling heat, cooled to −18° C., filtered off and washed with little ethanol and dried (fraction 1). The mother liquor was concentrated on a rotary evaporator until product started to precipitate again, cool stored and a second fraction isolated. After drying 26.0 g (1. fraction, purity>98%) and 11.0 g (2. fraction, contained 32% NH4Cl as by-product) of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([F:18])([F:17])[CH2:6][NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([F:18])([F:17])[CH2:6][N:7]([C:23]1[C:24]([N+:28]([O-:30])=[O:29])=[CH:25][N:26]=[C:21]([Cl:20])[N:22]=1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)CN[C@@H]1C[C@H]1c1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.3 %

Procedure:
A solution of 7.8 g (0.029 mole) of 2,2-difluoro-3-(trans-2-phenyl-cyclopropylamino)-propionic acid ethyl ester in 20 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 5.6 g (0.029 mole) of 2,4-dichloro-5-nitro-pyrimidine, 9.7 g (0.12 mole) of sodium bicarbonate and 80 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 11.8 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(trans-2-phenyl-cyclopropyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-287) as a yellow thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:29][NH2:30]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:30][CH3:29])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12
Reactant: CN
Product: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
5-Fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-formyl-1H-indole-2-carboxylic acid ethyl ester (from Example 119.1) was reacted with methyl amine as described in Example 86 to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-methylaminomethyl-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[F:19][C@@H:20]1[C@@H:24]([CH2:25][OH:26])[O:23][C@@H:22](N2C=CC(=O)NC2=O)[CH2:21]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:22]2[O:23][C@H:24]([CH2:25][OH:26])[C@@H:20]([F:19])[CH2:21]2)=[C:4]([S:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Nc1nc(SCc2ccccc2)c2nc[nH]c2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc(SCc2ccccc2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 48 h
Yield: 21.2 %

Procedure:
2-Amino-6-benzylmercapto-9H-purine (0.70 g, 2.7 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 6.8, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 2 days, 200 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:methanol (95:5). Fractions containing products were pooled, concentrated, and further chromatographed on silica gel (2.5×20 cm) with ethyl acetate:hexane (1:1). Solvent was removed and lyophilization yielded 0.175 g of 2-amino-6-benzylmercapto-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (21%): mp 150°-151° C.; [α]D20 -20.8 (c=0.50 DMF); UV λmax (ε×10-3) at pH 7, 247 (14.0) and 312 (14.0); at pH 13, 247 (13.6) and 312 (13.8); 1H NMR (300 MHz, DMSO-d6) δ8.18 (s, 1H, 8), 7.47 and 7.27 (2m, 5H, C6H5), 6.83 (b, 2H, NH2), 6.26 (dd, 1H, H1', J=9.2 Hz, J=5.8 Hz), 5.42 (dd, 1H, H3', J=53.7 Hz, J=4.3 Hz), 5.17 (t, 1H, OH5', J=5.6 Hz), 4.55 (s, 2H, SCH2), 4.18 (dt, 1H, H4', J=26.7 Hz, J=4.9 Hz), 3.57 (t, 2H, H5' and H5", J=5.2 Hz), 2.91 and 2.62 (2m, 2H, H2', and H2"); MS (ci) 376 (M+1), 356 (M-F), 258 (MH2 --C5H8FO2).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7](C(O)=O)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.NCC1OC=CN=1.CNC(N)=O.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1=Cn2c(cc3ccc(C(=O)O)cc32)-c2ccccc2C1
Agent: CNC(N)=O
Agent: NCc1ncco1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccc2cc3n(c2c1)C=CCc1ccccc1-3

Procedure:
(5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-6-[[(2-oxazolylmethyl)amino]carbonyl]-, methyl ester) was prepared from 5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-, 10-methyl ester and 2-aminomethyloxazole in a similar manner as described; Analytical thin layer chromatography (5% MeOH/CH2Cl2) Rf=0.40; Analytical HPLC method: Solvent A=10% MeO{tilde over (H)}90% H2Õ0.1% TFA, Solvent B=90% MeO{tilde over (H)}10% H2Õ0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=528.23, HPLC Rt=2.040 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][OH:11].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.O>C1C=CC=CC=1>[CH3:16][S:17]([O:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][CH2:13][CH2:14][CH3:15])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(CO)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCC(COS(C)(=O)=O)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To 24.7 g (0.1 mole) of the 2-(2,4-dichlorophenyl)hexan-1-ol and 13.8 g (0.12 mole) of methane sulfonyl chloride in 200 ml of benzene at 10° is slowly added 14.2 g (0.14 mole) of triethylamine. When the addition is complete the reaction is stirred and allowed to come up to ambient temperature over 1/2 hour period. The reaction slurry is then heated to reflux for 1/2 hour, cooled and poured into water. The organic solution is washed with dilute HCl then with water and finally with dilute sodium bicarbonate solution. After drying over anhydrous MgSO4, the benzene is stripped off to give 31.8 g (98%) of the crude product. This material is identified by ir and nmr. The purity is determined by glc.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:21]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO>[NH2:26][C:24]1[CH:23]=[CH:22][C:21]([C:29]2[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[C:32]([F:38])=[CH:31][C:30]=2[O:39][CH3:40])=[C:20]([CH2:19][N:15]2[C@@H:14]([CH3:41])[C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=3)[O:17][C:16]2=[O:18])[CH:25]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc([N+](=O)[O-])cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-5′-isopropyl-2′-methoxy-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (1.94 g, 3.16 mmol) in methanol (20 mL) was subject to H2 (40 psi., Parr shaker) at 20° C. for 1.5 h. LCMS indicated the presence of trace starting material. The crude mixture was filtered through a bed of Celite (521). The filtrate was evaporated in vacuo to afford a glass as the product. LC-MS: 585.32 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.83 (s, 1H), 7.67 (s, 2H), 6.93-7.06 (m, 2H), 6.87 (s, 0.5H), 6.72-6.82 (m, 1.5H), 5.57 (d, J=8.0 Hz, 0.5H), 5.36 (d, J=8.0 Hz, 0.5H), 4.77 (d, J=5.5 Hz, 0.5H), 4.74 (d, J=6.5 Hz, 0.5H), 3.95 (d, J=15.5 Hz, 0.5H), 3.75-3.86 (m, 1.5H), 3.73 (s, 3 E), 3.12-3.24 (m, 1H), 1.11-1.29 (m, 6H), 0.47 (d, J=6.5 Hz, 1.5H), 0.29 (d, J=6 Hz, 1.5H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[NH:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34][CH2:35][C:36](Br)=[O:37].C(=O)([O-])O.[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:36](=[O:37])[CH2:35][Br:34])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CBr)c3ccccc32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(benzyloxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (610 mg, 1.4 mmol) in dichloromethane (7 mL) was added bromoacetyl bromide (0.15 mL, 1.7 mmol) dropwise and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with water (5 mL) with vigorous stirring and neutralized with sodium hydrogen carbonate. The aqueous layer was separated and the organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethyl acetate to provide 519 mg (yield 66%) of the title compound. m.p. 222°-223° C. (decomp.).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[C:6]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[C:5]([CH3:25])=[N:4]1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:5]([CH3:25])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)c(C(=O)c2ccccc2)c1Oc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1nc(C)c(C(O)c2ccccc2)c1Oc1ccc(OC)cc1
Yield: 69.7 %

Procedure:
A solution of 77 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone and 119 mg of sodium borohydride in 5 ml of methanol was stirred at room temperature for 24 h. 20 ml of water was added and the mixture was extracted three times with 15 ml of diethyl ether. The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 54 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanol as a colourless gum which was used without further purification. Mass spectrum (ES) m/z 339 [M+H]+, 380 [M+H+CH3CN]+.
Reaction SMILES: [F:1][C:2]([S:5][C:6](Cl)=[N:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)([F:4])[F:3].Cl[C:18](=[CH2:21])[C:19]#[N:20].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[NH:7][C:6]([S:5][C:2]([F:4])([F:3])[F:1])=[CH:21][C:18]=2[C:19]#[N:20])=[CH:10][CH:11]=1
Reactant: FC(F)(F)SC(Cl)=NCc1ccc(Cl)cc1
Reactant: C=C(Cl)C#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Yield: 57.8 %

Procedure:
Under a nitrogen purge, a solution of trifluoromethyl-1-chloro-N-(p-chlorobenzyl)thioformimidate (1.1 g, 0.004 mol) and 2-chloroacrylonitrile (0.4 mL, 0.005 mol) is treated with a solution of triethylamine (1.3 mL, 0.009 mol) in toluene. After an induction period, solids begin to form as the reaction mixture exotherms slightly. When the exotherm subsides, the reaction mixture is heated at reflux temperature for 16 hours, cooled and filtered. The filter cake is washed with ethyl acetate and the filtrate is concentrated in vacuo to obtain a semi-solid. The semi-solid is dissolved in ethyl acetate and the organic solution is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is twice recrystallized from 1,2-dichloroethane to give the title product as a beige solid (0.7 g, mp 203°-205° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:11]=2[CH2:12][N:13]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:14]2[N:15]=[N:16][NH:17][N:18]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:42](=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.S(OC)(OC)(=O)=O>CC1CCCO1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1([C:10]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][C:11]=2[CH2:12][N:13]([CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:25]=2)[C:14]2[N:15]=[N:16][N:17]([CH3:42])[N:18]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)CCCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Solvent: COS(=O)(=O)OC
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCCCCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine (145 mg; 0.243 mmol) in 2-methyltetrahydrofuran (2.5 mL) was added sodium carbonate (110 mg; 1.03 mmol), N,N-dimethylformamide (1.0 mL) and dimethyl sulfate (70 uL; 0.739 mmol). Reaction was stirred for 16 hours at 60° C. The reaction was diluted with ethyl acetate, washed twice with water and then brine. The organic was dried sodium sulfate and concentrated under reduced pressure. The residue was purified by 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-30% ethyl acetate in heptane) to give 120 mg (80.9% yield) of a colorless gum which crystallized into a white solid upon sitting. Melting point: 103-104° C. MS (ES+): Calc: 609.5, Found: 610.5 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.72 (s, 2H), 7.47 (d, J=7.47 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=8.30 Hz, 1H), 5.10 (s, 2H), 4.79 (s, 2H), 4.20 (s, 3H), 2.94 (s, 3H), 2.12 (m, 2H), 1.97 (m, 2H), 1.8-1.46 (m, 8H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([C:24]([CH2:26][Cl:27])=[O:25])([CH3:23])[CH3:22]>C(C(C)=O)C>[CH3:20][C:21]([C:24]([CH2:26][Cl:27])=[O:25])([CH3:23])[CH3:22].[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:26][C:24](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 163.5 %

Procedure:
510 g (3 moles) of 4-hydroxybiphenyl were dissolved in 3 l of methyl ethyl ketone. 390 g of ground potassium carbonate were added and the mixture was heated to 80° C. 405 g (3 moles) of α-chloropinacoline were added dropwise over the course of 2 hours and the mixture was then stirred for a further 15 hours at 80° C. After cooling, it was filtered and the filter residue was rinsed with methyl ethyl ketone. The resulting filtrate was concentrated to dryness in vacuo by distilling off the solvent. The residue was taken up in methylene chloride and the solution was washed with 10% strength sodium hydroxide solution and twice with water, dried over sodium sulfate and concentrated in vacuo by distilling off the solvent. The residue was distilled, using a condenser cooled with hot water (50° C.), to avoid crystallization. After a small amount of first runnings of chloropinacoline at 40° C./0.4 mm Hg, 658 g (82% of theory) of 1-(4'-phenyl-phenoxy)3,3-dimethylbutan-2-one were obtained at 170° to 180° C./0.4 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:20][C:21](=[CH2:23])[CH3:22]>COCCOC>[NH2:9][C@@H:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([O:14][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: COCCOC
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 32 h
Yield: 33.1 %

Procedure:
A mixture of 7-ADCA (10.0 g, 0.0467 mol), ethylene glycol dimethyl ether (80 ml), concentrated sulfuric acid (6.0 ml) and isobutylene (36.0 g, 0.6416 mol) in a pressure bottle was stirred at room temperature for 32 hours. Solvent was removed under reduced pressure. The residue was diluted with methylene chloride, washed with water, sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to give 4.18 g of t-butyl 7β-amino-3-methyl-3-cephem-4-carboxylate.