Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C([Li])CCC.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].[Cl-].[NH4+]>C1COCC1>[C:19]([O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)Cl
Reactant: OCc1ccc2cc(O)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1ccc2cc(O)ccc2c1
Temperature: 5 °C
Yield: 56 %

Procedure:
To a 3-necked, 500-mL round bottomed flask equipped with an overhead stirrer, a digital thermometer and a 250-mL constant-pressure addition funnel with a nitrogen inlet was added 25 g (0.14 mol) of 6-hydroxymethyl-2-naphthol and 100 mL of anhydrous THF. The addition funnel was charged with 190 mL (0.3 mol) of n-butyllithium (1.6 M in hexane). The flask was cooled to 5° C. and the butyllithium was added slowly while maintaining a temperature of less than 15° C. The resulting suspension was stirred for 1 h at which time a solution of 14.9 g (0.15 mol) of methacryloyl chloride in 100 mL of anhydrous THF was slowly added while maintaining a temperature of less than 10° C. Stirring was continued with cooling for 6 h at which time the reaction mixture was poured into 300 mL of saturated ammonium chloride with vigorous stirring. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried and evaporated. The resulting residue was chromatographed on silica gel with 35% ethyl acetate in hexane. The fractions containing the pure product were combined and evaporated to yield 19 g (56%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:41]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C1(C)C=CC=CC=1>[NH2:41][C:10]1[CH:11]=[C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetic acid (R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethyl ester in a mixture of THF and toluene is stirred under hydrogen in the presence of PrO2 at room temperature for 15 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo. ES+ MS m/e 549 (MH+).
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[Br:12][CH2:13][C:14](Cl)=[O:15]>C1COCC1>[Br:12][CH2:13][C:14]([O:9][C:8]1[CH:10]=[CH:11][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)=[O:15]
Reactant: O=C(Cl)CBr
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OC(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.8 %

Procedure:
TEA (0.28 ml, 1.98 mmol, 3.0 eq) was added to a solution of paracetamol [4147] (0.10 g, 0.66 mmol, 1.0 eq) of in dry THF under argon atmosphere. At 0° C., bromoacetyl chloride [244] (0.123 g, 0.79 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 24 h. After 24 h, solvent was evaporated under vacuum and residue was taken in dichloromethane (50 ml) and washed with a 10% solution of NaHCO3 (15 ml) and then with brine (10 ml), followed by drying of the organic layer over anhydrous sodium sulfate. Evaporation of the solvent provided white solid which was purified by silica gel column chromatography (0.5% MeOH: DCM, 100-200 mesh silica) to give the product 4-acetamidophenyl 2-bromoacetate [299] (0.05 g, 28%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:16]([CH3:17])=[N:15][C:14]([CH:18]2[CH2:20][CH2:19]2)=[CH:13][C:9]=1[C:10]([OH:12])=O)#[N:2].[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:16]([CH3:17])=[N:15][C:14]([CH:18]2[CH2:20][CH2:19]2)=[CH:13][C:9]=1[C:10]([NH:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=1)=[O:12])#[N:2]
Reactant: Cc1nc(C2CC2)cc(C(=O)O)c1OCc1cccc(C#N)c1
Reactant: N#Cc1cccc(N)c1
Product: Cc1nc(C2CC2)cc(C(=O)Nc2cccc(C#N)c2)c1OCc1cccc(C#N)c1
Yield: 24.1 %

Procedure:
The amide coupling of 3-(3-cyano-benzyloxy)-6-cyclopropyl-2-methyl-isonicotinic acid (189) (128 mg, 0.4 mmol) and 3-aminobenzonitrile (59 mg, 0.4 mol), as described in Example 67, gave 3-(3-cyano-benzyloxy)-N-(3-cyano-phenyl)-6-cyclopropyl-2-methyl-isonicotinamide (192) (39.4 mg, 23% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[C:9]([CH3:10])[N:4]2[N:3]=1.O[N:16]=[C:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1.N>>[CH3:1][C:2]1[CH:14]=[C:5]2[N:6]=[CH:7][C:8]([C:11]3[O:13][N:24]=[C:17]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[N:16]=3)=[C:9]([CH3:10])[N:4]2[N:3]=1
Reactant: Cc1cc2ncc(C(=O)O)c(C)n2n1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Cc1cc2ncc(-c3nc(-c4cccnc4)no3)c(C)n2n1

Procedure:
The title compound was prepared according Method C using 2,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ2.52 (s, 3 H), 3.27 (s, 3 H), 6.77 (s, 1 H), 7.67 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 8.48 (dt, J=8.6, 1.9 Hz, 1 H), 8.84 (dd, J=4.7, 1.7 Hz, 1 H), 9.06 (s, 1 H), 9.30 (dd, J=2.2, 0.8 Hz, 1 H), 9.30 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 293 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12][CH:13]=[CH2:14])[CH:5]=1.O[C:17]1C=C(C=C(O)C=1)C(OC)=O.C(=O)([O-])[O-].[K+].[K+].BrCC(C)=C>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:11][CH2:12][C:13]([CH3:17])=[CH2:14])[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: C=CCOc1cc(O)cc(C(=O)OC)c1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)COc1cc(O)cc(C(=O)OC)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (15.0 g, 89.2 mmol), potassium carbonate (24.7 g, 178.4 mmol) and 3-bromo-2-methyl-propene (9.0 mL, 89.2 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.80 g, 39% yield). 1H NMR (400 MHz, CDCl3) δ 7.13-7.22 (m, 2 H) 6.66 (t, J=2.27 Hz, 1 H) 5.81 (s, 1 H) 5.06-5.16 (m, 1 H) 4.93-5.04 (m, 1 H) 4.44 (s, 2 H) 3.91 (s, 3 H) 1.68-1.94 (m, 3 H); LCMS for C12H14O4 m/z 223.10 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]1([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC(=O)C)(=O)C.Cl>C(N(CC)CC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]([OH:22])=[O:21]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=Cc1ccc2ccccc2c1)c1ccccc1
Yield: 89 %

Procedure:
A mixture of 2-naphthaldehyde (5 g, 32 mmole), phenylacetic acid (4.4 g, 32 mmole), triethylamine (5 mL) and acetic anhydride (10 mL) were refluxed for 5 hours. The solution was poured into 2N HCl (150 mL) and a precipitate formed immediately. This was recrystallized from 50% aqueous ethanol to yield 7.8 g (89% yield) of a white power.
Reaction SMILES: [CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)=[O:2].C[Li].[CH3:17]COCC>O1CCCC1>[OH:2][CH:1]([C:3]1[C:9](=[O:10])[C:8]([OH:11])=[CH:7][C:6]([CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1)[CH3:17]
Reactant: CC(C)c1ccc(C=O)c(=O)c(O)c1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(C)O)c(=O)c(O)c1
Temperature: -78 °C

Procedure:
7-formyl-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one (2.00 g, 10 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to -78° C. in a dry ice/acetone bath. A solution of methyllithium the ether (1.4M, 15 ml) was added dropwise to the solution, then dry ice/acetone bath was removed and stirring was continued until the insolubles were dissolved. An aqueous saturated ammonium chloride was added to the reaction mixture and extracted with methylene chloride. The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate and solvent was distilled off to give 2.18 g of 7-(α-hydroxyethyl)-4-isopropyl-2-hydroxy-2,4,6-cycloheptatrien-1-one as a reddish brown oil (yield: quantitative).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:33][N:32]=3)[C:27](=[O:44])[N:26]([CH3:45])[CH:25]=2)[C:5]([CH2:22][OH:23])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1.[C:46]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)=[CH:33][N:32]=3)[C:27](=[O:44])[N:26]([CH3:45])[CH:25]=2)[C:5]([CH2:22][O:23][CH3:46])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 2-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 197 (200 mg, 0.33 mmol) and K2CO3(135 mg, 0.99 mmol) in DMF(30 mL) was added the solution of iodomethane (70 mg, 0.50 mmol) in DMF(5 mL) at room temperature. The reaction mixture was stirred for 1 h. It was then filtered and the residue was purified by prep-HPLC to afford 333 as a yellow solid (165 mg, 80%). MS: [M+H]+ 626. 1H NMR (500 MHz, DMSO) δ 8.59 (d, J=2.0, 1H), 8.49 (s, 1H), 7.97 (d, J=2.0, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.32 (m, 2H), 7.17 (m, 1H), 6.52 (s, 1H), 4.31 (s, 2H), 4.14 (m, 3H), 3.88 (s, 1H), 3.56 (s, 3H), 3.54 (s, 4H), 3.44 (s, 4H), 3.12 (s, 6H), 2.58 (m, 2H), 2.46 (s, 2H), 1.79 (s, 2H), 1.68 (s, 2H).
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][N:25]=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]([CH3:37])[S:33]([NH2:36])(=[O:35])=[O:34].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH:1]1([C:7]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([NH:36][S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])=[O:23])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:24][N:25]=[N:26][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=NCN12
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Solvent: CO
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=NCN12
Temperature: 45 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of 10-cyclohexyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylic acid (50 mg, 0.13 mmol) and N,N-dimethylsulfamide (78 mg, 0.63 mmol) in DMA (2 mL), was added DMAP (77 mg, 0.63 mmol) and then EDCI-HCl (96 mg, 0.50 mmol). The mixture was stirred at 45° C. overnight, diluted with DMSO and MeOH and purified by prep HPLC (MeOH/H2O with 10 mM TFA buffer) to yield 10-cyclohexyl-N-((dimethylamino)sulfonyl)-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxamide (20 mg, 0.040 mmol, 31%) as light pink solid. 1H NMR (500 MHz, CD3OD) δ 1.16-1.26 (m, 1H), 1.39-1.55 (m, 3H), 1.73-1.83 (m, 2H), 1.93-2.22 (m, 4H), 2.86-2.96 (m, 1H), 3.04 (s, 6H), 5.14 (d, J=15.9 Hz, 1H), 6.05 (d, J=15.9 Hz, 1H), 7.66 (dd, J=8.55, 1.5 Hz, 1H), 7.72-7.80 (m, 3H), 7.82-7.87 (m, 1H), 7.99 (d, J=8.5, 1H), 8.34 (s, 1H), 9.08 (s, 1H). LCMS: m/e 505 (M+H)+, ret time 1.94 min.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[O:23][CH3:24].[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:36][C:34]2[CH:33]=[CH:32][C:29]3[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=3[N:35]=2)[C@H:3]([O:23][CH3:24])[CH2:4]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1NCc1ccc2c(n1)NC(=O)CO2
Yield: 57.2 %

Procedure:
Cis(±)1-[2-(4-amino-3-methoxypiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 167, 140 mg, 0.42 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (75 mg, 0.42 mmol) and sodium triacetoxy borohydride (250 mg, 1.20 mmol) were reacted as described according to Example 69. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.50% ammonium hydroxide gave 120 mg (57%) of the free base of the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH2:23]([O:25][C:26](=[O:38])[CH:27]([OH:37])[CH:28]([NH3+:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:24]>>[Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:36][CH:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]([OH:37])[C:26]([O:25][CH2:23][CH3:24])=[O:38])=[O:11])[CH:6]=1
Reactant: O=C(O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-chloro-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+: 505.15
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.S1C=CC=C1CC([NH:21][C@@H:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12)=O.CO>C(Cl)Cl>[NH2:21][C@@H:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33][CH:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.33 h
Yield: 68.8 %

Procedure:
A suspension of phosphorus pentachloride (4.71 g., 22.5 mmole) in methylene dichloride (35 ml.) was warmed uuntil most of the phosphorus pentachloride had dissolved. A solution of pyridine in methylene dichloride (18.2 ml., as a 10% v:v solution, ca22.5 mmole pyridine) was added, and the white suspension was warmed to 23° for 10 minutes, then cooled to 0°. A solution of diphenylmethyl 7β-(2-thienylacetamido)-3-vinylceph-3-em-4-carboxylate (5.16 g., 10 mmole) in methylene dichloride (70 ml.), cooled to 0°, was added and the mixture stirred for 20 minutes. The solution was run into a vigorously stirred mixture of methanol (10 ml.) in methylene dichloride (50 ml.) and the resulting solution washed with aqueous sodium bicarbonate and water, and dried and evaporated in vacuo. The residual gum, in a small volume of chloroform, was run onto a column (7 × 4 cm.) of Kieselgel (0.02 to 0.5 mm.), and the column eluted with chloroform (2 × 100 ml.), then chloroform:ethyl acetate = 1:1 (3 × 100 ml.). The first chloroform fraction and the last chloroform : ethyl acetate fraction were discarded and the other fractions combined and evaporated in vacuo. The residue was triturated with ether to give the amine (2.7 g., 69%) as small needles, m.p 157°-160° (decomp), [α]D - 155.4° (CHCl3), λmax. 296.5 nm. (ε, 12,400), νmax. (CHBr3) 3460 and 3390 (NH), 1780 (β-lactam), 1730 (CO2R) and 910 cm.-1 (CH=CH2), τ (CDCl3) 2.65 (Ph), 3.02 (CH Ph2), 33.09 (CH=CH2, dd, J 11 and 18 Hz.), 4.64 and 4.82 (CH=CH2, two d, J 18 and 11 Hz. resp.), 5.09 (C(7) -H, d, J 5 Hz.), 5.32 (C(6) -H, d, J 5 Hz.), 6.35 (C(2) -CH2, AB-q J 18 Hz), and 8.21 (NH2); (DMSO-d6) 2.60 (Ph), 3.03 (CH Ph2), 3.28 (CH = CH2, dd J 11 and 17 Hz.), 4.40 and 4.76 (CH=CH2, two d, J 17 and 11 Hz. resp.), 4.91 (C(7) -H, d, J 5 Hz.), 5.12 (C(6) -H, d, J 5 Hz), 6.09 and 6.45 (C(2) -CH2, AB-q J 18 Hz.) and 7.62 (NH2) (Found: C, 66.2; H, 5.1; N, 6.8; S, 8.1. C22H20N2O3S requires C, 67..3; , H, 5.15; N, 7.15; S, 8.2%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:12][CH2:11]1)(=O)=O.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.O>[CH:10]1([CH2:9][CH2:8][CH2:7][CH2:6][N:13]=[N+:14]=[N-:15])[CH2:12][CH2:11]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCCCC1CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCC1CC1
Temperature: 25 °C

Procedure:
A solution of 880 mg (4.6 mmol) of 4-cyclopropylbutyl methanesulfonate and 585 mg (9.0 mmol) of sodium azide in 6.0 mL of DMF was heated at 60° C. under Ar overnight. After cooling to rt, the mixture was diluted with water, and extracted with two portions of ether. The combined organic layers were washed twice with water, brine, and dried over MgSO4. The solvents were concentrated by distillation at atmospheric pressure to give a solution of the title compound in ether that was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4].[CH3:19][N:20]=[C:21]=[O:22].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:21]([NH:20][CH3:19])=[O:22])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4]
Reactant: NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F

Procedure:
The 2-pentafluoroethoxyphenylsulfonamide obtained in Example 4b is suspended in 400 ml of methylene chloride. Then 16.3 g of methyl isocyanate are added and 28.2 g of triethylamine are subsequently added dropwise over 15 minutes to form a clear solution. The solution is evaporated to dryness, and the residue is dissolved in 5% sodium carbonate solution. N-(2-pentafluoroethoxyphenylsulfonyl)-N'-methylurea with a melting point of 177°-179° C., is precipitated from the solution by acidification with 10% hydrochloric acid. Yield: 74.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14](=[O:16])[CH3:15])=[C:9]([CH3:17])[CH:8]=1.[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:21][CH2:15][C:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:8][C:9]=1[CH3:17])=[O:16]
Reactant: [Br-]
Reactant: COc1cccc(Oc2cc(C)c(C(C)=O)c(C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: COc1cccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (5.40 g, 20.0 mmol) in acetonitrile (40.0 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.1 g, 21.0 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (7.00 g), which was used directly for the next step without further purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].O>O1CCCC1>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1
Reactant: ClCCCCBr
Reactant: Cc1cccc2nccn12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: ClCCCCCc1cccc2nccn12
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, 51.5 ml (103 mmol) of a 2M lithium diisopropylamide solution (produced by Aldrich Company) was added to a solution of 13.6 g (103 mmol) of 5-metylimidazo[1,2-a]pyridine in 100 ml of tetrahydrofuran at -78° C. After stirring at constant temperature for 15 minutes, 17.64 g (103 mmol) of 1-bromo-4-chlorobutane was added, followed by stirring for 1 more hour. After stirring at 0° C. for 1 hour, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent; ethyl acetate) to yield 18.74 g (81.7%, light yellow oily substance) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:21]([CH:27]4[CH2:29][CH2:28]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:30]1(=[O:37])(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1>>[CH:24]1([C:23]2[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:10]([C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][S:30]5(=[O:37])=[O:36])=[CH:9][C:6]=4[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]3)=[N:19][CH:20]=[C:21]([CH:27]3[CH2:29][CH2:28]3)[CH:22]=2)[CH2:26][CH2:25]1
Reactant: O=S1(=O)CCCCN1
Reactant: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: N#Cc1cc(N2CCCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 86.7 %

Procedure:
Using 5-bromo-2-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (451 mg) described in Preparation Example 245 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (438 mg) was obtained.