Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]([OH:22])=O)=[CH:18][C:5]2[CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:8][C:4]=2[CH:3]=1.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25]>>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:19]2[C:2]([Cl:1])=[CH:3][C:4]3[O:8][CH:7]([CH2:9][CH2:10][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:6][C:5]=3[CH:18]=2)=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: O=C(O)c1cc2c(cc1Cl)OC(CCCc1ccccc1)C2
Product: CC(=O)c1cccc(NC(=O)c2cc3c(cc2Cl)OC(CCCc2ccccc2)C3)c1O
Yield: 42 %

Procedure:
Following the process described in example 1 (point K), starting from 6-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with hexane:ethyl acetate, 1:1 (42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 22 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 4-floro-3-trifloromethyl aniline (0.070 g, 1.5 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.030 g of desired product. 1H NMR (DMSO-d6): δ 3.94 (s, 3H), 7.50-7.60 (m, 3H), 7.67-7.72 (m, 2H), 7.77-7.82 (m, 2H), 8.01 (m, 1H), 8.26 (m, 1H), 10.38 (br s, 1H), 12.80 (br s, 1H); MS (m/z): 525.17 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.N1CCNCC1.[C:43](#[N:47])[CH2:44][C:45]#[N:46].C(O)(=O)C1C=CC=CC=1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[C:44]([C:43]#[N:47])[C:45]#[N:46])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: N#CCC#N
Agent: C1CNCCN1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=C(C#N)C#N)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 79.6 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), piperazine (0.02 g), malononitrile (0.065 g), benzoic acid (0.020 g) and toluene (30 mL) was heated under reflux for 2 hrs with azeotropic removal of water. Ethyl acetate was added to the reaction mixture. The ethyl acetate layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl)methylene) malononitrile as yellow crystals (0.35 g, yield 80%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 190-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20].[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:20])([F:21])[F:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution containing 64.2 g (0.5 mole) of 4-chlorophenol and 112.7 g (0.5 mole) of 2-chloro-5-nitrobenzotrifluoride in 400 ml of DMSO was added dropwise with stirring at 30°-35° C. a solution containing 20 g (0.5 mole) of sodium hydroxide in 20 ml of water. After 1.5 hours, the reaction mixture was poured into cold water and extracted with 800 ml of ether. The ether solution was dried and concentrated under reduced pressure to give 158 g (99%) of product that crystallized on standing; melting point, 46°-48° C. (from hexane).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:13][CH2:14][C:15]2([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:21][CH2:20][CH:19]=[CH:18][O:17][CH2:16]2)[C:3]1=[O:29].[CH:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][N:13]([CH2:14][C:15]2([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:21][CH2:20][CH:19]=[CH:18][O:17][CH2:16]2)[C:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:37])[C:3]1=[O:29]
Reactant: CN1CCN(C2(CNCc3cc4ccccc4n(C)c3=O)CCC=COC2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Product: CN1CCN(C2(CN(Cc3cc4ccccc4n(C)c3=O)C(=O)C3CCCCC3)CCC=COC2)CC1
Yield: 69.7 %

Procedure:
To a solution of 1-methyl-3-[({[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methyl}amino)methyl]quinolin-2(1H)-one (100 mg, 0.252 mmole) in CH2Cl2 (1.5 ml) was added TEA (0.053 ml, 0.378 mmole) then cyclohexanecarbonyl chloride (0.044 ml, 0.328 mmole). After 2 hr the mixture was concentrated. The crude material was purified by preparative reversed-phase HPLC (30×150 mm Waters Sunfire, 5-50% CH3CN/water containing 0.1% TFA over 20 min at 50 mL/min). Fractions containing the product were pooled and concentrated. The residue was taken up in MeOH then passed through Dowex 1×2-400 ion exchange resin (prewashed with 1M NaOH, H2O, MeOH) washing with MeOH. The filtrate was concentrated to give the title compound as a white solid (89 mg, 70%). 1H-NMR (CDCl3, 500 MHz) d 7.58 (t, J=8.30 Hz, 1 H), 7.52 (d, J=7.57 Hz, 1 H), 7.39 (d, J=8.30 Hz, 1 H), 7.25 (m, 1 H), 7.22 (s, 1 H), 6.21 (d, J=6.34 Hz, 1 H), 5.24 (d, J=19.77 Hz, 1 H), 4.60 (m, 2 H), 4.44 (d, J=13.19 Hz, 1 H), 4.24 (d, J=14.16 Hz, 1 H), 4.05 (d, J=13.18 Hz, 1 H), 3.78 (s, 3 H), 3.07 (d, J=14.16 Hz, 1 H), 2.74 (m, 1 H), 2.62 (m, 2 H), 2.45-2.21 (m, 6 H), 2.26 (s, 3 H), 2.16-2.05 (m, 2 H), 1.82-1.48 (m, 9 H), 1.25-1.06 (m, 3 H). HRMS (M+H)+ calculated 507.3330. found 507.3329.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH3:1][C:2]1([CH3:15])[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([O:13][CH3:14])[CH:9]=2)[NH:6][C:4](=[O:5])[CH2:3]1
Reactant: COc1ccc(NC(=O)C=C(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(C)(C)CC(=O)N2
Yield: 78.3 %

Procedure:
A solution of 3-methyl-N-[4-(methyloxy)phenyl]-2-butenamide (5.8 g, 28 mmol) in dichloromethane (250 mL) was treated with aluminum trichloride (13 g, 97 mmol, Aldrich). The mixture was refluxed for 7 h, cooled, and then poured over ice. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to give 4,4-dimethyl-6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (4.5 g, 77%). 1H NMR (400 MHz, DMSO-d6) δppm 1.20 (s, 6 H), 2.29 (s, 2 H), 3.71 (s, 3 H), 6.72-6.81 (m, 2 H), 6.83 (d, J=2.6 Hz, 1 H), 9.97 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[OH-].[K+:19]>O1CCCC1.CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O-:16])=[O:15])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[K+:19]
Reactant: COC(=O)c1cn(Cc2cccc(Br)n2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1cn(Cc2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 1-[(6-bromopyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (840 mg, 2.83 mmol) in tetrahydrofuran (6.0 mL) and methanol (3.0 mL) was added 1 M aqueous potassium hydroxide (3.11 mL, 3.11 mmol). The solution was stirred at room temperature for 3 h, during which time it became a white slurry. The solvent was evaporated to afford the title salt as a colorless solid that was carried forward without purification. LRMS (APCI) calc'd for C9H8BrN4O2 [M+H]+: 283, Found: 283.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=O)=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:71]1([CH2:76][CH2:77][NH2:78])[CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:34])[C:5]([C:35]([NH:78][CH2:77][CH2:76][N:71]2[CH2:75][CH2:74][CH2:73][CH2:72]2)=[O:37])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 40a) (8 g, 15.76 mmol) in N,N-Dimethylformamide (DMF) (15 mL) was added HATU (8.99 g, 23.64 mmol) and DIPEA (8.26 mL, 47.3 mmol), the resulting mixture was stirred at r.t. for 30 min. 2-(Pyrrolidin-1-yl)ethanamine (2.98 mL, 23.64 mmol) was added and the resulting mixture was stirred at r.t. for 3 h. The mixture was concentrated and the residue was purified by normal phase automatic silica column chromatography (Combiflash RF) eluting with MeOH/DCM (0-20%) to afford 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (6.6 g, 10.93 mmol, 69.4% yield) as a pale yellow solid. LCMS: (M+H)+: 604.5.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[CH3:12][C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([OH:2])[CH:11]=2
Reactant: COc1ccc2cc(C)[nH]c2c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc2ccc(O)cc2[nH]1
Yield: 65.8 %

Procedure:
To a suspension of lithium aluminum hydride (3.7 g, 97 mmol) in 1,4-dioxane (97 mL) was slowly added dropwise a solution of methyl 6-methoxy-1H-indole-2-carboxylate (2.0 g, 9.8 mmol) in 1,4-dioxane (30 mL) under ice-cooling. After dropwise addition, the reaction mixture was heated under reflux for 24 hr. A saturated aqueous sodium sulfate solution was added to the mixture under cooling, magnesium sulfate was added and the insoluble material was filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from hexane to give 6-methoxy-2-methyl-1H-indole (1.0 g, 6.5 mmol) as a yellow solid. To a solution of 6-methoxy-2-methyl-1H-indole (1.0 g, 6.2 mmol) in acetic acid (15 mL) was added 48% aqueous hydrogen bromide (31 mL) at room temperature, and the reaction mixture was heated under reflux for 3 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (600 mg, 65%) as a white solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:38])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:36])(=[O:35])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=3[CH3:34])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:37])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:37][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:38])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:36])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[CH3:34])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3cccc(Cl)c3C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NS(=O)(=O)c1ccc(-c2c(C)c(CC(=O)O)cc3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
Lithium hydroxide monohydrate (0.013 g, 0.3 mmol) was added to a stirred solution of {6-chloro-4-[4-(3-chloro-2-methyl-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.040 g, 0.07 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-4-[4-(3-chloro-2-methyl-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.035 g, 90%) as a solid. 1H NMR (DMSO-d6) δ: 12.49 (br. s, 1H), 9.97 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.41-7.55 (m, 3H), 7.36 (d, J=7.8 Hz, 1H), 7.19 (t, J=8.1 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.97 (s, 1H), 3.86 (s, 2H), 2.07 (d, J=5.9 Hz, 6H). MS calcd. for C26H20Cl2NO4S [(M−H)−] 512, obsd. 512.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]([OH:20])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C)C=O>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:18]([CH2:17][C:16]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:20])[CH2:30][CH2:29]1
Reactant: O=C(O)Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CN1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C(=O)Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4.5 g (15.64 millimols) of 2-(4-chlorophenyl)-imidazo[1,2-a]pyridine-3-acetic acid are added to a suspension of N,N-dimethyl-chloro-methyleneiminium chloride prepared by adding 2.2 g (17.75 millimols) of oxalyl chloride to 30 ml of dimethylformamide (DMF) at -10° C. The suspension is stirred for 15 minutes at 0° C. and a solution of 5.4 g (54 millimols) of 4-methylpiperazine in 10 ml of dry DMF is then added gradually thereto at 0° C. The solution is stirred for 8 hours and then poured into 750 ml of water. The amide is extracted with CH2Cl2, the organic phase is dried over Na2SO4 and concentrated, the residue is passed through a silica column (eluant: CH2Cl2 /CH3OH 9/1) and the compound obtained is recrystallised from an isopropyl ether/acetonitrile mixture. Melting point=175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]1([C:18](=O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCC1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:18]([CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CC1(c2ccccc2)CC(=O)c2cc(Br)ccc2O1
Yield: 24.9 %

Procedure:
A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (64.2 g, 0.3 mol), 1-phenyl-ethanone (46.8 g, 0.39 mol) and pyrrolidine (6 g, 0.084 mol) in toluene (125 mL) was stirred vigorously at room temperature overnight. Then the mixture was refluxed for 6 h. After cooling, the mixture was treated with water (100 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were concentrated and the residue was purified by column to give 6-bromo-2-methyl-2-phenyl-chroman-4-one (23.7 g, 25%). 1H-NMR (CDCl3): 1.74 (s, 3H), 3.06 (d, 1H), 3.31 (d, 1H), 6.95 (d, 1H), 7.20-7.37 (m, 5H), 7.52 (d, 1H), 7.84 (s, 1H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[CH:15]([C:21]([OH:23])=[O:22])[C:16]([CH3:20])([CH2:18]Br)[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C[Si](Cl)(C)C.C(OCC)(=O)C>C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH3:20])[CH2:18][S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
6-(2-phenoxyacetamido)-2-methyl-2-bromomethylpenam-3-carboxylic acid (429 mg.) was suspended in dry benzene (10 cc), and pyridine (400 mg.) and trimethylsilylchloride (5 cc) were added thereto. The mixture was stirred for 1.5 hours at room temperature and pyridine (400 mg.) was added thereto. The mixture was heated under reflux for 3 hours, mixed with ethyl acetate (30 cc), washed with dilute phosphoric acid and further with an aqueous solution saturated with sodium chloride, dried and then concentrated. A small amount of ethyl acetate was added to the residue and the precipitate was collected by filtration to yield crystals (250 mg.) of 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylic acid, m.p. 170.5°-172° C.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([C:29]#[C:30][C:31]([CH3:41])([CH3:40])[CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:10][C:11]=1[N:12]([CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14])=[O:6].F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.O>CN(C=O)C>[CH3:41][C:31]([CH3:40])([CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[C:30]#[C:29][C:9]1[S:8][C:7]([C:5]([OH:4])=[O:6])=[C:11]([N:12]([C:13]([CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:22]2[CH2:23][CH2:24][CH:25]([O:28][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:26][CH2:27]2)[CH:10]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)COC2CCCCO2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)COC3CCCCO3)sc2C(=O)O)C2CCC(Oc3ccccn3)CC2)CC1
Yield: 43.6 %

Procedure:
NaH (45 mg of a 60% oil dispersion, 1.12 mmol) was added in one portion to a solution of 5-[3,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (124 mg, 0.221 mmol) and 2-fluoropyridine (0.095 mL, 1.1 mmol) in dry DMF (2.0 mL). After several minutes, the reaction was placed in a 85° C. oil bath and heated for 4 h. The reaction was cooled, water (0.50 mL) was added and the reaction mixture evaporated to dryness to provide a solid residue. The solid was washed with ethyl ether/hexanes then water, collected by centrifugation and washed with ethyl ether followed by water. The solid was collected and dried under vacuum to provide 5-[3,3-dimethyl-4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid (Compound 311) (60 mg, 42%) as an off-white solid. MS (m/z): 528.3 [M+H-(2-hydroxypyridine)]+; HPLC retention time: 4.61 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11]N)[C:4]=2[O:3]1.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.Cl>C(O)C.O1CCOCC1>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]3[C:17]4[CH2:16][NH:15][CH2:20][CH2:19][C:18]=4[NH:11][C:10]=3[C:4]=2[O:3]1
Reactant: O=C1CCNCC1
Reactant: NNc1cccc2c1OC(F)(F)O2
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: FC1(F)Oc2ccc3c4c([nH]c3c2O1)CCNC4
Temperature: 110 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
The (2,2-difluoro-benzo[1,3]dioxol-4-yl)-hydrazine (753 mg, 4.00 mmol) and 4-piperidone hydrochloride (543 mg, 4.00 mmol) in ethanol (10 mL) were heated to reflux for 45 min. The 4M HCl in dioxane (2 mL) was added and heating continued for 2 h. A sample was removed and after bubbling HCl gas briefly was heated in the microwave to 110° C. for 10 min. The rest of the material was processed in 5 batches and the combined black reactions filtered, washed with a little water and then precipitation with Et2O:Hexane 1:2 (c.f. 10 mL) before drying the resulting grey solid (147 mg, 13% yield)
Reaction SMILES: [CH2:1]1[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH2:4][CH2:3][N:2]1[C:14]1[N:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:27]=[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][N:38]([CH:41]5[CH2:44][O:43][CH2:42]5)[CH2:37][C@@H:36]4[CH3:45])=[CH:31][N:30]=3)[C:25](=[O:46])[N:24]([CH3:47])[CH:23]=2)[C:15]=1[CH:16]=[O:17].[BH4-].[Na+].CO>ClCCl>[CH2:1]1[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH2:4][CH2:3][N:2]1[C:14]1[C:15]([CH2:16][OH:17])=[C:18]([C:22]2[CH:27]=[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][N:38]([CH:41]5[CH2:42][O:43][CH2:44]5)[CH2:37][C@@H:36]4[CH3:45])=[CH:31][N:30]=3)[C:25](=[O:46])[N:24]([CH3:47])[CH:23]=2)[CH:19]=[CH:20][N:21]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4)c3CO)cn(C)c2=O)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10.5 %

Procedure:
A 50-mL single-neck round-bottomed flask was charged with 220b (100 mg, 1.0 eq., 0.15 mmol), NaBH4 (30 mg, 5.0 eq., 0.75 mmol), methanol (5 mL), and dichloromethane (5 mL). The mixture was stirred at 0° C. for 10 min and quenched with water (5 mL). It was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford the title compound (10 mg, 10%). MS-ESI: [M+H]+ 637.5. 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=2.0 Hz, 1H), 8.44 (s, 1H), 8.24 (d, J=5.0 Hz, 1H), 7.82 (d, J=3.0 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.24 (d, J=9.0 Hz, 1H), 6.99 (d, J=5.0 Hz, 1H), 5.55 (s, 1H), 5.36-5.35 (m, 1H), 4.57-4.54 (m, 2H), 4.48-4.40 (m, 6H), 3.92-3.90 (m, 2H), 3.79-3.67 (m, 3H), 3.59 (s, 3H), 3.40-3.37 (m, 2H), 3.09-3.07 (m, 1H), 2.95-2.92 (m, 1H), 2.55-2.51 (m, 2H), 2.38-2.30 (m, 4H), 2.17-2.16 (m, 1H), 1.75-1.74 (m, 2H), 1.68-1.65 (m, 2H), 0.92 (d, J=6.5 Hz, 3H).