Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-(4-fluorobenzoyl)benzyl bromide (2.93 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as white powder (2.79 g, 74%). 1H-NMR (CDCl3) δ: 3.41(3H,s), 3.60(3H,s), 5.59(2H,s), 7.08-7.86(9H,m).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.NO.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CO.ClCCl>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N=C(c3ccccc3)c3ccccc3)c2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Using a method similar to preparation 28, using 4-(3-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 14, 5.01 g, 14.07 mmol) gives 6.42 g of the corresponding 4-[3-(benzhydrylidene-amino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester. Add sequentially sodium acetate (anhydrous, 2.77 g, 33.78 mmol) and hydroxylamine hydrochloride (1.76 g, 25.33 mmol) to a stirred solution of 4-[3-(benzhydrylidene-amino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (6.42 g, 14.07 mmol) in methanol (anhydrous, 140 mL) and stir at ambient room temperature. After 1 hr., dilute with dichloromethane (40 mL) and wash with sodium hydroxide (aq. 0.1 N, 60 mL), extract with dichloromethane (2×60 mL), dry over magnesium sulfate, filter under reduced vacuum and concentrate to dryness. Purify by flash chromatography (20-60% ethyl acetate/hexanes) to give the title compound as a pale yellow solid (3.85 g, 93%, 2 steps). Mass spectrum (ion spray): m/z=237.1 (M+1); 1H NMR (CDCl3): 7.04 (t, J=8.0 Hz, 1H), 6.34-6.26 (m, 3H), 4.41 (septet, J=3.5 Hz, 1H), 3.72-3.64 (m, 2H), 3.32 (ddd, J=3.9 Hz, 7.7 Hz, 13.2 Hz, 2H), 1.93-1.84 (m, 2H), 1.77-1.68 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13].Cl.C([O:19][N:20]=O)CCC>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:20][OH:19])[C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CCCCON=O
Reactant: COc1cc2c(cc1F)C(=O)CC2
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1F)C(=O)C(=NO)C2
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 6-Fluoro-5-methoxy-indan-1-one (4.8 g) in 65 ml of MeOH was added 2.7 ml of concentrated HCl, then a solution of n-butylnitrite (3.47 ml) at room temperature. The resulting mixture was stirred for 2 hrs, the precipitate was collected and dried to yield the product as a white solid (3.9 g, 70% yield). LC-MS: m/e 210 (MH+)
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:29])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][C:17]=2[Cl:28])[CH2:7][CH2:6][CH2:5]1)#[N:2].[Cl-].[NH4+].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[NH:32]1[C:1]([CH2:3][CH:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]([C:15](=[O:29])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][C:17]=3[Cl:28])[CH2:7][CH2:6][CH2:5]2)=[N:2][N:34]=[N:33]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC1CCCN(C(=O)c2ccc(-c3ccccc3)cc2Cl)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccc2)cc1Cl)N1CCCC(Cc2nnn[nH]2)c2ccccc21
Temperature: 115 °C
Yield: 81.3 %

Procedure:
5-Cyanomethyl-1-(4-phenyl-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1 g), ammonium chloride (0.4 g) and sodium azide (0.48 g) are suspended in dimethylformamide (10 ml), and the mixture is heated at 110-120° C. for 16 hours. To the mixture are added ammonium chloride (0.4 g) and sodium azide (0.48 g), and the mixture is heated for 16 hours. The mixture is evaporated to remove dimethylformamide, and the resultant is acidified with a 1N hydrochloric acid. The mixture is extracted with chloroform, and the organic layer is washed with water, dried over magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography (solvent; dichloromethane→dichloromethane:methanol=20:1), and the resulting oily product is crystallized from diethyl ether to give 5-(5-tetrazolyl)methyl-1-(4-phenyl-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.9 g) as white powder.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[N:7]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[N:2]1([O:1][C:13]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[O:14])[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: On1cccn1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(On1cccn1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxypyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (94%, crystals).
Reaction SMILES: [OH-].[K+:2].[C:3]([OH:15])(=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:13]=[CH:12][C:10]([OH:11])=[C:8](O)[CH:7]=1>>[OH:11][C:10]1[CH:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([O-:15])=[O:14])=[CH:13][CH:12]=1.[K+:2]
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: [K+]
Agent: [OH-]
Product: O=C([O-])C=Cc1ccc(O)cc1

Procedure:
To 15 mL of a 0.002 mM aqueous solution of potassium hydroxide was slowly added 5 g coumaric acid 190 (30 mmol) with mixing at 60-70° C. The resulting potassium coumarate (200) was dried under vacuum at 30-40° C.
Reaction SMILES: C1(S)C=CC=CC=1.[N:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]4[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]4)=[CH:25][CH:24]=3)=[C:19]([O:41]C)[CH:18]=2)[N:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=12.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[N:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[N:27][C:26]([N:29]([CH3:40])[CH:30]4[CH2:35][C:34]([CH3:36])([CH3:37])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]4)=[CH:25][CH:24]=3)=[C:19]([OH:41])[CH:18]=2)[N:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=12
Reactant: COc1cc(-c2cnc3cnccn23)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(c1ccc(-c2ccc(-c3cnc4cnccn34)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 17.5 %

Procedure:
Following GENERAL METHOD 3-1 for methoxy deprotection using thiophenol, 6-(4-(imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (49 mg, 0.1 mmol) was treated with thiophenol (0.01 mL, 0.12 mmol) and K2CO3 (14 mg, 0.11 mmol) in NMP (2 mL) for 30 minutes at 190° C. to afford 5-(imidazo[1,2-a]pyrazin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (8 mg). MS: 458.4 [M+H+]; LCMS Rt=0.47 min [Method Q]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.16 (s, 1H), 8.41 (d, J=5.05 Hz, 1H), 7.92-7.97 (m, 2H), 7.88 (d, J=10.11 Hz, 1H), 7.75 (d, J=8.08 Hz, 1H), 7.31 (s, 1H), 7.13 (s, 1H), 7.05 (d, J=9.60 Hz, 1H), 4.99 (br. s., 1H), 3.05 (s, 3H), 1.72 (d, J=12.13 Hz, 2H), 1.46 (t, J=12.38 Hz, 2H), 1.39 (s, 6H), 1.23 (s, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[NH2:7])([CH3:3])[CH3:2].O[CH2:14][CH:15]([CH2:17]O)O.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[C:6]2[C:8]([CH:14]=[CH:15][CH:17]=[N:7]2)=[CH:9][C:10]=1[O:11][CH3:12])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1C(C)C
Reactant: OCC(O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2cccnc2cc1C(C)C
Temperature: 100 °C
Yield: 54.3 %

Procedure:
A mixture of 3-isopropyl-4-methoxyaniline (4.22 g, 23.6 mmol), 5.87 g (63.7 mmole) of glycerol and 3.25 g (14 mmol) of As2O5 was heated to 100° C. with stirring At 100° C., 4.0 mL of concentrated H2SO4 was added dropwise. The mixture was heated at 150-160° C. for six hours, then cooled to 80° C., and 20 mL water was added, followed by aqueous saturated NaHCO3 until the mixture reached pH7-8. The mixture was diluted with 100 mL of water and 300 mL of ethyl acetate and the solution mixture was decanted from insolubles. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography with silica eluting with 20% ethyl acetate in hexanes to give 2.58 g of 7-isopropyl-6-methoxyquinoline, together with 0.65 g of 6-hydroxy-7-isopropylquinoline as a minority product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.O.CN(C)[CH:32]=[O:33]>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:32]([OH:33])=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)cc23)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2coc3ccc(-c4nnc(O)o4)cc23)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-[4-(methylthio)phenyl]-1-benzofuran-5-carbohydrazide (0.25 g, 0.83 mmol) and triethylamine (0.17 mL, 1.25 mmol) in N,N-dimethylformamide (5 mL) was added N,N′-carbonyldiimidazole (0.27 g, 1.68 mmol) at 0° C., and the resulting mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (0.20 g, yield 74%) as colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[C:21]([CH:23]4[CH2:25][CH:24]4[C:26]([OH:29])([CH3:28])[CH3:27])[N:20]([CH3:30])[C:19]=3[CH:31]=2)[C:11](=[O:32])[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[C:21]([CH:23]4[CH2:25][CH:24]4[C:26]([OH:29])([CH3:27])[CH3:28])[N:20]([CH3:30])[C:19]=3[CH:31]=2)[C:11](=[O:32])[CH:10]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
A mixture of 4-(benzyloxy)-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (1.35 g), 10% Pd/C (0.6 g) and MeOH (30 ml) was stirred under H2 atmosphere at room temperature for 3 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (950 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][OH:11])[O:7]2)[O:3]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.O>[OH:12][CH:5]1[CH:4]2[CH:8]([O:9][C:2]([CH3:13])([CH3:1])[O:3]2)[O:7][CH:6]1[CH2:10][O:11][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)O[C@H]2O[C@H](CO)[C@H](O)[C@H]2O1
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC2OC(COC(=O)c3ccccc3)C(O)C2O1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
1,2-O-Isopropylidene-α-D-xylofuranose (Aldrich, 20 g, 100 mmol) in CH2Cl2 (300 mL) and TEA (44 mL, 310 mmol) was cooled to 0° C. The solution was treated with benzoyl chloride (12.8 mL, 110 mmol) in CH2Cl2 (10 mL) dropwise and stirred for 2 h. The solution was diluted with H2O (30 mL) and washed with saturated NaHCO3 (2×30 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was treated to flash column chromatography (SiO2, 4×20 cm, 0-100% EtOAc-hexanes gradient) to afford compound 9.2 (22.0 g, 71% yield). (Taken from: Johnson, C. R.; Bhumralkar, D. R. Nucleosides & Nucleotides 1995, 14, 185.)
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]=[CH2:14])=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16].[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C1(C)C=CC=CC=1>[CH3:17][C:2]([CH3:1])([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:14][C@H:21]3[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][CH:11]=2)[N:6]([CH3:15])[C:5]1=[O:16]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 100 °C

Procedure:
1-(2,2-Dimethylpropyl)-5-ethenyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31-2, 636.4 mg, 2.6 mmol, 1.0 equiv) was added to anhydrous toluene (5.5 mL). Ethyl diazoacetate (807 μL, 7.8 mmol, 3.0 equiv) was added and the resulting solution was heated to 100° C. for 18 h. Following this duration, LCMS showed complete consumption of 31-2. The reaction mixture was diluted with ethyl acetate (50 mL) and saturated NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. Purification by normal-phase HPLC (0-40% EtOAc:hexanes) provided 31-3 as a white solid. MS m/z (M+H): calculated=332.1969; observed=332.1971.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[CH2:20]([NH2:26])[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[O:25]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][NH:26][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:3]
Reactant: NCC1CCCO1
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: O=C(NCC1CCCO1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline to afford the urea.
Reaction SMILES: [C:1]([C:3](=[C:9]([CH3:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CCOCC>[C:1]([CH:3]([C:9]([CH3:10])([CH3:11])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC(=O)C(C#N)=C(C)C
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C(C)(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a solution of ethyl 2-cyano-3-methylbut-2-enoate (0.91 mL, 6 mmol) in ether (4 mL) under N2 was added 1.0 M benzylmagnesium chloride in ether (9 mL, 9 mmol) dropwise to give a pale yellow solution. The reaction was stirred at room temperature for 3 h, and was then cooled to 0° C. and acidified with 10% HCl (10 mL). The organic layer was isolated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give bright yellow oil. Purification by flash column chromatography (10% ethyl acetate in hexanes, Rf=0.26) gave the title compound as a pale yellow oil (1.08 g, 73.5%). 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.22 (d, J=7.6 Hz, 2H), 4.22 (m, 2H), 3.44 (s, 1H), 3.07 (d, J=16.5 Hz, 1H), 2.83 (d, J=16.5 Hz, 1H), 1.28 (t, J=7.1 Hz, 2H), 1.18 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[C:15]([CH2:18][OH:19])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O1CCCC1.C(O)C.[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:20]([O:22][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)=CS[C@H]12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)CS[C@H]12
Yield: 56.4 %

Procedure:
A suspension of 10% palladium-carbon (30 g.) in acetic acid (300 ml.) was added to a solution of diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethyl-2-cephem-4-carboxylate (30.0 g.) in tetrahydrofuran (500 ml.) and ethanol (100 ml.), and the mixture was subjected to catalytic reduction under hydrogen pressure of 10 kg/cm2 at 50°-55° C. for 4 hours. After removing the insoluble substance from the resultant mixture by filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate (500 ml.) was added to a residue and adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (17 g.).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[S:18]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:20])(=[O:19])[CH3:17]
Reactant: CC(C)OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OCCOS(C)(=O)=O
Reaction time: 2 h

Procedure:
Combine 2-isopropoxyethanol (1.0 g, 9.6 mmol), N,N-diisopropylethylamine (2.73 g, 21.12 mmol), and dichloromethane (20 mL). Cool in an ice bath. Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extract with 1 M hydrochloric acid solution, a saturated solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(isopropoxy)ethyl mesylate: bp; 84° C. at 0.1 mm Hg.
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9](=O)[CH2:10][N:11]1[C:24]2[CH:23]=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1.Cl.CO>[CH2:1]([N:8]([CH2:9][CH2:10][N:11]1[C:24]2[CH:23]=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)CN1c2ccccc2Sc2ccc(Cl)cc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCN1c2ccccc2Sc2ccc(Cl)cc21)Cc1ccccc1
Reaction time: 0.5 h
Yield: 118.3 %

Procedure:
N-Benzyl-2-(2-chlorophenothiazin-10-yl)-N-methylacetamide (140 mg, 0.355 mmol) was dissolved in THF (5 mL). A solution of borane.THF complex in THF (1.0 M, 5 mL, 5 mmol) was added, and the solution heated to reflux for 4 h. The mixture was carefully diluted with saturated HCl in methanol and stirred for 30 min. The solvent was removed under vacuum, and the residue dissolved in ethyl acetate and aqueous sodium hydroxide (1 N). The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to provide benzyl-[2-(2-chlorophenothiazin-10-yl)-ethyl]methyl amine as a white solid (160 mg). The crude product was purified by SiO2 chromatography to provide pure product (50 mg, 34%) and 100 mg of impure product. The pure product was dissolved in acetone and a solution of fumaric acid (0.8 mL, 0.02 g/mL in methanol) was added. The solvents were removed under vacuum, and the residue slurried in chloroform and filtered to provide the sub-titled compound (47 mg) as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20]>CN(C=O)C>[Br:17][C:18]([F:25])([F:24])[C:19]([NH:1][CH2:2][C:3]1([OH:16])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1)=[O:20]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CNC(=O)C(F)(F)Br)CC1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (1.702 g) in DMF (20 mL) at 20° C. was treated with ethyl 2-bromo-2,2-difluoroacetate (1.5 g) and the mixture stirred for 90 minutes at 20° C. under nitrogen. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 2.5 g.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[CH2:27]([C:29]1[CH:30]=[C:31]([CH2:35]O)[CH:32]=[CH:33][CH:34]=1)[CH3:28]>C(Cl)Cl>[Br:1][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:27][CH3:28])[CH:30]=1
Reactant: CCc1cccc(CO)c1
Reactant: BrBr
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
Bromine (0.21 mL, 4.08 mmol) was added dropwise to a solution of triphenylphosphine (1.08 g, 4.12 mmol) and imidazole (280 mg, 4.11 mmol) in CH2Cl2 (13.5 mL) at 0° C. The mixture was allowed to warm to room temperature and then a solution of (3-ethylphenyl)methanol (˜3.05 mmol) in CH2Cl2 (3.5 mL) was added. After 1 h, the mixture was diluted with hexanes and filtered through celite, washing with excess hexanes. The filtrate was concentrated in vacuo. Purification of the crude residue by chromatography on silica gel (hexanes→10% EtOAc/hexanes, gradient) afforded 530 mg (87% over two steps) of 1-(bromomethyl)-3-ethylbenzene.
Reaction SMILES: O.C1O[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4]C1.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(C(O)=O)(F)(F)F>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:12]=1
Reactant: c1cncc(C2CCC3(CC2)OCCO3)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.2 %

Procedure:
Water (1 mL) was added to a cod solution of 4-(3-pyridyl)cyclohexanone ethylene acetal (4.79 g, 21.9 mmol) in CF3CO2H (20 mL). After stirring room temperature for 6 h, the reaction mixture was added dropwise to sat. NaHCO3. aq. The resulting mixture was adjusted to pH 8 with 2M NaOH aq. and extracted with CH2Cl2, After drying and consentration, the crude product was purified by column chromatography (Hexane/EtOAc=1/1→0/1) to yield 4-(3-pyridyl)cyclohexanone (3.23 g, 84%) as a colorless powder.