Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)(=[O:20])=[O:19])=[CH:14][C:13]=1[F:30])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:35]([C:33]1[CH:32]=[CH:31][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)(=[O:20])=[O:19])=[CH:14][C:13]=2[F:30])=[C:9]([OH:8])[CH:34]=1)[CH3:36]
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)NCCCn3ccnc3)cc2F)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NCCCn3ccnc3)cc2F)c(O)c1
Yield: 42.3 %

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benzenesulfonamide (160 mg; 0.31 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (55 mg; 42%) was obtained as a clear oil, after purification via preparative TLC (dichloromethane/methanol/triethylamine)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccncc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccncc3)c3ccccc3nc21
Yield: 34.5 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-(aminomethyl)pyridine (0.92 ml, 9 mmol) was heated at 80°-90° C. overnight. The reaction mixture was poured into water (200 ml)NH4OH (1 ml) and the mixture was extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers were combined, dried over MgSO4 and evaporated. The residue was crystallized from ethyl acetate and recrystallized from ethyl acetate to afford 450 mg of 1-ethyl-N-(4-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 191°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7]([NH:9][CH2:10][CH2:11][O:12][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCO
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)NCCOc1ccc(C=O)cc1

Procedure:
A mixture of 2-(N-(5-chloro-2-methoxybenzoyl)amino)ethanol (4.5 g), potassium carbonate (5 g) and 4-fluorobenzaldehyde (2.5 g, 2.16 ml) were heated at 100° C. in dry dimethylsulphoxide (50 ml) for 18 hours. The mixture was cooled, diluted with water and extracted with diethyl ether containing a little methanol. The organic layers were combined, dried (MgSO4) and evaporated. The residual oil was chromatographed on silica gel with 2% methanol in dichloromethane as solvent to afford the title compound as an oil.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10](Br)[CH2:11][CH2:12][CH2:13]Br)=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:28](=[O:29])[CH2:27][N:26]([CH3:30])[C:25]2=[O:31])[CH:20]=[C:21]([Cl:23])[CH:22]=1.O>CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:11][CH2:12][CH2:13][C@:27]32[N:26]([CH3:30])[C:25](=[O:31])[N:24]([C:19]2[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[CH:20]=2)[C:28]3=[O:29])=[CH:6][CH:5]=1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: BrCCCC(Br)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1
Reaction time: 30 h
Yield: 110.8 %

Procedure:
KOH flakes (1.3 g, 23.2 mmol) were added at RT to a solution of 1-bromo-4-(1,4-dibromobutyl)benzene (4.08 g, 10.6 mmol) (Preparation 4) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (2.5 g, 9.6 mmol, prepared according to Fujinami et al. cited above) in dry DMSO (40 ml). After 30 h at RT, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to yield an orange oil (4.98 g) which was chromatographed over silica gel (DCM/pentane 50/50) to give 6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (2.1 g) as a white solid having the relative stereochemistry depicted above. 1H NMR (CDCl3): 7.45 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.03 (2H, d, J=8.4 Hz), 6.65 (2H, m), 3.36 (1H, dd, J1=12.9 Hz, J2=6.2 Hz), 3.13 (3H, s), 2.4-2.65 (1H, m), 1.8-2.4 (5H, m).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[CH2:9][C:10]1[O:14][C:13]([C:15]2[N:16]=[CH:17][N:18]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22](=[O:29])[N:21]4[CH2:30][CH2:31][C@H:20]4[C:19]=23)=[N:12][N:11]=1>CN(C)C=O>[CH2:1]([N:4]([CH2:9][C:10]1[O:14][C:13]([C:15]2[N:16]=[CH:17][N:18]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22](=[O:29])[N:21]4[CH2:30][CH2:31][C@H:20]4[C:19]=23)=[N:12][N:11]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCNCCC
Reactant: O=C1c2ccccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
0.94 ml (73 mmol) of dipropylamine was added to a solution of 1.17 g (3.42 mmol) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 10 ml of dimethylformamide, whereupon the mixture was stirred at room temperature for 12 hours. The dimethylformamide was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 95:5) yielded 0.900 g (65%) of (S)-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]benzodiazepin-9-one as a colourless foam, Rf=0.46 (silica gel, methylene chloride/methanol 95:5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[N:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cnccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccncc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3cccnc3)noc2C)nc1
Product: Cc1onc(-c2cccnc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 83 %

Procedure:
As described for example 155, 6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (130 mg, 0.4 mmol), was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (112 mg, 83%) which was obtained as an off white solid. MS: m/e=353.0 [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][C:21]1[CH:22]=[C:23]([C:28]2[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([C:28]2[C:29]([C:34]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1C
Product: Cc1ccc(-c2ccccc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1C

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3′,4′-Dimethyl-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.40 min; [M+H]+=485.2.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[C:23]([NH:31][NH2:32])(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:31][N:32]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccccc5)[nH]4)cc23)cc1
Yield: 47.7 %

Procedure:
The procedure described in example 119 using ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylainine (0.25 mL, 1.86 mmol) and benzoic hydrazide (170 mg, 1.25 mmol) was followed to yield the title compound (105 mg, 48% yield). 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.74 (s, 1H), 8.0–8.2 (m, 5H), 7.75 (d, 1H), 7.35–7.6 (m, 5H), ES-MS (m/z) 356 [M+1]+.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[O:19][CH3:20]>C1COCC1.[OH-].[Na+]>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of benzyl chloride (24.6 ml, 209 mmol, 1.1 eq.) in THF (100 ml) was added dropwise at 0° C. over 15 min, to a mechanically stirred solution of 4-hydroxy-3-methoxybenzoic acid (vanillic acid, 1) (30 g, 179 mmol) in THF (90 ml) and 2.0 M aq. NaOH (225 ml). The mixture was allowed to warm to room temperature and then heated under reflux for 48 hours. After cooling, the mixture was washed with hexane (2×100 ml) and the THF was removed in vacuo. The remaining aqueous phase was acidified to pH 1 with conc. HCl. The resulting precipitate was collected by filtration, washed with water and dried to afford 4-benzyloxy-3-methoxybenzoic acid (2) as a pale amorphous solid.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH2:6]([O:13][C:14](=[O:28])[CH:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([OH:19])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14](=[O:28])[CH:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)C(=O)OCc1ccccc1
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)CC(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
This compound was prepared by a method analogous to that of Example 3-part (d) from N,O-Dimethylhydroxylamine hydrochloride and 2-tert-Butoxycarbonylamino-succinic acid 1-benzyl ester.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:20]=[CH2:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C12BC(CCC1)CCC2.[OH-:42].[Na+].OO>C1COCC1>[CH2:26]([O:25][C:23]([NH:22][C@@H:18]([C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:19][CH2:20][CH2:21][OH:42])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [OH-]
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4R)-4-(4,5-diphenyloxazol-2-yl)-4-benzyloxycarbonylamino-1-butene (5.2 g) in THF (50 ml) was added 9-borabicyclo(3.3.1]nonane (9-BBN) (98 ml, 0.5M solution of THF) at 0° C. After stirred for 4 hours at room temperature, 2N NaOH solution (20 ml) and 35% H2O2 solution (20 ml) were added to the mixture at the 0° C. The mixture was stirred for 1 hour at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatogaphy on silica gel to give (1R)-N-benzyloxycarbonyl-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (13 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 2-methyl-4-nitroaniline (2.03 g, 13.3 mmol), triethylamine (2.00 ml, 14.6 mmol) and benzoyl chloride (1.70 ml, 14.6 mmol) were heated in toluene (50 ml) at reflux for 2 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature overnight, causing precipitation of a white solid. The solid was collected by suction filtration, washed with toluene (3×50 ml), dissolved in dichloromethane (100 ml) and washed with water (3×50 ml). Drying of the organic layer over magnesium sulphate, followed by solvent evaporation in vacuo, yielded N-benzoyl 2-methyl-4-nitroaniline (3.06 g, 90% yield) as a white solid:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N+:16](/[CH:19]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(Oc2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A mixture of 4-(pyridin-2-yloxy)-benzaldehyde (9.3 g, 47 mmol) described in Manufacturing Example 209-1-1, nitromethane (14 g, 230 mmol), ammonium acetate (11 g, 140 mmol), and acetic acid (50 mL) was stirred for 1 hour and 30 minutes at 100° C. This mixture was cooled to room temperature, and water was added to precipitate a solid. The solid was filtered to obtain the title compound (9.9 g, 87%).
Reaction SMILES: C(OCC)C.Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[CH2:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)[CH2:19][CH2:20][CH3:21]>O>[CH2:7]([O:14][NH:15][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=1)=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCc1ccc(NC(=O)NOCc2ccccc2)cc1
Yield: 82.1 %

Procedure:
Diethyl ether (10 mL) was added to a suspension of O-benzylhydroxylamine hydrochloride (0.82 g, 5.1 mmol) in water (1 mL). A solution of sodium hydroxide (0.23 g, 5.8 mmol) in water (1 mL) was added and the mixture was stirred for several minutes. The aqueous layer was removed by pipette and extracted with diethyl ether (3 mL). The ether extract was added to the reaction flask. 4-Butylphenyl isocyanate (0.90 g, 5.1 mole) was added to the reaction flask via pipette in a single portion. A mild reflux occurred. The reaction mixture was allowed to stir at ambient temperature for 15 minutes then purified by flash chromatography (silica gel; 1:4 ethyl acetate:hexanes) to provide 1.25 g of 1-benzyloxy-3-(4-butylphenyl)urea as a fluffy white solid, m.p. 90.6°-91.4° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[Cl:19][CH2:20][C:21]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:22]=1[CH:23]([OH:27])[C:24](Cl)=[O:25]>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH:14][C:24](=[O:25])[CH:23]([C:22]2[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:21]=2[CH2:20][Cl:19])[OH:27])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(O)C(=O)Cl)c(CCl)c1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(COC(C)=O)CSC23)c(CCl)c1

Procedure:
A mixture of 1 g of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1.2 g of 2-chloromethyl-4-methoxymandelic acid chloride in 200 ml of ethyl acetate is refluxed for 50 minutes after which the solvent is removed under high vacuum. The resulting product is chromatographed on silica gel using benzene-actone as the eluant. The product obtained is triturated with ether to give 3-[(acetyloxy)methyl]-7-[[2-[2-(chloromethyl)-4-methoxyphenyl]-2-hydroxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 140°-142°C (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH:19]([S:20]([NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])(=[O:22])=[O:21])=[CH2:18]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cold (−10° C.) stirred solution of glycine tert-butyl ester (3.0 g, 22.9 mmol) and triethylamine (7.1 mL, 50.9 mmol) in dichloromethane (150 mL), 2-chloro-ethanesulfonyl chloride (2.4 m/L, 23 mmol) in dichloromethane (10 mL) was added over a period of 15 minutes. The resulting mixture was stirred at 0° C. for 8 hours, and at room temperature overnight. The product mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluted with 40-50% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided tert-butyl N-(ethenesulfonyl)glycinate.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1F>C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1[N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccccc3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 105 h
Yield: 96.33 %

Procedure:
50 ml of ethyl acetate, 13.5 ml of 4-phenyl piperazine, and 15.30 ml of diisopropyl ethyl amine were added into a 250 ml triple-neck flask. After magnetic stirring at room temperature, 9.0 ml of 3,4-difluoro-nitrobenzene was added. The reaction was carried out for 105 hours, followed by extraction with 150 ml of ethyl acetate for three times (150 ml×3). The extract was washed three times with saturated NaCl solution (150 ml×3), dried with anhydrous magnesium sulfate (MgSO4), and evaporated to dryness. An orange yellow solid was obtained which was recrystallized with a mixture of acetone and water in volumetric ratio of 9:1 to produce orange yellow crystals (23.66 g) with a yield of 96.33%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.O[CH2:43][C:44]1[CH:45]=[C:46]([CH:59]=[CH:60][CH:61]=1)[CH2:47][C:48]12[CH:58]=[CH:57][CH:56]=[CH:55][CH:49]1[C:50]([NH:52][C:53]2=[O:54])=[O:51]>C1COCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:43][C:44]2[CH:45]=[C:46]([CH:59]=[CH:60][CH:61]=2)[CH2:47][C:48]23[CH:58]=[CH:57][CH:56]=[CH:55][CH:49]2[C:50]([NH:52][C:53]3=[O:54])=[O:51])=[CH:37][CH:36]=1
Reactant: O=C1NC(=O)C2(Cc3cccc(CO)c3)C=CC=CC12
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C2(Cc3cccc(COc4ccc(Cl)cc4)c3)C=CC=CC12
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (280 mg, 1.07 mmol) was dissolved in dry THF (2 mL) under an atmosphere of argon. After cooling to −40° C., DIAD (0.21 mL, 1.07 mmol) was added and the mixture was stirred at −40° C. for 10 min. A solution of 4-chlorophenol (138 mg g, 1.07 mmol) and 2-(3-hydroxymethylbenzyl)-phthalimide (261 mg, 0.98 mmol) in dry THF (3 mL) was added dropwise. After addition, the cooling bath was removed and stirring was continued for 2 h. The solution was diluted with Et2O (40 mL) and washed with pH-7-phosphate buffer solution (1×20 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (EtOAc/hexane 1:5) to give the title compound.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[C@H:27]([F:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[C:29]([O-])([O-])=O.[Na+].[Na+].C(O)=O.C=O>C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[C@H:27]([F:28])[CH2:26][CH2:25][N:24]([CH3:29])[CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: F[C@@H]1CCNCC[C@H]1Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: CN1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A mixture of Stereoisomers 1 and 2 of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoroazepan-4-yloxy)quinoline (0.023 g, 0.0511 mmol) was slurried in CH2Cl2 (3 mL). A saturated aqueous Na2CO3 solution (5 mL) was added and the mixture was stirred at ambient temperature for 0.5 hours. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The crude residue was treated with formic acid (0.289 mL, 7.66 mmol) and formaldehyde (0.0380 mL, 0.511 mmol). The mixture was stirred at 90° C. for 4 hours. The mixture was cooled to ambient temperature and carefully treated with a saturated aqueous Na2CO3 solution to adjust the mixture to about pH 11. The mixture was extracted with CHCl3 and the combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by Preparative TLC (0.5 mm, 10% MeOH/CH2Cl2 with 1% 7N NH3/MeOH) to provide the desired product (0.011 g, 55%) as a white solid. MS ESI (+) m/z 392.1 (M+1) detected.