Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)CCCCC(O)=O.[CH2:11]([NH2:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:21]([N:30](CCCCCCCCC)[C:31](=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][C:36](N)=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[OH-].[Na+]>O>[CH2:11]([NH:20][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][C:31]([NH:30][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCN(CCCCCCCCC)C(=O)CCCCC(N)=O
Reactant: CCCCCCCCCN
Agent: O=C(O)CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCNC(=O)CCCCC(=O)NCCCCCCCCC
Temperature: 160 °C
Reaction time: 3 h

Procedure:
Into a 1 L flask equipped as described as above in Example 1 were added 350.9 grams (2.4 moles) of adipic acid. This acid was heated to 160° C. with agitation until melted. After all of the adipic acid was melted, there were added 28.6 g (0.2 mole) of nonylamine over a period of about 15 minutes. The reaction mixture was held at 170° C. with agitation for an additional 3 hours under nitrogen. The reaction mixture was then gradually poured into 2 L of hot (70° C.) water, with agitation to dissolve the unreacted adipic acid. The mixture was filtered and the wetcake was washed with hot water to obtain a mixture of monoamido adipic acid and N,N1 -dinonyl adipamide. The wetcake was reslurried in a caustic solution (16 g of 50% sodium hydroxide and 200 g of water) whereby the acid dissolved leaving the insoluble N,N'-dinonyl adipamide as an insoluble which was removed by filtration. After drying overnight at 70° C., the amount of dinonyl amido adipamide was found to be 1.78 g (0.0045 mole). This amount of diamide represents a molar selectivity of 4.5% based upon the amine reactant. The alkaline solution was then acidified with an equivalent of sulfuric acid to precipitate the desired monoamido adipic acid which precipitated and was collected by filtration. After drying in an oven overnight at 70° C., the amount of monoamido adipic acid obtained was found to be 49 g (0.1808 mole) having a purity of 99.9% by HPLC. This amount of monoamido adipic acid represents a molar selectivity of 90% based upon the amine reactant. A sample of the acid was subjected to melting point determination which was found to be in the range of 108° C.-110° C. The filtrate containing dissolved adipic acid was cooled to room temperature, whereupon the adipic acid precipitated and was recovered by filtration. The solid collected from this filtration contained mostly adipic acid and a small amount of monoamido adipic acid. After removal of residual water, the adipic acid, containing small amounts of monoamido adipic acid, was ready to be used as starting material for further reaction with an amine. The filtrate obtained from the recovery of the adipic acid contained about 2% adipic acid and was used as the water source to dissolve further unreacted adipic acid from the next batch in the further production of monoamido adipic acid by the reaction of nonylamine with adipic acid.
Reaction SMILES: C[O:2][C:3]([C:5]([C@H:27]1[CH2:30][C@@H:29]([C:31]([O:33]C)=[O:32])[CH2:28]1)([CH2:9][CH2:10][CH:11]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:18](=[O:26])(=[O:25])[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)C(O)=O)=[O:4].C([N:37](CC)CC)C>C1(C)C=CC=CC=1>[NH2:37][C:5]([C@H:27]1[CH2:30][C@@H:29]([C:31]([OH:33])=[O:32])[CH2:28]1)([CH2:9][CH2:10][CH:11]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:18](=[O:26])(=[O:25])[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:3]([OH:2])=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)C(CCC1c2ccccc2S(=O)(=O)c2ccccc21)(C(=O)O)[C@H]1C[C@@H](C(=O)OC)C1
Solvent: Cc1ccccc1
Product: NC(CCC1c2ccccc2S(=O)(=O)c2ccccc21)(C(=O)O)[C@H]1C[C@@H](C(=O)O)C1
Temperature: 75 °C

Procedure:
A mixture of cis-2-methoxycarbonyl-2-(3-methoxy carbonylcyclobutyl)-4-(10,10-dioxido-9-thioxanthyl)butanoic acid (0.87 g, 1.79 mmol), triethylamine (0.19 g, 1.88 mmol) and diphenyl phosphonic azide (0.33 g, 1.88 mmol) in toluene (30 ml) were heated at 75° C. and worked up following the procedure described in Example 17(iii). The crude product was purified by chromatography on flash silica eluting with diethyl ether-hexane (7:3) to give a colourless oil and then crystallised from diethyl ether to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=1.[CH2:37](I)[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:37][CH3:38])[CH:26]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(NS(C)(=O)=O)c1
Reactant: CCI
Product: CCN(c1cccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3)ccc2C)c1)S(C)(=O)=O
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 61, N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-methanesulphonylaminobenzamide was reacted with ethyl iodide to give the title compound in 64% yield; m.p. 192-193° C.; NMR Spectrum: (DMSOd6) 1.05 (t, 3H), 2.21 (s, 3H), 3.16 (t, 4H), 3.73 (m, 6H), 7.13 (m, 1H), 7.23 (d, 1H), 7.36 (m, 2H), 7.43 (d, 1H), 7.58 (m, 3H), 7.81 (d, 1H), 7.95 (m, 2H), 7.99 (d, 1H), 10.0 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+ 537.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:22][CH:18]4[CH2:19][NH:20][CH2:21][CH:17]4[CH2:16]3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].[OH:27][C@H:28]([CH3:32])[C:29](O)=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:26][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([CH:15]3[CH2:22][CH:18]4[CH2:19][N:20]([C:29](=[O:30])[C@H:28]([OH:27])[CH3:32])[CH2:21][CH:17]4[CH2:16]3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: C[C@@H](O)C(=O)O
Reactant: CN1c2nc(C3CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CC2CC(c3ccc4c(n3)N(C)S(=O)(=O)N4CC3CC3(F)F)CC2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-3-methyl-5-(octahydrocyclopenta[c]-pyrrol-5-yl)-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (25-1, 20 mg, 0.052 mmol, 1.0 equiv), (2R)-2-hydroxypropanoic acid (25-2, 7.0 mg, 0.078 mmol, 1.5 equiv), DIPEA (27 μL, 0.16 mmol, 3.0 equiv) and HATU (29.7 mg, 0.078 mmol, 1.5 equiv) were added to anhydrous acetonitrile (520 μL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 25-3 as a white solid. MS m/z (M+H): calculated=457.1716; observed=457.1726.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[Sn](CCCC)(CCCC)CCCC.[OH-].[Na+]>CN(C)C=O>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:12]2[N:11]([CH3:10])[CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: COc1cccc(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nccn2C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A mixture of 3-iodoanisole (0.6 mL, 5 mmol), 1-methyl-2-(tributylstannyl)-1H-imidazole (Bull. Chem. Soc. Jpn. 1986, 59, 677, 2.5 g, 6 mmol), and dichlorobis(triphenylphosphine)palladoim(II) (421 mg, 0.6 mmol) in N,N-dimethylformamide (10 mL) was stirred at 60° C. for 8 h under nitrogen atmosphere. The reaction mixture was poured into 2 N sodium hydroxide aqueous solution (10 mL) and the basic mixture was extracted with ethyl acetate (30 mL×6). The combined organic extracts were washed with brine (10 mL×2) and dried (sodium sulfate). After removal of solvent, the residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20/1) to afford 724 mg (77%) of the title compound as pale orange oil: 1H-NMR (CDCl3) δ 7.39–7.33 (1H, m), 7.22–7.16 (2H, m), 7.13–7.12 (1H, m), 6.97–6.94 (2H, m), 3.86 (3H, s), 3.76 (3H, s); MS (ESI) m/z 189 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19]C4C=CC=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[CH2:46]([C:48]1[CH:54]=[CH:53][C:51](N)=[CH:50][CH:49]=1)[CH3:47]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][NH:15][C:14]([C:51]4[CH:53]=[CH:54][C:48]([CH2:46][CH3:47])=[CH:49][CH:50]=4)([NH2:19])[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CCc1ccc(N)cc1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CCc1ccc(C2(N)N=C(Nc3ccc4c(c3)OCCO4)C(F)=CN2)cc1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-ethylaniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.87 (bs, 1H), 7.42 (d, 2H, J=8.7 Hz), 7.26 (d, 1H, J=3.0 Hz), 7.13–7.08 (m, 3H), 6.95 (dd, 1H, J=2.4 and 8.7 Hz), 6.82 (d, 1H, J=9.0 Hz), 6.60 (bs, 1H), 4.23 (s, 4H), 2.59 (q, 2H, J=7.5 Hz), 1.20 (t, 3H, J=7.5 Hz); 19F NMR (CDCl3): −47549; LCMS: ret. time: 25.31 min.; purity: 99%; MS (m/e): 367 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[C:5]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=O)=[CH:4][CH:3]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][CH2:10][CH2:11][O:12][CH3:13])[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[N:14][C:5]2=[CH:4][CH:3]=1
Reactant: COCCCNc1nc(Cl)ccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COCCCn1c(C2CCCNC2)nc2ccc(Cl)nc21
Yield: 10 %

Procedure:
Compound 35B (crude material, 2.84 mmol max) prepared in Step 13 was added to a 50 trLL round-bottomed flask equipped for stirring under nitrogen. Glacial acetic acid (10 mL) was then added and the resultant solution was stirred at reflux under nitrogen for 16 hr. The reaction solution was concentrated in-vacuo to give a brownish oil. Toluene (30 mL) was added and the subsequent solution was concentrated in vacuo; this was repeated three times to remove any trace quantities of acetic acid affording the title compound as a brown oil. This oil was then purified by preparative LC/MS (5-50% CH3CN in H2O) to afford 5-chloro-3-(3-methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-b]pyridine (35C) as a tan oil. (088 mmol, 0.122 g, 10% yield over 3-steps). Subsequent analysis of a later derivative of this compound revealed that the chiral center had been epimerized during this reaction sequence. ESI-MS: m/z 309.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:12]=[CH:11][CH:10]=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[C:9]2[N:14]=[C:13]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]3)[CH:12]=[CH:11][CH:10]=2)=[CH:32][CH:31]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3O)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a vial containing the title compound from Example 12 Step B (320 mg, 0.82 mmol) were added 4-bromobenzyl bromide (245 mg, 0.98 mmol), cesium carbonate (533 mg, 1.64 mmol), and DMF (3 mL), and the resulting mixture was stirred at 45° C. After 1 h, the reaction mixture was allowed to cool to ambient temperature, then was loaded directly onto a silica gel column and purified (0 to 30% EtOAc in hexanes, then 30% EtOAc in hexanes) to provide the title compound: LCMS m/z 562.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.77 (d, J=3.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.16 (dd, J=8.0, 3.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 5.06 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.35 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:15])[CH2:13]Br)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:15])[CH2:13][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: FC(=CC1(c2ccc(Cl)cc2)CC1)CBr
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-(p-chlorophenyl)-1-(3-bromo-2-fluoropropenyl)cyclopropane, (Z)—(0.434 g, 1.5 mmol), 4-fluoro-3-phenoxybenzene-boronic acid (0.452 g, 1.95 mmol), potassium carbonate (1.86 g, 13.5 mmol) and bis(dibenzylideneacetone)-palladium(O) (Pd(dba)2, 4.3 mg, 0.075 mmol) in toluene is heated at 80° C. for one hour, cooled to room temperature, diluted with water, and filtered through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extract are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 3:20 methylene chloride/hexanes solution gives the title product as an oil (0.274 g, 63% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[C:10]([F:11])[C:5]=2[NH:4][CH:3]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[C:10]([F:11])[C:5]=2[N:4]([CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)I
Reactant: Fc1cncc2c(Br)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)n1cc(Br)c2cncc(F)c21
Yield: 56 %

Procedure:
Prepared according to the method described for Preparation 45 using 3-bromo-7-fluoro-1H-pyrrolo[3,2-c]pyridine (Preparation 48), 2-iodopropane and potassium carbonate as base. Purified using silica gel column chromatography eluting with 100% heptanes to 50:50 Heptane:EtOAc to afford the title compound (845 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10]CC)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1>N1C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:8](=[O:10])[C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:21]2=[S:22])=[CH:16][CH:15]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCOC(=O)c1ncccc1N
Solvent: c1ccncc1
Product: O=c1c2ncccc2[nH]c(=S)n1-c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 21 h

Procedure:
A mixture of ethyl 3-aminopyridine-2-carboxylate (2.0 g, 12.0 mmol) and 4-fluorophenylisothiocyanate (1.84 g, 12.0 mmol) in 7 mL of anhydrous pyridine is stirred at 45° C. for 21 h. After cooling, the pyridine is evaporated in vacuo, and ice water is added to the residue. The resulting mixture is slurried in EtOAc and filtered to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (1H, m), 7.79 (2H, m), 7.33 (4H, m).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:57][S:58]([N:61]1[CH2:66][CH2:65][N:64]([CH2:67][CH2:68][CH2:69]O)[CH2:63][CH2:62]1)(=[O:60])=[O:59]>CN(C=O)C.C(Cl)Cl>[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:36][CH2:69][CH2:68][CH2:67][N:64]4[CH2:65][CH2:66][N:61]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:62][CH2:63]4)=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2
Reactant: CS(=O)(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Under nitrogen, diethyl azodicarboxylate (0.19 ml, 1.2 mmol) was added dropwise to a suspension of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), triphenylphosphine (0.31 g, 1.2 mmol) and 3-(4-methylsulfonylpiperazin-1-yl)propan-1-ol (0.2 g, 0.9 mmol) in DMF (4 ml). The mixture was stirred for 2 hours at ambient temperature. Methylene chloride was added and the mixture was poured onto silica and eluted with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/4) followed by methanol/methylene chloride (1/9). The fractions containing the expected product were combined and evaporated. The residue was triturated with diethyl ether and filtered. The solid was washed with ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylsulfonylpiperazin-1-yl)propoxy)cinnoline (90 mg, 28%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)=[CH:8][C:7]=1[F:33])=[O:5])C.O.[OH-].[Li+].Cl>C(O)C.O>[C:4]([C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)=[CH:8][C:7]=1[F:33])([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C(=O)O)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a solution of tert-butyl 4-[2-(4-ethoxycarbonyl-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 9) (60 mg, 0.131 mmol) in ethanol (0.9 mL)-water (0.2 mL) was added lithium hydroxide monohydrate (16 mg, 0.393 mmol). The mixture was stirred at room temperature overnight, diluted with water, neutralized by the addition of 1N hydrochloric acid and then extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a white crystal (57 mg, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[NH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:29])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reaction time: 18 h
Yield: 101.2 %

Procedure:
In a mixture of 3.0 g of concentrated ammonia water and 15 ml of tetrahydrofuran, a solution of 3.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl chloride in 20 ml of tetrahydrofuran was added dropwise, after the completion of the addition, continued to stir further for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate, washed with 50 ml of water, dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 2.9 g of the aimed product as orange crystal.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:15]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:25]([NH:29][NH2:30])(=O)[CH2:26][CH3:27]>C(O)C>[C:1]([NH:4][C:5]1[C:15]2[N:14]3[C:25]([CH2:26][CH3:27])=[N:29][N:30]=[C:13]3[CH2:12][N:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1NC(=S)CN=C2c1ccc(C#N)cc1
Reactant: CCC(=O)NN
Solvent: CCO
Product: CCc1nnc2n1-c1c(NC(C)=O)cccc1C(c1ccc(C#N)cc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 9-acetylamino-1,3-dihydro-5-(p-cyanophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with propionic acid hydrazide and the resulting product heated to 250° C. to give 10-(acetylamino)-1-ethyl-6-(p-cyanophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[C:3](=[NH:7])[O:4]CC.C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26]>O1CCCC1>[F:17][C:14]([F:15])([F:16])[C:10]1[CH:9]=[C:8]([CH:2]2[O:1][C:25](=[O:26])[NH:4][C:3]2=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=N)C(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cccc(C(F)(F)F)c2)O1
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Ethyl 1-hydroxy-1-(3-trifluoromethylphenyl)methane carboximidate (9.5 g., 0.038 mole) was dissolved in 500 ml. of tetrahydrofuran and cooled to 0°-5° C. Triethylamine (7.68 g., 0.076 mole) was added and the solution perfused with phosgene for 35 minutes at 0°-5° C. After stirring for 1.5 hours, isolation and recrystallization according to Example 3 gave 5-(3-trifluoromethylphenyl)-oxazolidine-2,4-dione (6.4 g., 69%, m.p. 93°-96° C.). A second recrystallization from toluene gave purified product (4.9 g., 53% over-all; m.p. 97°-99° C., m/e 245).