Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:36])[CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.O.NN>C(O)C>[NH2:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:37])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:36]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 99.3 %

Procedure:
A mixture of 8-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-2-methylquinoline (3.98 g), hydrazine monohydrate (0.72 ml) and ethanol (40 ml) was heated under reflux for 1 hour. The precipitate was removed by vacuum filtration and the filtrate was evaporated in vacuo. The residue was dissolved with dichloromethane and the precipitate was removed by vacuum filtration. The filtrate was evaporated in vacuo to give 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (2.99 g) as a yellow amorphous powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][C:4]=1[CH3:16])#[N:2].O1CCCC1.O.[OH-].[Na+]>C(OC(=O)C)C.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:5][C:4]=1[CH3:16])#[N:2]
Reactant: CCOC(=O)C(C)c1ccc(C#N)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(C)C(=O)O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.6 %

Procedure:
To a stirred solution of ethyl 2-(4-cyano-3-methylphenyl)propanoate (1.05 g, 4.82 mmol) in co-solvent with tetrahydrofuran and water (1:1) were added sodium hydroxide (482 mg, 12.06 mmol). The reaction mixture was stirred for overnight at room temperature, then acidified to pH 3˜4 with acetic acid. The residue was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude 2-(4-cyano-3-methylphenyl)propanoic acid (1.1 g) was obtained as 99% yield.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH3:42])=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[F:30][C:7]1[CH:6]=[C:5]([CH:4]=[N:3][NH:2][C:39]([O:41][CH3:42])=[O:40])[CH:29]=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=2[CH:27]=1)=[O:10]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3F)ccc2O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NNC(=O)OC)cc3F)ccc2O1

Procedure:
436 mg (1.0 mmol) of the amidine from Example 69, 0.3 ml triethylamine, and 20 mg 4-dimethylaminopyridine were dissolved in 29 ml dichloromethane followed by addition of 104 mg (1.1 mmol) methyl chloroformate at 0° C. After stirring overnight at room temperature a white precipitate of the title compound had been formed. It was filtered with suction and washed successively with water and with ether. Yield: 0.35 g (77%) of a pale yellow powder, m.p. 202-204° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34]([OH:36])=O)[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[C:23]([CH3:33])=[C:22]([C:34]([NH:37][CH:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[O:36])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c8) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:15]2[C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[Cl:23])C1C=CC=CC=1.CS(O)(=O)=O>>[Cl:23][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:16]([C:19]([F:20])([F:21])[F:22])=[N:17][N:18]=2)[C:10]=1[CH2:9][OH:8]
Reactant: FC(F)(F)c1nnc2ccc(Cl)c(COCc3ccccc3)n12
Agent: CS(=O)(=O)O
Product: OCc1c(Cl)ccc2nnc(C(F)(F)F)n12

Procedure:
To a solution of 5-(benzyloxymethyl)-6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine, prepared as described in Step 4 (700 mg, 2.1 mmol) was added methanesulfonic acid (2 mL, 70% in water) and the reaction was heated to reflux overnight. The reaction was concentrated and the residue purified by flash chromatography to yield (6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)methanol.
Reaction SMILES: Cl.[CH3:2][C:3]([Si:6]([CH3:14])([CH3:13])[O:7][CH2:8][CH2:9][CH2:10][NH:11][CH3:12])([CH3:5])[CH3:4].C(N(CC)C(C)C)(C)C.[CH3:24][C:25]([O:28][C:29]([N:31]1C(C2C=CC(C#N)=CC=2)O1)=[O:30])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:28][C:29]([NH:31][N:11]([CH2:10][CH2:9][CH2:8][O:7][Si:6]([C:3]([CH3:2])([CH3:4])[CH3:5])([CH3:13])[CH3:14])[CH3:12])=[O:30])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: CNCCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-N-methyl-1-propanamine hydrochloride (1:1) (720 mg, 3.0 mmol) was combined with dichloromethane (30 mL) to give a colorless solution. N,N-Diisopropylethylamine (313 mg, 423 μl, 2.42 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (542 mg, 2.2 mmol) in dichloromethane (20 mL) was added during 15 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 70% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 20 g, ethyl acetate/n-heptane 1/1) to give the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:32]([CH3:34])[CH3:33])[NH:11]1.O.[OH-].[Li+].CO>C1COCC1.O.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:32]([CH3:34])[CH3:33])[NH:11]1
Reactant: CCOC(=O)c1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(C(=O)O)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Part E: To a stirred solution of 130 mg (0.250 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carbethoxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of THF was added 42 mg (1.0 mmol) of lithium hydroxide hydrate in 2 mL of water followed by 0.25 mL of methanol. The solution was stirred 3.5 h at RT and 10 min. at reflux. The reaction was diluted with ether, and washed twice with 0.1 N aq. NaOH. The combined aq. washings were acidified, and the resulting mixture was extracted with chloroform, then EtOAc. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to afford 123 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carboxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-on as a white solid, mp. 294-295° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:3]=1N.Cl.NC1C=CC=CC=1.N([O-])=O.[Na+].[I-:24].[K+]>O.ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:3]=1[I:24]
Reactant: [I-]
Reactant: COc1cc(Cl)c(N)cc1F
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Nc1ccccc1
Solvent: O
Product: COc1cc(Cl)c(I)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
2-Chloro-5-fluoro-4-methoxyaniline (14.0 g, 79.7 mmol) was cooled to 0° C. and conc. HCl (40 mL) was added over 20 min. The suspension was heated to 55° C. until the aniline was completely dissolved, then cooled back to 0° C. A solution of sodium nitrite (6.1 g, 87.7 mmol) in water (15 mL) was added dropwise over 15 min. After complete addition the mixture was stirred at 0° C. for 30 min. Hexanes (24 mL) and dichloromethane (24 mL) were added followed by a solution of potassium iodide (26.5 g, 159.4 mmol) in water (25 mL) which was added dropwise over 30 min. After stirring at 0° C. for 4 h dichloromethane (50 mL) was added and the reaction quenched with sat. aq. NaHSO3. The solution was extracted with dichloromethane. The organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 21 g (92%) of 1-chloro-4-fluoro-2-iodo-5-methoxy-benzene: Crude 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J=10.3 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 3.86 (s, 3H). The crude material was pure enough to carry on to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Br:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26](Cl)(=[O:28])=[O:27])[CH:25]=1.N12CCN(CC1)CC2>C1COCC1>[Br:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:28])=[O:27])[CH:25]=1
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)cc1F
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Br)c(F)cc2F)c(OC)c1
Yield: 58.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.50 g, 2.06 mmol) prepared in Example 14a, 5-bromo-2,4-difluorobenzenesulfonyl chloride (0.90 g, 3.08 mmol), 1,4-diazabicyclo[2.2.2]octane (0.46 g, 4.11 mmol) and THF (10 mL), to yield the title compound (0.60 g, 58%) as a colorless amorphous solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.[CH2:31]([O:38][C@H:39]1[C@H:44]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:43]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@@H:42](O)[CH:41]=[C:40]1[CH2:62][O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C(/N=N/C(N(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C@H:42]3[C@H:43]([O:53][CH2:54][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C@@H:44]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C@H:39]([O:38][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:40]([CH2:62][O:63][CH2:64][C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:41]3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: O[C@H]1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Oc1ccccc1Cc1ccc(C2CC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C1=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1Oc1ccccc1Cc1ccc(C2CC2)cc1
Reaction time: 20 h
Yield: 62 %

Procedure:
In a nitrogen stream, 2-(4-cyclopropylbenzyl)phenol and tributylphosphine (70 μL, 0.28 mmol) were added to a solution of (1S,4R,5S,6S)-4,5,6-tris(benzyloxy)-3-(benzyloxymethyl)cyclohex-2-enol (51 mg, 0.095 mmol) as described in a document [J. Org. Chem., 63, 5668-5671 (1998)] in toluene (300 μL) under cooling with ice, and then tetramethylazodicarboxamide (48 mg, 0.28 mmol) was added thereto at the same temperature. The reaction mixture was stirred at the same temperature for 20 hours and then hexane was added thereto and the precipitate was filtered and the solvent of the filtrate was distilled. The obtained residue was purified by preparative TLC [developing solution=ethyl acetate:n-hexane (1:5) to obtain the title compound (44 mg, 62%).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:19]([NH:21][C:22]2[CH:34]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:32]=[CH:31][C:23]=2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])=[CH:11][C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[C:10]([C:19]([NH:21][C:22]2[CH:34]=[C:33]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:32]=[CH:31][C:23]=2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])=[CH:11][C:12]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc2c(cc1OCc1ccccc1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc2c(cc1O)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(7-(benzyloxy)-2,3-dihydrobenzo[1,4]dioxine-6-carboxamido)-4-phenylbenzoate (0.49 g) in methanol (4 mL) and ethyl acetate (4 mL), 10% palladium-carbon (0.24 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.37 g of tert-butyl 2-(7-hydroxy-2,3-dihydrobenzo[1,4]dioxine-6-carboxamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Na+].[I-].[Cl:3][C:4]1[S:8][N:7]=[C:6]([CH2:9]Cl)[N:5]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.CCOC(C)=O.O>[Cl:3][C:4]1[S:8][N:7]=[C:6]([CH2:9][S:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: Sc1ccccc1
Reactant: ClCc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: Clc1nc(CSc2ccccc2)ns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.05 eq of NaI were dissolved in dry acetone. 1 eq of 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, 1.03 eq of the thiophenol and 1 eq of Na2CO3 were added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with EtOAc and water. The organic phase was washed with an aqueous solution of Na2SO3 (sat), dried over MgSO4 and evaporated in vacuo. Preparative HPLC purification gave the 5-chloro-3-[(phenylthio)methyl]-1,2,4-thiadiazole. This was subsequently dissolved in 95% ethanol and conc. NH3 (aq) was added. In some cases acetonitrile was added in order to completely dissolve the starting material. The mixture was transferred to a microwave tube and run in the microwave at 150° C. for 5 min. the reaction was quenched with water and the desired 3-arylthiomethyl-5-amino-1,2,4-thiadiazole worked up and purified using standard procedures.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9]/[C:10]/2=[CH:13]/[C:14]#[N:15])=[CH:5][CH:4]=1.N.C(O)C>C(O)C.[Co]>[NH2:15][CH2:14][CH:13]=[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)/C(=C\C#N)CCC2
Agent: [Co]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)C(=CCN)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (Z)-(1,2,3,4-tetrahydro-7-methoxy-1-naphthylidene)acetonitrile produced in Reference Example 2 (1.84 g, 9.23 mmol) in ethanol (10 ml) were added a saturated ammonia/ethanol solution (5 ml) and Raney cobalt (ODHT-60, 1.8 g). The mixture was stirred for 3 hours at room temperature under hydrogen atmosphere (about 4 kgf/cm2). The Raney cobalt was filtered off, then the solvent was distilled off to give the above-titled compound (a mixture of isomers) (yield 1.46 g, 78%, oil). This compound was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (4.40 g, 8.96 mmol) in DCM (20 ml) was treated with TFA (20 ml). After stirring for 2 hours. The reaction mixture was concentrated and the crude material was purified by silica gel chromatography using a gradient of 0.5% MeOH/DCM containing 0.5% AcOH to 10% MeOH/DCM containing 0.5% AcOH to provide 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetic acid (3.30 g, 84.7% yield). 1H NMR (400 MHz, CD3OD) 7.85 (d, 2H), 7.65 (s, 1H), 7.45 (d, 1H), 7.35 (s, 1H), 7.25 (d, 2H), 7.20 (d, 2H), 7.10 (d, 2H), 6.95 (d, 1H), 3.62 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([CH:18]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)=[O:23])[CH2:19][CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:29]1[C:30]2[C:26](=[CH:25][C:24]([C:22]([NH:21][CH:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH3:20])=[O:23])=[CH:32][CH:31]=2)[CH:27]=[CH:28]1)=[O:5]
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Reactant: O=C(Cl)c1cccc(F)c1F
Product: CCC(NC(=O)c1ccc2c(ccn2C(=O)c2cccc(F)c2F)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Example 25, using 2,3-difluorobenzoylchloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 419 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N+:5]([O-])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17]>>[OH:17][CH:7]1[C:6]2[N:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12][C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: N#Cc1cc2c([n+]([O-])c1)CCCC2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cnc2c(c1)CCCC2O
Temperature: 23 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a solution of 3-cyano-5,6,7,8-tetrahydroquinoline 1-oxide (645 mg, 3.7 mmol) was added dropwise under ice cooling trifluoroacetic anhydride (6.22 g, 4.18 ml, 29.6 mmol). The light yellow solution was stirred at 23° C. for 18 h. The mixture was quenched with 1 N NaOH solution and stirred vigorously for 30 min., then extracted twice with dichloromethane, the combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the 8-hydroxy-5,6,7,8-tetrahydroquinoline-3-carbonitrile (562 mg, 3.23 mmol, 87.1% yield) as a white solid. MS (ISP): m/z=175.1 [(M+H)+].
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: OCCCCCCCCCCO
Reactant: Clc1ccc2ccccc2n1
Product: OCCCCCCCCCCOc1ccc2ccccc2n1

Procedure:
1,10-Decanediol (ex. Lancaster) was reacted with 2-chloroquinoline, by analogy with compound 33, step (i), to give 10-(2-quinolinyloxy)decan-1-ol. The latter was subjected to Swern oxidation (cf. example XIV) and the aldehyde reacted with ethyl fluoroacetate and diethyl oxalate to give (2Z) ethyl 2-fluoro-12-(2-quinoliny-loxy)dodec-2-enoate. The latter was converted to the title compound by analogy with compound 33, step (iv).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[N:18]1([C:24]2[C:32]3[N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[NH:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:36][C:33]([F:34])([F:35])[C:30]1[NH:31][C:32]2[C:24]([N:18]3[CH2:19][CH2:20][N:21]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH:4]=[CH:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:22][CH2:23]3)=[CH:25][CH:26]=[CH:27][C:28]=2[N:29]=1
Reactant: FC(F)(F)c1nc2c(N3CCNCC3)cccc2[nH]1
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5nc(C(F)(F)F)[nH]c45)CC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a suspension of 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.211 g, 0.908 mmol, 1.29 eq) and 4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.190 g, 0.703 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.558 g, 2.631 mmol, 3.74 eq). The slurry was allowed to stir overnight at room temperature (18 h). The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.230 g, 62%). MS: APCI: M+1: 487.1 (Exact Mass: 486.20).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:11]2[CH:21]=[C:15]3[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]3[C:13](=[O:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(NCc1ccc(F)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E59 starting from (4-fluorophenyl)methanamine and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.