Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][CH:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([C:37]4[O:38][CH:39]=[CH:40][C:41]=4[CH3:42])=[O:36])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:52]1N=N[C:54]2C=CC=N[C:53]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>O1CCCC1.O>[CH2:53]([NH:52][C:10](=[O:11])[CH:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([C:37]4[O:38][CH:39]=[CH:40][C:41]=4[CH3:42])=[O:36])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:43])[CH3:54]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c[nH]3)c2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 5-tert-butoxy-2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid (100 mg, 0.17 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (76 mg, 0.20 mmol) and N,N-diisopropylethylamine (66 mg, 0.51 mmol). The mixture was heated at 60° C. for 15 minutes and cooled to room temperature, followed by addition of 2-Methylamine solution in THF (0.25 ml, 0.50 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give tert-butyl 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoate as white solid. Yield: 82 mg, 78%.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=O)[O:22]C1C=CC=CC=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([CH:3]1[C:2](=[O:1])[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]1=2)=[O:22]
Reactant: O=C1Cc2ccccc2S1
Reactant: O=C(Nc1ccccc1F)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1ccccc1F)C1C(=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 50 g of 2,3-dihydro-2-oxo-benzo[b]thiophene in 200 ml of hexamethylphosphoric acid triamide is added dropwise to a suspension of 16 g of a 50% strength sodium hydride/mineral oil dispersion in 500 ml of hexamethylphosphoric acid triamide, whilst cooling, the temperature being kept below 15°. After stirring for one hour at room temperature, 77 g of phenyl N-(2-fluorophenyl)-carbamate are added in portions, with external cooling. The reaction mixture is stirred for a further 16 hours at room temperature and poured into a mixture of 300 ml of 2 N hydrochloric acid and 3,000 ml of ice water. An oil separates out and this crystallises after about 2 hours. The crystalline product, in which solvent is incorporated, is dissolved in 1,000 ml of diethyl ether and the solution is washed with water. The organic phase is separated off, dried over sodium sulphate and evaporated to dryness. The crude product is recrystallised from diethyl ether and gives N-(2-fluorophenyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophenecarboxamide, melting point 155°-156°.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[CH3:18]>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][C:12]=1[CH3:18]
Reactant: Cc1cc(Br)ccc1F
Reactant: OB(O)c1ccccc1
Product: Cc1cc(-c2ccccc2)ccc1F

Procedure:
In the case of Q10-Br, the desired 2-fluoro-5-phenyl-toluene (S1=F) was prepared from phenylboronic acid and 2-fluoro-5-bromo-toluene via a Suzuki reaction, analogously to procedure A2. See scheme A3.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.[Na].[SH:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.O>COCCOC>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[S:29][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=1)[C:12]#[N:13]
Reactant: Sc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: [Na]
Solvent: O
Solvent: COCCOC
Product: N#CC(Sc1nc2ccccc2s1)c1cccc(Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
1.517 g of O-[p-toluenesulfonyl)-m-phenoxymandelonitrile was dissolved in 5 ml of DME, and the solution was stirred in an argon atmosphere under ice cooling. Sodium salt of 2-mercaptobenzothiazole (760 mg) was added, and the mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 1.5 hours. Water (20 ml) was added to the reaction mixture, and it was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene and methylene chloride) to afford 1.233 g (yield 85%) of alpha-(2-benzothiazolylthio)(m-phenoxyphenyl)acetonitrile as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:28][CH3:29])[C:19]([NH:20]C(=O)OC(C)(C)C)=[C:15]2[CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:28][CH3:29])[C:19]([NH2:20])=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N)c(SC)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (50 mg) was dissolved in a 4 N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide and extracted with ethyl acetate, and the organic layer was concentrated to obtain 7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridine-3-amine. This was dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.078 mL) and 3 M aqueous sulfuric acid (0.363 mL), sodium borohydride (27 mg) was added in five portions at a time while vigorously stirring on ice, and stirring was continued for 30 minutes. After adding saturated aqueous sodium hydrogencarbonate to neutralize the reaction mixture, extraction was performed with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography, and the title compound (20.6 mg) was obtained from the n-hexane:ethyl acetate (7:1) fraction as a light yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[CH2:10][C@@H:4]2[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:42]([C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=1)([O-:44])=[O:43].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[N+:42]([C:45]1[CH:46]=[CH:47][C:48]([C:49]([O:1][C@@H:2]2[CH2:22][N:5]3[C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][N:12]=4)[CH2:10][C@@H:4]3[CH2:3]2)=[O:50])=[CH:52][CH:53]=1)([O-:44])=[O:43]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@@H](O)CN12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O[C@H]1C[C@H]2CN(c3ccc(C(F)(F)F)cn3)CCC(=O)N2C1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
(8R,9aS)-8-Hydroxy-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one (100 mg, 0.317 mmol, Part B), triphenylphosphine (104 mg, 0.396 mmol), and 4-nitrobenzoic acid (80 mg, 0.476 mmol) were dissolved in tetrahydrofuran (2 mL), and the resulting solution was cooled to −78° C. Diisopropyl azodicarboxylate (77 mg, 0.381 mmol) in tetrahydrofuran (0.5 mL) was added. The mixture was warmed to room temperature and stirred for two hours. Then 1 drop of water was added. The mixture was purified by chromatography on silica gel (ethyl acetate/heptanes=1:1 then 100% ethyl acetate) to give 138 mg (94% yield) of the titled compound as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (m, 1H), 2.77 (m, 3 H), 3.33 (m, 1 H), 3.47 (m, 1 H), 3.88 (m, 1 H), 4.00 (m, 1H), 4.12 (m, 1H), 4.37 (m, 1H), 4.77 (dd, J=14, 4 Hz, 1 H), 5.54 (m, 1H), 6.67 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1 H), 8.20 (d, J=8 Hz, 2 H), 8.35 (d, J=8 Hz, 2 H), 8.42 (s, 1 H); MS (ESI) m/z 465.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[C:15](Cl)[N:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[C:15]([NH:9][C:6]2[CH:7]=[N:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=[CH:13][N:12]=1
Reactant: N#Cc1c(Cl)ncnc1Cl
Reactant: CSc1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(Nc2ncnc(Cl)c2C#N)cn1
Reaction time: 1.5 h

Procedure:
6-Methylsulfanyl-pyridin-3-ylamine (500.0 mg, 3.57 mmol, 1.0 equivalent) in DMF (1 mL) was added drop wise to a suspension of 4,6-dichloro-pyrimidine-5-carbonitrile (616.9 mg, 3.57 mmol, 1.0 equivalent), potassium carbonate (542.1 mg, 3.92 mmol, 1.1 equivalent) at 0° C. under stirring. The reaction was left reacting at room temperature for 1.5 hours. Product was crystallized using ethyl acetate, hexane getting a yellow solid as product (650.00 mg, 65.62%). LCMS (ESI) for C11H8ClN5S: m/z 278.0 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.[CH3:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[NH2:31]>C(O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:31][C:30]2[CH:32]=[C:33]([CH3:35])[CH:34]=[C:28]([CH3:27])[CH:29]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:5]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C)cc(Nc2nc(Cl)nc(Nc3ccc(P(C)(C)=O)cc3)n2)c1

Procedure:
To a solution of 4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 102: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 3,5-dimethylaniline (24 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH2:29][CH2:28]3)=O)[CH3:23])[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1.C([O-])(=O)C([O-])=O.[OH-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:61].Cl>C1COCC1.CCOCC.O>[ClH:61].[ClH:61].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][N:27]3[CH2:28][CH2:29][CH:30]([O:33][C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[CH2:31][CH2:32]3)[CH3:23])[O:15][CH2:16][CH2:17][O:18]2)=[CH:10][CH:9]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CC(=O)N1CCC(Oc2ccc(F)cc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])C(=O)[O-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a suspension of 1.4 g (21.1 mmol) of lithium aluminum hydride (57% in oil; washed 3 times with hexane) in 50 ml of dry THF, cooled at 0°, was added dropwise a solution of 1-{N-{3-[2-(4-Fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylaminoacetyl}-4-(4-fluorophenoxy)piperidine (liberated from 5.94 g (10.5 mmol) of the oxalate) in 50 ml of dry THF. The mixture was allowed to warm to room temperature and was then heated at reflux for 16 hours under nitrogen, allowed to cool to room temperature and subsequently cooled in an ice bath. To the mixture were added dropwise, slowly, 0.7 ml of water, 0.7 ml of 15% NaOH and 2 ml of water. The mixture was filtered and washed with 100 ml of THF. The solvent was evaporated from the filtrate to provide an oil. The oil was dissolved in ether, washed with water and saturated sodium chloride and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The yield of the dihydrochloride was 3.83 g (68%). Recrystallization from ethanol provided analytically pure material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:18])[CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33](Cl)=[O:34])[C:28]2=[O:36])=[CH:23][CH:22]=1>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:33]([C:29]2[C:28](=[O:36])[N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH:32]=[CH:31][CH:30]=2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:18])[CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Cc1ccn2ncnc(Oc3ccc(N)cc3F)c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccn2ncnc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 3-fluoro-4-(5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (62 mg, 0.24 mmol) in dichloromethane (2 mL) and pyridine (0.5 mL), was added dropwise a solution of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (30 mg, 0.12 mmol) in dichloromethane (0.5 mL). The reaction mixture was stirred at rt for 30 min, and then concentrated to dryness. The residue was washed with methanol. The solid that formed was collected by filtration and dried under vaccum to give the title compound (35 mg, 61%). 1H NMR (DMSO-d6) δ 12.10 (br s, 1H), 8.58 (dd, 1H, J=7.15, 2.20 Hz), 8.12 (dd, 1H, J=6.60, 1.65 Hz), 7.98 (s, 1H), 7.95 (d, 2H, J=2.75 Hz), 7.62-7.58 (m, 2H), 7.40-7.47 (m, 4H), 6.78 (d, 1H, J=2.75 Hz), 6.72 (t, 1H, J=7.15 Hz), 2.54 (s, 3H); MS(ESI+) m/z 474.23 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O.CN(C=O)C>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(OC(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of 3-chloroisonicotinic acid, 1.04 g of (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(N2CCO[C@@H](C(=O)N3CCCC3)C2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc(N2CCO[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
To a solution of (R)-(4-(4-amino-5-nitropyrimidin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone (0.15 g, 0.46 mmol) in ethanol (15 mL) was added 10% palladium-on-carbon (300 mg). The mixture was hydrogenated using a balloon filled with hydrogen gas at room temperature for 3 h. The mixture was filtered through a pad of Celite and the filtrate was used for the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH2:30])=[N:21][N:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24][C:23]=23)=[CH:15][C:14]=1[CH3:31]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([NH:30][C:9](=[O:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:21][N:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24][C:23]=23)=[CH:15][C:14]=1[CH3:31]
Reactant: Cc1cc(C)n2nc(N)c(-c3ccc(Cl)c(C)c3)c2n1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(NC(=O)CCc3ccccc3)c(-c3ccc(Cl)c(C)c3)c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Phenylpropionyl chloride (0.078 mL, 0.53 mmol) was added to a stirring solution of the product from Example 47C (85 mg, 0.296 mmol) in pyridine (5 mL), and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated under vacuum, and the residue diluted with MeOH (5 mL) and stirred for 30 minutes at room temperature. The mixture was concentrated under vacuum and the residue was crystallized from 80% aqueous ethanol (15 mL) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.34 (s, 3H) 2.53 (s, 3H) 2.60-2.69 (m, 2H) 2.66 (s, 3H) 2.87 (t, J=7.6 Hz, 2H) 6.98 (d, J=0.7 Hz, 1H) 7.14-7.32 (m, 5H) 7.38 (d, J=8.5 Hz, 1H) 7.56 (dd, J=8.5, 2.0 Hz, 1H) 7.72 (d, J=1.7 Hz, 1H) 10.21 (s, 1H); MS (ESI) m/z 419/421 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]I)[CH:3]=1.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[CH3:28][NH2:29]>O1CCCC1.CO>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][NH:29][CH3:28])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCI)c1ccccc1
Reactant: CN
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNCCC[C@@H](Oc1cc(Cl)ccc1C#N)c1ccccc1

Procedure:
A solution of the product from step (c) (286 mg) in 40% aqueous methylamine (1 ml) and tetrahydrofuran (10 ml) was stirred for 6 h. The solvent was removed in vacuo and the residue dissolved in water and extracted with ethyl acetate (three times). The combined organic extracts were washed with water, dried (magnesium sulphate) and evaporated to give an oil. To a solution of this amine in methanol (10 ml) was added a solution of oxalic acid (57 mg) in methanol. The solvent was removed in vacuo and the residue triturated with ethyl acetate. The solid was collected and dried to afford the title compound as a white solid (110 mg). M.p. 167-169° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([CH:19]=[O:20])[CH:11]=[C:12]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:13]=2)[N:8]=[C:7]([CH3:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([CH2:19][OH:20])[CH:11]=[C:12]([CH:15]([CH2:17][CH3:18])[CH3:16])[CH:13]=2)[N:8]=[C:7]([CH3:21])[C:6]=1[CH3:22])(=[O:3])[CH3:2]
Reactant: CCC(C)c1cc(C=O)c2nc(C)c(C)c(OC(C)=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C)c1cc(CO)c2nc(C)c(C)c(OC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 84 %

Procedure:
210 Milligrams of 4-acetoxy-6-s-butyl-8-formyl-2,3-dimethylquinoline obtained in Example 33 was dissolved in 4 ml of methanol, to which 7 mg of sodium borohydride dissolved in 4 ml of methanol was added dropwise and the mixture was stirred at room temperature for 1 minute. After the addition of 20 ml of water, the reaction mixture was extracted with ethyl acetate. The resultant organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (10:1) to obtain 186 mg of 4-acetoxy-6-s-butyl-8-hydroxymethyl-2,3-dimethylquinoline (yield 84%). Its NMR spectral data are shown in the following Table 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:25]=1)[C:7](=[O:24])[CH:8]=[C:9]([CH:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12])[N:10]=2.[Br:26]Br.O>C(O)(=O)C>[Br:26][C:8]1[C:7](=[O:24])[N:6]2[CH:25]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: BrBr
Reactant: CC(NC(=O)OCc1ccccc1)c1cc(=O)n2cc(F)ccc2n1
Solvent: O
Solvent: CC(=O)O
Product: CC(NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
E1 (385 mg, 1.13 mmol) was dissolved in 14 mL of acetic acid. Bromine (58 μL, 1.13 mmol) was added dropwise. The reaction was stirred for 30 min at room temperature. Water (40 mL) was added into the reaction, and the reaction was stirred for another 30 min generating a white precipitate that was filtered, washed with water and dried to yield E2 (312 mg).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[C:13]2[N:14]([CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1>O>[Cl:11][C:12]1[C:13]2[N:14]([C:18]([CH:3]=[O:4])=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(-c2cn3cccc(Cl)c3n2)c1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nc3c(Cl)cccn3c2C=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
N,N-Dimethylformamide (30 mL) was cooled to 0° C. and treated with phosphorous oxychloride (1.08 mL, 11.6 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for 10 minutes. To this was added 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine (2.0 g, 7.75 mmol) and the resulting solution was stirred for 48 hours. Water was added to the reaction. The solids were then filtered and azeoptroped with methanol to give 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (2.2 g, 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH3:12][C:13]1[N:14]=[C:15]([NH2:18])[O:16][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:18][C:15]2[O:16][CH:17]=[C:13]([CH3:12])[N:14]=2)=[S:10])[CH:7]=1
Reactant: Cc1coc(N)n1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1coc(NC(=S)Nc2cc(Cl)ccc2C)n1
Yield: 54.1 %

Procedure:
Prepared using Method A from 10.0 g (54.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 5.39 g (55 mmol) of 4-methyl-2-amino-oxazole to give 8.3 g of title compound as a yellow solid, m.p. 207-208° C. An additional crop (4.8 g, m.p. 207-208° C.) was obtained from the mother liquor (86% combined yield).