Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:21]#[N:22])=[CH:4][C:5]([F:20])=[C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:10]([NH2:12])=[O:11])[CH:7]=1.Cl.[NH2:24][C:25]1[S:29][N:28]=[C:27]([CH3:30])[CH:26]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[C:2]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[CH:26]=2)=[CH:7][C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:10]([NH2:12])=[O:11])=[C:5]([F:20])[CH:4]=1)#[N:22]
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1cc(F)c(N[C@H](Cc2ccccn2)C(N)=O)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccccn3)C(N)=O)c(F)cc2C#N)sn1
Reaction time: 18 h
Yield: 38.9 %

Procedure:
A mixture of (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-(pyridin-2-yl)propanamide (125 mg, 0.344 mmol), 5-amino-3-methylisothiazole hydrochloride (80 mg, 0.531 mmol), K2CO3 (220 mg, 1.59 mmol), BINAP (40 mg, 0.064 mmol) and Pd(OAc)2 (30 mg, 0.133 mmol) in dioxane (3 mL) was degassed with argon, then was stirred at 120 C for 18 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-(pyridin-2-yl)propanamide (53 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][N:32]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1Cl

Procedure:
51 mg (68%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0,142 mmol), 1-(3,4-dichlorophenyl)piperazine (33 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: CC([O:5][CH2:6][C:7]1[C:11]([CH2:12][OH:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[O:9][N:8]=1)(C)C.O[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:28]=[CH:27]3)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[OH:5][CH2:6][C:7]1[C:11]([CH2:12][O:13][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:10]([CH:14]([CH3:15])[CH3:16])[O:9][N:8]=1
Reactant: CC(C)c1onc(COC(C)(C)C)c1CO
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
To a solution of [3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (407 mg, 1.79 mmol), methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (500 mg, 1.79 mmol) and triphenylphosphine (517 mg, 1.97 mmol) in dichloromethane (4 mL) was added diisopropyl azodicarboxylate (0.354 mL, 1.97 mmol) dropwise. The solution was heated in a microwave reactor at 100° C. for 10 minutes and then adsorbed onto silica gel and purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes gradient elution) to afford a solid which was dissolved in dichloromethane (114 mL). Trifluoroacetic acid (114 mL, 1.48 mol) was added at a rapid pace. The mixture was stirred for approximately 1.5 hours and then concentrated. The residue was taken up with ethyl acetate and poured into water. Then solid sodium carbonate was added until the pH was between 9 and 10. The layers were separated and the ethyl acetate layer was dried over magnesium sulfate and concentrated. The resulting solid was washed with ether to afford methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (545 mg, 54%). 1H-NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=9 Hz, 1H), 8.33 (s, 1H), 8.18 (s, 2H), 8.12 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 5.46 (br s, 1H), 5.06 (s, 2H), 4.54 (s, 2H), 3.94 (s, 3H), 3.33 (septet, J=7 Hz, 1H), 1.24 (d, J=7 Hz, 6H). LRMS (ESI) m/z 433 (M+H)+.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH2:8][C:9]([CH2:11][NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=O)([O-])=O.[H][H]>C(O)C.[Pt]>[O:7]1[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[NH:2][CH:9]([CH2:11][NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:8]1
Reactant: C[C@@H](NCC(=O)COc1ccccc1[N+](=O)[O-])c1ccccc1
Reactant: [H][H]
Agent: [Pt]
Agent: Br
Solvent: CCO
Product: C[C@@H](NCC1COc2ccccc2N1)c1ccccc1

Procedure:
The product from Example 1E (9.7 g, 24.5 mmol) and 5% Pt/C (2.0 g) in ethanol (1 L) was hydrogenated for 16 hours at ambient temperature under 4 atm of hydrogen, filtered through Celite® and concentrated to provide a mixture of diastereomers. The diastereomers were separated by flash chromatography on silica gel with 100:1:1 diethyl ether:ethanol:triethylamine to provide the title compound as the more mobile band. Rf 0.38 (100:1:1 diethyl ether:ethanol:triethylamine); mp 91-92° C.; [α]23D −3.4° (c 1.105, CHCl3); 1H NMR (300 MHz, CDCl3) δ1.35 (d, 3H), 1.45 (bs, 1H), 2.50-2.62 (m, 2H), 3.33 (bm, 1H), 3.73 (q, 1H), 3.86 (dd, 1H), 4.15 (dd, 1H), 4.21 (bs, 1H), 6.62 (m, 2H), 6.75 (m, 2H), 7.20-7.40 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][NH:23][C:24](=[O:31])[CH2:25][C:26]([O:28]CC)=[O:27])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][NH:23][C:24](=[O:31])[CH2:25][C:26]([OH:28])=[O:27])[S:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)NCc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc(CNC(=O)CC(=O)O)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 57.1 %

Procedure:
A mixture of 4,5-bis(4-methoxyphenyl)-2-ethoxycarbonylacetylaminomethylthiazole (0.43 g) and 4N sodium hydroxide (3 ml), methanol (5 ml) and water (5 ml) was stirred at ambient temperature for 4.5 hours. After allowing to cool to room temperature, the mixture was poured to water, and the aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with water and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The resulting residue was triturated with isopropyl ether and diethyl ether, to give 4,5-bis(4-methoxyphenyl)-2-(carboxyacetylaminomethyl)thiazole (0.23 g).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[F:22][C:23]([F:42])([F:41])[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]3[O:38][N:37]=[C:36]([OH:39])[C:35]=3[CH:40]=2)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:62][N:63]1[CH:67]=[C:66]([CH2:68]O)[N:65]=[CH:64]1>C1COCC1>[CH3:62][N:63]1[CH:67]=[C:66]([CH2:68][O:39][C:36]2[C:35]3[CH:40]=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:41])[F:42])=[CH:26][CH:27]=4)[CH:32]=[CH:33][C:34]=3[O:38][N:37]=2)[N:65]=[CH:64]1
Reactant: Cn1cnc(CO)c1
Reactant: Oc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1cnc(COc2noc3ccc(-c4ccc(OC(F)(F)F)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Diisopropylazodicarboxylate 40% solution in toluene (0.27 mL, 0.51 mmol) was added under stirring to a solution of 5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol), triphenylphosphine on resin (3 mmol/g) (330 mg, 1 mmol), and 1-methylimidazol-4-yl methanol (60 mg, 0.51 mmol) in THF. The reaction mixture was stirred at ambient temperature overnight. Volatiles were evaporated under vacuum and the residue was purified on 12 g silica gel with 0-20% methanol in dichloromethane and gave the title compound (40 mg, 0.103 mmol) as yellowish oil.
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[NH2:14][C:15]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][N:16]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH3:12][O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1[CH:13]=[CH:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Nc1ncccc1C=O
Reactant: COC(=O)CCCCCCC(C)=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: COC(=O)CCCCCCc1ccc2cccnc2n1
Temperature: 95 °C

Procedure:
To a stirred solution of methyl 8-oxo-nonanoate 29-2 (3.8 g, 20.4 mmol) in absolute ethanol (100 mL) was added 2-aminopyridine-3-carboxaldehyde (2.49 g, 20.4 mmol) and L-proline (1.17 g, 10.2 mmol) and the mixture was heated to 95° C. for 18 hours, after which the mixture was cooled to ambient temperature and then concentrated at reduced pressure. The resulting solid was purified by flash column chromatography over silica gel with 95:5 ethyl acetate/methanol to give 29-3 as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[C:12]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH:13]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:12]2[CH2:16][CH2:15][CH2:14][CH:13]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)C1=CCCC1
Product: Clc1cc(C2=CCCC2)nc2c1CCC2
Temperature: 140 °C
Yield: 65 %

Procedure:
Following general procedure F except the reaction was heated to 140° C. under microwave irradiation for 2 h, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.157 g, 0.84 mmol) was reacted with cyclopent-1-en-1-ylboronic acid (0.112 g, 1.0 mmol) to afford the title compound (0.120 g, 65%) as a white solid. MW=219.71. 1H NMR (CDCl3, 500 MHz) δ 7.06 (s, 1H), 6.62-6.57 (m, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.77-2.70 (m, 2H), 2.58-2.52 (m, 2H), 2.13 (quin, J=7.5 Hz, 2H), 2.08-2.00 (m, 2H); APCI MS m/z 220 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1.N([O-])=O.[Na+].Cl>O.CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([N:16]2[C:17](=[O:18])[NH:3][N:2]=[N:1]2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]nnn1-c1cccc(Cl)c1
Temperature: 70 °C

Procedure:
DMF (5.0 ml) was cooled to 0° C. and stirred as 0.48 gram (0.0074 mole) of sodium azide was added. To this mixture was added 50 milligrams of aluminum chloride. The mixture was heated to 70° C. for 15 minutes, then the known compound 3-chlorophenylisocyanate was added neet in one portion. The mixture was heated at 75° C. for 3 hours and then cooled and poured into 100 ml of water containing 0.5 gram of sodium nitrite and 50 grams ice. To this was slowly added sufficient 10% hydrogen chloride to cause a change in KI/starch test paper. The resulting solid was filtered and dried. The filtrate was dissolved in ethyl acetate, washed with water and concentrated to a residue. The crude residue was purified with column chromatography on silica gel using 95:5 dichloromethane-methanol as an eluant yielding 0.38 gram of 1-(3-chlorophenyl)-tetrazolin-5-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[O:16][CH:17]=[CH:18][C:19]=3[CH3:20])[C:10]([CH:11]([OH:14])[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[O:16][CH:17]=[CH:18][C:19]=3[CH3:20])[C:10]([C:11](=[O:14])[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)c1c(-c2occc2C)nn2c(Cl)cccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C#CC(=O)c1c(-c2occc2C)nn2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
1-[7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (12.29 g, 42.9 mmol) was dissolved in dichloromethane (200 mL) and manganese dioxide (112 g, 1.29 mol) was added. This slurry was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration and the filtrate was concentrated to a solid. This solid was purified by flash chromatography (dichloromethane) to give 1-[7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (7.53 g, 62%) as a white solid. 1H-NMR (CDCl3): δ 8.37 (d, 1H), 7.48 (m, 2H), 7.19 (d, 1H), 6.41 (d, 1H), 3.12 (s, 1H), 2.20 (s, 3H). MS m/z 285 (M+1).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[CH3:13][O:14][N:15]=[CH:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)=[C:19]([Cl:31])[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:14][N:15]=[CH:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[C:19]([Cl:31])[CH:18]=1
Reactant: CON=Cc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=Cc1cc(Cl)c(OC[C@@H]2CCCN2C(=O)c2cn(C)nc2C(F)F)c(Cl)c1
Reaction time: 4 h
Yield: 57.3 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.103 g; 0.53 mmol) in dichloromethane (4 ml) was added dropwise to a stirred solution of 3,5-dichloro-4-[(S)-1-pyrrolidin-2-ylmethoxy)-benzaldehyde O-methyl-oxime (0.16 g; 0.53 mmol), which was prepared in analogy as described for example P12, and triethylamine (146 μl; 1.05 mmol) in dichloromethane (7 ml). The ice bath was removed and reaction mixture was allowed stirring for 4 hours. The reaction mixture was washed with 2M HCl (10 ml), 1M NaOH (10 ml) and saturated NaCl (30 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.20 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.14 g (57% of theory) of 3,5-dichloro-4-[(S)-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-2-ylmethoxy]-benzaldehyde O-methyl-oxime was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.95 (m, 1H), 2.20 (m, 2H), 2.45 (m, 1H), 3.68 (m, 2H), 3.96 (s, 3H, NCH3), 3.98 (s, 3H, OCH3), 4.22-4.24 (m, 1H), 4.38 (m, 1H), 4.61 (m, 1H), 7.01-7.28 (t, 1H, CHF2), 7.50 (s, 2H, Ar—H), 7.61 (s, 1H), 7.89 (s, 1H). MS [M+H]+ 361/363/365.
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1>>[CH3:1][NH:2][CH2:4][C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CN
Product: CNCc1csc(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
An aqueous solution of methylamine (18 mL, 40%) was treated with the product from Example 109A (2.0 g, 13.5 mmol) in portions over 0.5 hours, stirred at 25° C. for 16 hours, and concentrated. The residue was chromatographed on silica gel eluting with 5% methanol in chloroform to give the title compound (1.23 g, 64% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8].ClCCl.C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(#N)C.O.FC(F)(F)C(O)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([O:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[CH2:5][NH:6][C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)=[O:8])=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=C(NCc1cccc(O)c1)c1ccc2ncccc2c1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 20 %

Procedure:
To a mixture solution of quinoline-6-carboxylic acid 3-hydroxybenzylamide described in Preparation Example E+-4 (3.0 mg, 0.011 mmol), copper(II) acetate (2.9 mg, 0.016 mmol), molecular sieves 4A (50 mg) and dichloromethane (2 mL) were added triethylamine (0.0077 mL, 0.055 mmol) and 4-nitrophenylboronic acid (1.8 mg, 0.011 mmol), and the solution was stirred in the presence of air at room temperature for 10 days. The reaction solution was filtered, then, water, ethyl acetate and an aqueous solution of 29% ammonia were added for extraction, the solution was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (1.14 mg, 0.0022 mmol, 20%) was obtained.
Reaction SMILES: O[Li].O.[NH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[C:15]([O-:17])=[O:16].Cl>O1CCOCC1.O>[NH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc(N)c(C(=O)[O-])c1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(C(=O)O)cc1C(=O)O
Yield: 95.7 %

Procedure:
6.3 g (150 mmol) of LiOH.H2O are added to a stirred solution of 15.7 g (75 mmol) of methyl 4-amino-isophtalate in 300 ml of dioxane and 1200 ml of water. The reaction mixture is heated for 1 hour to 100° C., cooled and acidified to pH=1 by the addition of concentrated HCl. A precipitate is obtained then filtered off, washed, and dried under vacuum to yield 13 g (yield=95.7%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17](O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1nc(O)c2ccccc2n1
Product: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Yield: 93 %

Procedure:
A solution of 2-(2-methoxy-phenyl)-quinazolin-4-ol (2.94 g, 11.65 mmol) in phosphorus oxychloride (60 mL) was heated to reflux for 4.5 hours. The orange reaction mixture was concentrated and the resulting gum was treated with ice-cold saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried (MgSO4) and concentrated to give the title compound as a yellow solid (2.92 g, 93%).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH2:47])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH:47][C:7](=[O:9])[C@@H:2]([NH:1][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:3][CH:4]([CH3:5])[CH3:6])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C

Procedure:
The title compound was prepared substantially in a similar manner as Step 1 of Example 10 using N-Z-Leu-OH and [(R)-3-((S)-2-amino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride as the starting materials. The title compound was purified by SiO2 chromatography using 0-4% MeOH/CH2Cl2 as the eluent. 1H NMR (CD3OD, 300 MHz): δ 7.34 (m, 10H), 5.50 (m, 4H), 4.19 (m, 2H), 4.01-3.94 (m, 1H), 3.30 (m, 2H), 2.15 (m, 1H), 1.92 (m, 2H), 1.77-1.64 (m, 8H), 1.50 (m, 2H), 1.40-1.12 (m, 4H), 1.11-0.97 (m, 14H). 31P NMR (CD3OD, 300 MHz): δ 60.56, 59.87. LCMS m/z: [M+H]+=672.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH2:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Product: CC(=O)N1c2ccc(C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 69.7 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 29 mg of (2S)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3, 4-tetrahydroquinoline-6-carboxylic acid and 40 mg of tert-butyl 12-amino-4,7,10-trioxadodecanoate. Thus, 33 mg (69%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17]O)[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:41]3[C:42](=[O:44])[CH2:43][S:39][C:40]3=[O:45])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CO
Reactant: O=C1CSC(=O)N1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN1C(=O)CSC1=O
Temperature: 0 °C
Yield: 50.3 %

Procedure:
To a solution of 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.13 g, 0.46 mmol) in tetrahydrofuran (3 ml) was added triphenylphosphine (0.13 g, 0.51 mmol), and thiazolidin-2,4-dione (60 mg, 0.51 mmol). The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (99 μl, 0.51 mmol) was added via syringe. The resultant mixture was stirred for 18 hours, gradually warming to room temperature. The volatiles were evaporated in vacuo and the resulting oil was diluted in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of dichloromethane/methanol (9:1) as eluent. Pure fractions were collected (Rf=0.70) and the solvent evaporated in vacuo which afforded 89 mg (51%) of 2-amino-7-(2,4-dioxo-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.