Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:20])[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[C:6]([O:8][CH3:9])=[O:7].[BH4-].[Na+].[ClH:23]>CO>[Cl:23][CH:2]([CH3:20])[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[C:6]([O:8][CH3:9])=[O:7]
Reactant: Cl
Reactant: COC(=O)C(CCC(C)=O)c1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCC(C)Cl)c1ccccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
Methyl 5-oxo-2-(2-trifluoromethylphenyl)hexanoate (728 mg) was dissolved in methanol (15.2 mL). Sodium borohydride (47.8 mg) was added under ice-cooling, and the reaction solution was stirred at the same temperature for 30 minutes. A 1 N hydrochloric acid aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL). Thionyl chloride (576 μL) was added and the reaction solution was stirred at 50° C. for three hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: Chromatorex Si; elution solvent: heptane:ethyl acetate=19:1→heptane:ethyl acetate=1:1) to obtain methyl 5-chloro-2-(2-trifluoromethylphenyl)hexanoate (380 mg) as a diastereomer mixture. The mixture (320 mg) was dissolved in ethanol (7.8 mL). Hydrazine monohydrate (1.5 mL) was added and the reaction solution was stirred at 100° C. for 14 hours. The reaction solution was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: Chromatorex Si; elution solvent: heptane:ethyl acetate=19:1→heptane:ethyl acetate=1:1) to obtain the title compound (380 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH2:26]([NH2:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:26]([NH:28][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:23])[CH3:27]
Reactant: CCN
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CC

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid ethylamide (70.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), ethylamine (2.0 M solution in THF, 1.0 mL), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 401; and 1H NMR (DMSO-d6, 400 MHz): δ 8.44 (1H, m), 8.08 (1H, m), 7.95-7.92 (1H, m), 7.75-7.64 (2H, m), 7.53-7.51 (1H, m), 7.41-7.38 (1H, m), 4.21-4.19 (2H, m), 3.32-3.28 (2H, m), 1.34-1.32 (3H, t), 1.17-1.13 (3H, t), —NH proton signal was not observed.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:36][N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:34][CH:35]=1
Reactant: CN(C)CCCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Product: CN(C)CCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 4-(3-dimethylaminopropyl)-aniline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[O:31][CH3:32])[CH3:21]>CS(C)=O.CCOC(C)=O>[CH2:20]([O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][C:27]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH:9]3[O:10][CH2:11][CH2:12][O:13]3)[CH:4]=2)=[CH:26][C:25]=1[O:31][CH3:32])[CH3:21]
Reactant: CCOC(=O)c1ccc(F)cc1OC
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccc(Br)c(C3OCCO3)c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of compound 2 (9.27 g, 37.83 mmol) in DMSO (50 mL) was added potassium carbonate (15.68 g, 113.48 mmol). The resulting mixture was stirred at rt for 30 min. followed by addition of compound 5 (8.99 g, 45.39 mmol). The resulting mixture was heated at 120° C., O/N. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford the title compound 6 (5.6 g, 35%) as a pale yellow solid. 1H NMR 400 MHz (CDCl3) δ: 7.81 (d, J=9.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.35 (s, 1H), 6.97 (dd, J=8.6, 2.7 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 6.49 (dd, J=8.6, 2.4 Hz, 1H), 6.01 (s, 1H), 4.39 (q, J=7.4 Hz, 2H), 4.20-4.01 (m, 4H), 3.81 (s, 3H), 1.40 (t, J=7.4 Hz, 3H); MS (ES) m/z: 423 (M+1)+, 425 (M+3)+.
Reaction SMILES: [I-].[K+].[CH3:3][N:4]1[C:9]2=[CH:10][NH:11][C:12]([C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)=[C:8]2[C:7](=[O:19])[N:6]([CH3:20])[C:5]1=[O:21].Cl[CH2:23][CH:24]([S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][CH2:25][CH:24]([S:36][C:37]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:23][N:11]2[C:12]([C:13]3[S:14][CH:15]=[C:16]([CH3:18])[N:17]=3)=[C:8]3[C:9]([N:4]([CH3:3])[C:5](=[O:21])[N:6]([CH3:20])[C:7]3=[O:19])=[CH:10]2)=[CH:33][CH:32]=1
Reactant: COc1ccc(COCC(CCl)SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1csc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(=O)N(C)C
Product: COc1ccc(COCC(Cn2cc3c(c2-c2nc(C)cs2)c(=O)n(C)c(=O)n3C)SC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
Potassium iodide (9.80 mg, 0.059 mmol) was added to a mixture of 1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate Nd) (81 mg, 0.294 mmol), (1-chloro-3-((4-methoxybenzyl)oxy)propan-2-yl)(trityl)sulfane (158 mg, 0.323 mmol) and cesium carbonate (191 mg, 0.587 mmol) in dimethylacetamide (2 ml). The mixture was stirred at 50° C. for 3 days. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml), the phases were separated and the aqueous phase extracted with ethyl acetate (10 ml). The combined organic extracts were washed with brine (20 ml), dried over magnesium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-50% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1c(Cl)cccc1Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3c(Cl)cccc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (R)-1-(2,6-dichlorophenyl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[CH:15][C:10]3=[C:9](/[CH:29]=[CH:30]/[C:31]([O:33]CC)=[O:32])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[C:9](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)/C=C/c1nc(C2CCCCC2)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1nc(C2CCCCC2)n2c1cnc1[nH]ccc12
Temperature: 65 °C
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a solution of (E)-ethyl 3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylate (0.064 g, 0.13 mmol) in 1,4-dioxane (5 mL) was added aqueous NaOH (2 N, 1.30 mL, 2.60 mmol). The mixture was heated to about 65° C. After about 15 h, the mixture was cooled to rt and the pH of the reaction mixture was adjusted to about pH=1 with concentrated HCl. The mixture was partially concentrated in vacuo and the precipitate was collected by filtration and dried in vacuo to provide (E)-3-(1-cyclohexyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylic acid (0.015 g, 37%): LC/MS (Table 2, Method a) Rt=1.85 min; MS m/z: 311 (M+H)+. Syk IC50=B.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([C:26]3C=CC(Cl)=[CH:28][CH:27]=3)[OH:25])=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:36]C([N-]C(C)C)C.CC(C)CC=O>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([OH:25])[CH2:26][CH:27]([CH3:36])[CH3:28])=[C:20]([Cl:23])[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Cl)ncc21
Reactant: CC(C)[N-]C(C)C
Agent: CC(C)CC=O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(Cl)ncc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (See Compound 49, step 3, 1.149 g, 3 mmol) in THF (30 mL) at −78° C. was added LDA (2M in THF, 7.5 mL, 15 mmol) dropwise. The reaction was stirred at −78° C. for 30 min then 3-methylbutanal (516 mg, 6 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at −78° C. for 20 min, quenched with aq. NH4Cl (5 mL) then diluted with EA (15 mL) and water (5 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-(1-hydroxy-3-methylbutyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (464 mg, 30% yield) as a white solid. LCMS: MH+ 470 and TR=2.198 min.
Reaction SMILES: C1([C@H](NC(C(C2C=CC=C(F)C=2C(O)=O)C(=O)C)=O)C2C=CC=C(F)C=2)CCC1.C(OC(C)(C)C)(=O)NN.C(OC(=O)[NH:45][N:46]1[C:55]([CH3:56])=[C:54]([C:57](=[O:71])[NH:58][C@@H:59]([CH:67]2[CH2:70][CH2:69][CH2:68]2)[C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[CH:61]=2)[C:53]2[C:48](=[C:49]([F:72])[CH:50]=[CH:51][CH:52]=2)[C:47]1=[O:73])(C)(C)C.C(O)(C(F)(F)F)=O>C1C=CC=CC=1.ClCCCl>[CH:67]1([C@H:59]([NH:58][C:57]([C:54]2[C:53]3[C:48](=[C:49]([F:72])[CH:50]=[CH:51][CH:52]=3)[C:47](=[O:73])[N:46]([NH2:45])[C:55]=2[CH3:56])=[O:71])[C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[CH:61]=2)[CH2:70][CH2:69][CH2:68]1
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Agent: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CCC1)c1cccc(F)c1C(=O)O
Agent: CC(C)(C)OC(=O)NN
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: ClCCCl
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c(=O)n1N

Procedure:
A solution of 2-(1-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-2-oxo-propyl)-6-fluoro-benzoic acid (2.148 g, 5.351 mmol) and tert-butyl carbazate (1.628 g, 12.32 mmol) in benzene (100 mL) was stirred under reflux for 20 hours. LC-MS indicated the formation of (4-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (tR=1.54, UV 39%, ELSD 80%, m/z 398.4 (major), 442.5, 498.7 (MH+)). The reaction mixture was rotovaped. The residue was dissolved in 1,2-dichloroethane (15 ml) and TFA (15 ml) was added. After 60 min it was evaporated, partitioned between sat. aq. NaHCO3 and ethyl acetate, evaporated to give a crude residue of the title compound (1.7 g) that was used in the next step without purification. LC-MS (m/z) 398.0 (MH+), tR=1.24.
Reaction SMILES: O.[CH3:2][N:3]1[C@H:13]2[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]4[O:22][C@H:7]5[C:8]([CH:10]=[CH:11][C@:12]2([OH:23])[C@:6]5([C:16]=34)[CH2:5][CH2:4]1)=[O:9].[H][H]>[Pd].C(O)(=O)C>[CH3:2][N:3]1[C@@H:13]2[CH2:14][C:15]3=[CH:20][CH:19]=[C:18]([OH:21])[C:17]4[O:22][C@H:7]5[C:8]([CH2:10][CH2:11][C@:12]2([OH:23])[C@:6]5([C:16]=43)[CH2:5][CH2:4]1)=[O:9]
Reactant: [H][H]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 30 °C

Procedure:
A hydrogenation vessel is charged with kg litre water and 0.73 kg acetic acid before adding 1 kg of 14-hydroxymorphinone prepared as in Example 1.1A and the mixture stirred until clear. 40 g of wet 10% Pd on carbon catalyst is added under a stream of nitrogen, and hydrogen supplied at 35-40 psi (2.41-2.76 bar). The temperature is maintained at 30±5° C. until hydrogen uptake stops, then the vessel is maintained at 35-40 psi (2.41-2.76 bar) and 30±5° C. for 3-4 hours. The reaction vessel is cooled to less than 25° C. and a sample subjected to HPLC to check for 14-hydroxymorphinone. If the 14-hydroxymorphinone area detected by HPLC is >0.1%, the hydrogenation is repeated.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:20](=O)[CH2:21][CH2:22][CH3:23].N1CCCCC1>C(O)C>[CH:20](=[C:16]1[S:15][C:14](=[O:19])[N:13]([CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:17]1=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.51 g (5.5 mmol) of 3-[3-(imidazo[1,2-a]pyridin-5-yl)propyl]thiazolidine-2,4-dione and 0.50 ml (5.5 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.22 g (67.3%, light yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)CCN>O1CCOCC1.[Cu](I)I>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CCCN1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1CCCN1c1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (150 mg), 90 μL of 2-pyrrolidinone, potassium phosphate tribasic (250 mg), copper iodide (7 mg), 4 μL of N,N-dimethylethylenediamine in 2 mL of 1,4-dioxane was heated to 100° C. for 16 h. The reaction mixture was evaporated and the residue was diluted with ethyl acetate (60 mL), washed with brine (30 mL), dried over MgSO4, filtered and evaporated. The crude product was purified on reverse phase HPLC to give 53 mg of 1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:18]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH2:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Yield: 71.3 %

Procedure:
To a solution of Ethyl-4,6-dichloroquinoline-3-carboxylate (1.0 g, 3.7 mmol) in 1,4-dioxane (10 mL) was added a solution of 4-benzylbenzenamine (733 mg, 4.0 mmol) in 1,4-dioxane (10 mL) at room temperature. After stirred at 85° C. 1 hour, the reaction mixture was then cooled down to room temperature and then treated with 20 mL of water. The resulting suspension treated with 10 N NaOH solutions to reach the pH about 9. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 9:1 v/v hexane:ethyl acetate as solvent to afford title compound (1.1 g, 65% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[C:26]1([N:32]=[C:33]=[S:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:23][C:20]([F:21])([F:22])[C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:24]=[C:2]([NH:1][C:33]([NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[S:34])[CH:3]=[CH:4][C:5]=2[OH:25])[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=1
Reactant: Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: S=C=Nc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(NC(=S)Nc2ccccc2)ccc1O
Yield: 66.3 %

Procedure:
Using 5-amino-N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide and phenylisothiocyanate as the raw materials, the same operation as the example 92 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 50.3 %

Procedure:
To a stirred solution of 4-bromophenol (10 g, 0.057 mol) and 2-(chloro methyl)quinoline (15.4 g, 0.063 mol) in AcN (25 mL) was added K2CO3 (24 g, 0.17 mol). The reaction mixture was refluxed for 3 h, filtered and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (2×200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain 2-((4-bromophenoxy)methyl)quinoline (9 g, 50%) as a solid.
Reaction SMILES: [C:1]1([OH:8])[C:2]([OH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[O:9]=[P:10]12[O:21]P3(OP(OP(O3)([O:17]1)=O)(=O)[O:11]2)=O>>[P:10](=[O:9])([OH:21])([OH:17])[OH:11].[P:10](=[O:9])([OH:21])([OH:17])[OH:11].[C:1]1([OH:8])[C:2]([OH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: Oc1ccccc1O
Product: O=P(O)(O)O

Procedure:
An additional method which may be used to produce the compounds of this invention involves reacting a benzene diol with phosphorus pentoxide to produce a benzene diol bis(phosphoric acid);
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][C:15]2([Cl:18])[Cl:17])[CH:6]=1)=[O:3].[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>C(OCC)C>[S:19]1[CH2:23][CH2:22][N:21]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH:14]3[CH2:16][C:15]3([Cl:18])[Cl:17])[CH:6]=2)=[O:3])[CH2:20]1
Reactant: O=C(Cl)Oc1ccc(Cl)c(OCC2CC2(Cl)Cl)c1
Reactant: C1CSCN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Oc1ccc(Cl)c(OCC2CC2(Cl)Cl)c1)N1CCSC1
Yield: 88 %

Procedure:
1.00 g of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenyl chloroformate was dissolved in 20 ml of diethyl ether and, to the solution, there were added 0.32 g of thiazolidine and 0.37 g of triethylamine. The mixture was stirred at 0° to -5° C. for an hour and then washed with water. The ether was distilled off from the ether layer and the oily residue was purified by silica gel column chromatography to give 1.02 g of 4-chloro-3-[(2,2-dichlorocyclopropyl)methoxy]phenyl 3-thiazolidinecarboxylate [Compound (7)], which had the melting point of 74°-79.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[CH2:20]=O>C(O)=O>[CH3:20][N:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1
Reactant: COC(=O)c1ccc(NCc2cccc(Cl)c2)cn1
Reactant: C=O
Solvent: O=CO
Product: CN(Cc1cccc(Cl)c1)c1ccc(C(=O)O)nc1
Reaction time: 24 h

Procedure:
The mixture of 10 g of 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid methyl ester, 13 ml of 35% aqueous formaldehyde and 13 ml of formic acid is stirred at the steam bath for one day. It is evaporated, the residue boiled with 100 ml of methanol, until dissolution, the solution filtered hot and the filtrate cooled. The precipitate formed is collected and recrystallized from methanol, to yield the 5-(N-methyl-N-m-chlorobenzylamino)-pyridine-2-carboxylic acid melting at 138°-140°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=O)=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][NH2:33].C1COCC1>>[CH3:32][NH:33][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:23]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and monomethylamine THF solution. Colorless crystals (160 mg).