Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5]([CH2:8][CH:9]([CH2:15][S:16]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:18])=[O:17])[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]>Cl>[CH2:1]([S:5]([CH2:8][CH:9]([CH2:15][S:16]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:18])=[O:17])[C:10]([OH:12])=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)CC(CS(=O)(=O)CCCC)C(=O)OCC
Agent: Cl
Product: CCCCS(=O)(=O)CC(CS(=O)(=O)CCCC)C(=O)O

Procedure:
A mixture of 2-[(n-butylsulfonyl)methyl)-3-(n-butylsulfonyl)-propanoic acid, ethyl ester (1.0 g, 3.0 mmol) in 6N hydrochloric acid ( 20 mL) is refluxed overnight. The mixture is transferred to distilled water and extracted with ethyl acetate. The combined organic extracts are concentrated in vacuo to yield the title compound as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23](=[O:26])[NH:24][CH3:25])[CH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]([CH:16]=C)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23](=[O:26])[NH:24][CH3:25])[CH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]([CH:16]=[O:29])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(C(=O)NC)c(F)c2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1ccc(Cc2cc(C(=O)OC)c(C=O)c(C)c2C)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(3-fluoro-4-(methylcarbamoyl)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.19 g) in a mixed solvent of acetone (2.20 mL)-acetonitrile (2.20 mL)-water (2.20 mL) were added osmium oxide (fixed catalyst I) (0.07 g) and sodium periodate (0.56 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.19 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: Br[C:2]1[C:28]([O:29][CH3:30])=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][O:29][C:28]1[C:2]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)=[CH:3][C:4]2[N:8]=[CH:7][N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[C:5]=2[CH:27]=1
Reactant: COc1cc2c(cc1Br)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cnn(C)c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A suspension of (1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (30 mg, 0.06 mmol) from Step 1 of this Example and 1-methylpyrazole-4-boronic acid pinacol ester (26 mg, 0.1 mmol) in DME (300 μL) was added aq 2M K2CO3 (150 μL, 0.2 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of dichlorobis(triphenylphosphine)palladium II (4 mg, 0.006 mmol). Argon was bubbled into the mixture for an additional 5 min and then the mixture was heated in a sealed tube for 15 h. The mixture was cooled to rt and then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC, using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (16 mg, 53%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.97-8.06 (m, 2H), 7.87 (s, 1H), 7.80 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.27-7.33 (m, 1H), 7.19-7.25 (m, 2H), 5.44 (s, 2H), 4.78 (d, J=4.3 Hz, 1H), 3.85 (s, 6H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56-1.66 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 489 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2ncoc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ncoc2c1

Procedure:
6-Methylbenzoxazole was reacted with NBS (1 eq) and catalytic amount of benzoyl peroxide in CCl4 at 90° C. for 12 h to obtain 6-bromomethylbenzoxazole which was purified by flash chromatography (EtOAc:Hexane=1:5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ccncc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2Cl)CC1

Procedure:
The pyridine from step (a) above (5 g, 3.38 mmol) and tert-butylpiperazinecarboxylate (6.29 g, 3.38 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound as an orange oil. MS (ESI, pos. ion) m/z: 298 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH2:15][C@@:16]([OH:28])([CH3:27])[CH2:17][N:18]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[N:20]=[C:19]1Cl)=[O:13])[CH2:7][CH2:6][CH2:5]2.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH2:15][C@:16]1([CH3:27])[O:28][C:19]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:18]3[CH2:17]1)=[O:13])[CH2:7][CH2:6][CH2:5]2
Reactant: C[C@](O)(COC(=O)N1CCCc2cc(Cl)ccc21)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COC(=O)N2CCCc3cc(Cl)ccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To the solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 6-chloro-3,4-dihydro-2H-quinoline-1-carboxylate prepared in Example 116 (1.84 g, 4.29 mmol) in DMF (10 ml), sodium hydride (0.21 g, 5.15 mmol) was added followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice-water was added, the solution was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) and recrystallized from acetonitrile-isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 6-chloro-3,4-dihydro-2H-quinoline-1-carboxylate (0.68 g, yield 40%) as a white solid.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:36])[C:12]([O:28]CC3C=CC=CC=3)=[C:13]([C:15]3[S:16][C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:18][N:19]=3)[N:14]=[C:3]21.[CH3:37][N:38]([CH3:44])[C:39](=[O:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:17]2[S:16][C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:40](=[O:41])[C:39]([N:38]([CH3:44])[CH3:37])=[O:43])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]5)[CH2:5][N:4]4[C:11](=[O:36])[C:12]=3[OH:28])=[N:19][CH:18]=2)=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: NC12CCC(CC1)Cn1c2nc(-c2ncc(Cc3ccc(F)cc3)s2)c(OCc2ccccc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(-c2ncc(Cc3ccc(F)cc3)s2)c(O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.32 %

Procedure:
To a stirred solution of 10-amino-3-(benzyloxy)-2-(5-(4-fluorobenzyl)-1,3-thiazol-2-yl)-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Example 5 (35 mg, 0.085 mmol) in DMF (2 mL) was added 2-(dimethylamino)-2-oxoacetic acid (19.87 mg, 0.170 mmol), N,N-diisoproplylethylamine (0.119 mL, 0.679 mmol), HATU (64.5 mg, 0.170 mmol) and DMAP (5.18 mg, 0.042 mmol) and the resulting mixture stirred at room temperature for 16 h. The mixture was purified by preparative HPLC to afford the title compound (7 mg, 0.013 mmol, 15.32% yield) as a light green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (1H, br. s.), 9.04 (1H, br. s.), 7.87 (1H, br. s.), 7.36 (2H, dd, J=8.16, 5.65 Hz), 7.19 (2H, t, J=8.78 Hz), 4.29 (2H, s), 4.06 (2H, d, J=3.51 Hz), 3.04 (3H, s), 2.87 (3H, s), 2.33-2.45 (3H, m), 2.03-2.14 (2H, m), 1.79-1.90 (2H, m), 1.60-1.71 (2H, m). LCMS (M+H)=512.01.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.N1C=CC=CC=1.[CH3:22][N:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1>O1CCCC1.O>[NH2:12][C:9]1[N:10]=[CH:11][C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:28]([C:27]3[N:23]([CH3:22])[N:24]=[C:25]([CH3:31])[CH:26]=3)=[O:29])[CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n(C)n1
Yield: 61.5 %

Procedure:
To a solution of 5-(3-aminophenoxy)pyridin-2-amine (975 mg, 4.85 mmol) and pyridine (410 μL, 5.09 mmol) in tetrahydrofuran (10 mL) was added dropwise with stirring under ice-cooling a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (807 mg, 5.09 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, extracted with ethyl acetate (×3), and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=80/20→40/100) and recrystallized from ethyl acetate-hexane to give the title compound (964 mg, 61%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous pyridine (10 mL) was added dropwise hexanoyl chloride (550 μL) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (125 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (699 mg) was obtained as a white solid (85%) in 96.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][C:33]=1[F:34])[O:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][C:22]=1[CH3:30]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[N:26][C:21]([O:20][C:19]4[CH:31]=[CH:32][C:33]([F:34])=[C:17]([F:16])[CH:18]=4)=[C:22]([CH3:30])[CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1Oc1ccc(F)c(F)c1
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1Oc1ccc(F)c(F)c1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (190 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (220 mg, 0.79 mmol, Step-1 of Intermediate-1) and 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (260 mg, 0.87 mmol, Amine-44, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:36]#[C:35][CH2:34][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (230 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (159.5 mg; 1.28 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 160 mg. HPLC-MS: m/z: 586.5 (M+H)+; Rt: 2.18 min
Reaction SMILES: Cl[C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:15][CH2:16][CH3:17].[Na+]>C(O)C>[CH2:16]([O:15][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:17]
Reactant: CC[O-]
Reactant: CCc1c(Cl)nn2c(N)nnc2c1C
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c(C)c1CC
Temperature: 55 °C
Yield: 97.4 %

Procedure:
6-Chloro-7-ethyl-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.007; 380 mg) was initially charged in ethanol (45 ml) at RT while stirring, admixed with sodium ethoxide (244 mg) and heated to 55° C. for 3 h. Then a further equivalent of sodium ethoxide was added and the mixture was stirred once again at 55° C. for 3 h. After leaving to stand over the weekend, the mixture was dried, and the residue was taken up with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 387 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1CCO[CH:28]1[C:32]1[O:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=1>Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:35]4[O:36][C:32]([CH:28]=[O:27])=[CH:33][CH:34]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Product: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
(4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (4.0 g, 11.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (J. Chem. Soc., Chem. Commun., (1988), 560) (6.0 g, 14.0 mmol) were reacted together in a procedure analogous to Procedure B above for 20 hrs. The reaction mixture was allowed to cool, 1N HCl (50 ml) added and stirred at room temperature for 15 minutes. The reaction was filtered and the residue washed with dioxane (20 ml) and 2N HCl (20 ml). The combined filtrate and washings were stirred at room temperature for a further hour. The dioxane was removed under vacuum, the reaction diluted with water and the solid which precipitated was collected by filtration, and washed with water, iso-hexane and acetone. This precipitate was converted to the free base by partitioning into a mixture of triethylamine, ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulphate) and the solvent removed under vacuum. The residue was triturated with iso-hexane/ethyl acetate to give the product (2.41 g, 52%) as a yellow solid; δH [2H6]-DMSO 10.60 (1H, b, NH), 9.83 (1H, s, CHO), 9.30 (1H, s, 2-H), 9.08 (1H, s, 5-H or 8-H), 8.76 (1H, s, 5-H or 8-H), 7.89 (1H, d, furan-H), 7.82 (2H, d, 2′-H, 6′-H), 7.65–7.42 (6H, m, 5×Ph-H, furan-H), 7.21 (2H, d, 3′-H, 5′-H), 5.26 (2H, s, OCH2); m/z (M+1)+423.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](C(OCCCCCCCCCCCC)=O)([C:43]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:44])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](C(OCCCCCCCCCCCC)=O)([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])[C:2]1=2>CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:43]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[O:44])=[C:7]3[C:11](=[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:14])[C:2]1=2)[CH:10]=[CH:9][S:8]3
Reactant: CCCCCCCCCCCCOC(=O)C1(C(=O)OCCCCCCCCCCCC)c2ccsc2C(C(=O)OCCCCCCCCCCCC)(C(=O)OCCCCCCCCCCCC)c2ccsc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOC(=O)c1c2ccsc2c(C(=O)OCCCCCCCCCCCC)c2ccsc12
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 32.9 %

Procedure:
In a one-necked flask, tetradodecyl benzo[1,2-b:4,5-b′]dithiophene-4,4,8,8-tetracarboxylate (9.0 g, 8.65 mmol) was dispersed in DMF (80 mL). The mixture was stirred at 120° C. for 10 minutes until the solution became clear. After air was purged in the flask, NaI (800 mg) was added and the reaction mixture was refluxed for 24 hours. After the solvent was evaporated under vacuum, water (30 mL) was added to the residue to form a mixture, which was extracted with CH2Cl2. The organic layer was combined, dried, and concentrated. The crude product was purified by flash chromatography (eluent: CH2Cl2:hexane=7:3) to give didodecyl benzo[1,2-b:4,5-b′]dithiophene-4,8-dicarboxylate (yield: 1.75 g, 32.9%). 1H NMR (CDCl3): 0.9 (6H, t), 1.3 (28H, m), 1.4 (4H, m), 1.6 (4H, m), 1.9 (4H, m), 4.6 (4H, t), 7.8 (2H, d), 8.3 (2H, d).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[NH:7][C:8]([CH3:13])=[CH:9][C:10](=[O:12])[CH:11]=1.[C:14](O)(=[O:16])C>[OH-].[Na+]>[CH3:5][C:6]1[NH:7][C:8]([CH3:13])=[CH:9][C:10](=[O:12])[C:11]=1[CH:14]=[O:16]
Reactant: CC(=O)O
Reactant: Cc1cc(=O)cc(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)c(C=O)c(C)[nH]1

Procedure:
Chloroform (12 ml) was added in 1 ml portions over a period of 2 hours to a refluxing solution of 2,6-dimethyl-4-(1H)-pyridone (6.2 g) in 4M aqueous sodium hydroxide (112 ml). The solution was heated under reflux for 6 hours, cooled and acidified to pH 6 with acetic acid. Volatile material was removed by evaporation and the residue was extracted with methanol (3×100 ml). The extracts were concentrated and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (1:9 v/v), to give 2,6-dimethyl-3-formyl-4(1H)-pyridone (B) (2.1 g) as a solid, m.p. >100° C. (decomposition); NMR (d6 -DMSO): 2.2(s,3H), 2.5(s,3H), 6.1(s,1H), 10.25(s,1H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:10]=[N:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:13]([O:12][N:11]=[CH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1(C=NOCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-cyclopentanecarboxylic acid methyl ester (2.26 g, 8.65 mmol) and sodium hydroxide (1.0 g, 25.9 mmol) in THF (15 mL), methanol (15 mL) and water (5 mL) was stirred at room temperature for 18 h. The reaction mixture was acidified to pH 4 with 3N aqueous HCl and was extracted with dichloromethane (50 mL×3). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale yellow oil. (1.91 g, 89%). MH+248.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.C(O)C>C(O)(=O)C.[Ni].[Al]>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:2]=1[Cl:1])[C:6]([C:8]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)=[O:7]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1cc2ccccc2o1
Agent: [Ni]
Agent: [Al]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(C(=O)c2cc3ccccc3o2)ccc1Cl

Procedure:
37 g 2-(4-Chloro-3-nitrobenzoyl)-benzo[b]furan are refluxed with agitation for 4 hours in a mixture of 500 ml 50% aqueous acetic acid, 250 ml ethanol and 90 g powdered nickel/aluminum alloy (1:1). After filtration of the metal powder, the solvent is distilled off, water is added to the residue, and extraction is carried out with ethyl acetate. After evaporation of the solvent, colorless crystals having a melting point of 137° C. (from isopropanol) are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])[CH2:3][CH2:2]1.[O:13]1[CH2:28][CH:14]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:27])[NH:22]2.[ClH:29]>C(O)C>[ClH:29].[OH:13][CH:14]([CH2:28][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([O:9][CH2:10][CH3:11])=[O:12])[CH2:5][CH2:6]1)[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:27])[NH:22]2
Reactant: CCOC(=O)NC1CCNCC1
Reactant: O=C1CCc2c(cccc2OCC2CO2)N1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)NC1CCN(CC(O)COc2cccc3c2CCC(=O)N3)CC1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Ethyl 4-piperidylcarbamate (2 g), from Preparation 4, and 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (2.54 g), from Preparation 5, were dissolved in ethanol (50 mL) and the resulting solution was heated under reflux for 6 hours and then cooled to room temperature. Concentrated hydrochloric acid (1 mL) was added. A white product precipitated, which was collected by filtration. The crude product was recrystallized from ethanol to yield 2.8 g (56.5%) of 3,4-dihydro-5-[2-hydroxy-3-(4-(ethoxycarbonylamino)-1-piperidyl)propoxy]carbostyril hydrochloride, m.p. 232°-234° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: Cc1nnc(-c2cc3c(O)cccc3o2)o1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: Cc1nnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Yield: 28.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4-hydroxybenzo(b)furan-2-yl)-5-methyl-1,3,4-oxadiazole (3.3 g) and (S)-glycidyl nosylate (3.7 g), the title compound (1.1 g) was obtained as white crystals.