Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)[CH:5]=1.[C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH3:26]>>[C:29]([O:28][C:25](=[O:27])[CH2:26][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:11]=2)[CH:5]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Reactant: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1

Procedure:
Reaction of (RS)-3-[2-(tetrahydropyran-2-yloxymethyl)-pyridin-4-yl]-benzoic acid methyl ester with tert.-butyl acetate according to general procedure K (method d; example K15) yielded compound K9.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[OH:26][C@H:25]([CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: C1CCNC1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN1CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), and pyrrolidine (176 mg, 2.48 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified on silica gel, gradient elution with dichloromethane, dichloromethane/methanol (95/5), dichloromethane/methanolic ammonia (7M) (98/2 to 90/10), to give (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (326 mg, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:37]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1[Cl:37])=[CH:13][C:12]([F:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c2cc(F)cnc2n(Cc2ccc(OC)cc2)c1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cl)c2cc(F)cnc2n(Cc2ccc(OC)cc2)c1=O
Yield: 85 %

Procedure:
A solution of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (74) (7.0 g, 18.79 mmol) and triethylamine (5.2 mL, 37.58 mmol) was heated in neat POCl3 at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 6.2 g (85%) of 4-chloro-6-fluoro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (76) as yellow waxy solids. 1H-NMR (DMSO-d6): δ 1.31 (t, J=7.2 Hz, 3H), 3.70 (s, 3H), 4.37 (q, J=7.2 Hz, 2H), 5.51 (s, 2H), 6.84 (m, 2H), 7.24 (m, 2H), 8.37 (dd, J=2.8, 8.0 Hz, 1H), 8.82 (d, J=2.8 Hz, 1H); EIMS: 391 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:12])([CH3:13])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)C(C)(C)CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 79.4 %

Procedure:
2,2-Dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (156 mg, 0.78 mmol) from above was mixed with 2-chloro-5-nitropyridine (124 mg, 0.78 mol) in tetrahydrofuran (2 mL) containing triethylamine (0.24 mL). The mixture was heated in a microwave at 140° C. for 30 minutes. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was triturated with ether to give 2,2-dimethyl-3-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid methyl ester (199 mg) as a crystalline material. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([CH3:27])=[N:11][N:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[N:20]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH3:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:29][C:30]2[CH:31]=[C:32]([CH3:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=2)[C:9]2[C:10]([CH3:27])=[N:11][N:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[N:20]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1ccnc(OC)n1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C)nn1-c1ccnc(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2-methoxypyrimidin-4-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 59.4) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.90 min (HPLC 1); tR: 1.15 min (LC-MS 2); ESI-MS: 523 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[CH2:3]1.[CH3:18]O.Cl>>[O:1]=[C:2]1[N:6]([C@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1
Reactant: CO
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C(=O)O)CC1=O
Agent: Cl
Product: COC(=O)[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1

Procedure:
(S)-5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid (1.16 g, 5 mmol) was treated with CH3OH/HCl (10 mL, 1 M) for 3 h. The excess CH3OH/HCl was removed under reduced pressure. The residue was basified with saturated aqueous NaHCO3 to pH 8. The aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give (S)-methyl 5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate, which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 7.24-7.37 (m, 5H), 5.48 (q, J=7.2 Hz, 1H), 3.72 (s, 3H), 3.51-3.56 (m, 1H), 3.03-3.21 (m, 2H), 2.62-2.79 (m, 2H), 1.53 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:25]=[C:24]([C:26]#[N:27])[C:19]([C:20]([O:22]C)=O)=[C:18]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.CC(O)=O>[CH3:33][N:31]1[CH:32]=[C:28]([C:18]2[C:19]3[C:20](=[O:22])[NH:27][CH2:26][C:24]=3[CH:25]=[C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[N:17]=2)[CH:29]=[N:30]1
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A solution of methyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (110 mg, 0.242 mmol) and palladium on carbon (2.58 mg, 0.024 mmol) in MeOH (5 mL) and HOAc (1 mL) was stirred at RT overnight under H2 atmosphere. After reaction, the mixture was filtered through Celite, the filtrate was evaporated, and the residue was diluted with MeOH and sat aq NaHCO3. The mixture was stirred at RT for 30 min and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 and preparative HPLC to give the title compound (60 mg, 58.1%). 1H NMR (500 MHz, CDCl3) δ ppm 1.26-1.87 (m, 17H), 3.91 (s, 3H), 4.25 (br s, 2H), 5.16-5.49 (m 2H), 6.23 (br s, 1H), 6.75 (br s, 1H), 8.18-8.44 (m, 1H), 8.76-9.05 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC#N>[CH2:16]([N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([N:19]([CH3:18])[CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:3]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CNC1CCOCC1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(cnn2CC)c1N(C)C1CCOCC1
Yield: 76.5 %

Procedure:
Intermediate 1 (1.2 g, 4.76 mmol), Intermediate 50 (0.79 g, 5.2 mmol) and diisopropylethylamine (4 ml, 24 mmol) in MeCN (8 ml) was heated at 70° C. for 24 hours. The solvent was removed in vacuo and the residue partitioned between DCM and water. The organic phase was concentrated in vacuo and the residue chromatographed on silica (50 g) eluting with cyclohexane:ethyl acetate (2:1 followed by 1:1 then 1:2). Appropriate fractions were combined and evaporated to give Intermediate 51 as a brown oil (1.21 g). LCMS showed MH+=334; TRET=2.61 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:47])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=O)[C:42]([F:45])([F:44])[F:43])[CH:36]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:49][OH:50].N1C=CC=CC=1>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:47])[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[NH:22][C:21]=2[N:20]=[C:19]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=[N:49][OH:50])[C:42]([F:43])([F:44])[F:45])[CH:36]=2)[N:18]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Temperature: 65 °C
Yield: 100 %

Procedure:
A mixture of methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (0.180 g, 0.274 mmol), hydroxylamine hydrochloride (0.023 g, 0.329 mmol) and pyridine (0.355 mL) in MeOH (1.9 mL) was heated in a microwave oven to 65° C. for 48 hours. After concentration of the reaction mixture to dryness, a solution of the residue was washed with sat. NaHCO3 (15 mL), the organic layer was dried over anh. MgSO4, filtered and concentrated to dryness to afford methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (184 mg, 100% yield) as a light yellow foam: MS m/z 672.3 (M+H)+; HPLC 96.0% @ 220 nm and 91.4% @ 254 nm, RT=2.01 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=O)[CH2:8][C:7]=2[CH:13]=1.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[CH:13]=1
Reactant: CCCNCCC
Reactant: COc1ccc2c(c1)CC(=O)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1COc2ccc(OC)cc2C1

Procedure:
A mixture of 11.58 g of 6-methoxy-3,4-dihydro-2H-[1]-benzopyran-3-one, 26 g of dipropylamine, 0.3 ml of trifluoroacetic acid and 160 ml of toluene is refluxed in a Dean-Stark apparatus for 2 hours. The solution concentrated in vacuo and the residue is added to a solution of 8 g of sodium cyanoborohydride in 160 ml of ethanol and 40 ml of acetic acid. After 15 minutes at room temperature most of the solvent is removed in vacuo. The residue is dissolved in 6N hydrochloric acid and washed with ether. The aqueous layer is made basic and the product is extracted with ether. The aqueous layer is made basic and the product is extracted with ether. The ether layer is dried over magnesium sulfate and the solvent is removed in vacuo, to afford 6-methoxy-3,4-dihydro-N,N-di-propyl-2H-[1]-benzopyran-3-amine. The fumaric acid salt melts at 107°-113°.
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:9]1[C:2]2[S:16][C:15]([C:14]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: 140 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
A mixture of 600 mg of 2-fluoro-3-(trifluoromethyl)benzaldehyde, 398 mg of methyl thioglycolate, 694 mg of potassium carbonate and 10 ml of DMF was stirred at 140° C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was washed with tert-butyl methyl ether three times. To the aqueous layer was added hydrochloric acid, then, the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue was added water to cause deposition of a solid which was then collected by filtration, and dried under reduced pressure. To the resultant solid were added 20 ml of methanol and 0.31 ml of oxalyl chloride, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled down to room temperature, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 338 mg of methyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 4).
Reaction SMILES: Cl.[CH2:2]([NH:7][N:8]=[CH:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH:24]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22][C:21]=3[CH:32]=2)=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6].C(O)(=O)C>C(O)C.[OH-].[Na+]>[CH2:2]([NH:7][N:8]=[CH:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH:24]([CH2:26][C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C:21]=3[CH:32]=2)=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)OCC)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1

Procedure:
0.15 g (0.31 mmol) of the ester from Example 94 were stirred overnight at room temperature in a mixture of 10 ml ethanol and 0.7 ml 2 N aqueous sodium hydroxide solution. It was brought to pH 4 with 2 N acetic acid, and the precipitate of the title acid was filtered, washed successively with water and with acetone, and dried in vacuo. Yield: 98 mg (75%) of colorless crystals, m.p. 223-225° C. (dec.).
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[N:13]=[C:14]([CH3:20])[C:15](SC(=O)C)=[C:5]12)(=O)C.Cl>C(O)C>[CH3:20][C:14]1[CH:15]=[C:5]2[NH:4][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]2[N:13]=1
Reactant: CC(=O)Sc1c(C)nn2c3ccccc3n(C(C)=O)c12
Agent: Cl
Solvent: CCO
Product: Cc1cc2[nH]c3ccccc3n2n1

Procedure:
4-Acetyl-3-acetylthio-2-methylpyrazolo[1,5-a]benzimidazole (2.0 g, 6.97 mmole) was added to a mixture of concentrated hydrochloric acid (5 ml) and ethanol (30 ml) and refluxed for 5 hr. A yellow solid precipitated during the heating period and was filtered off after cooling, 0.9 g. This was a mixture of several components, none of them being the required product, and was discarded. The ethanolic solution was poured into a solution of sodium bicarbonate (excess) in water (300 ml) and the white solid filtered off, washed and dried, 0.7 g, 61%, mp. 250°-252° C. IR and TLC (+ Dox spray test) comparison with authentic (6) showed the samples to be identical.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][O:9][C:8]=2[CH:15]=1.Cl.[CH3:17][O:18][C:19](=O)[O:20]C>>[CH3:17][O:18][C:19]([CH:12]1[CH2:11][CH2:10][O:9][C:8]2[CH:15]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=2[C:13]1=[O:14])=[O:20]
Reactant: O=C1CCCOc2cc(F)ccc21
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCOc2cc(F)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A suspension of sodiumhydride in parrafin (0.49 g, 60%) was added to 5 ml dimethylcarbonate. To this suspension 8-Fluoro-3,4-dihydro-2H-benzo[b]oxepin-5-one (6.2 mmol) dissolved in 2 ml dimethylcarbonate was added dropwise at room temperature. The mixture was refluxed for two hours, cooled to room temperature and stirred overnight. 25 ml of 2 mol/l hydrochloric acid were added to the mixture. The resulting solution was extracted by ethyl acetate. The organic phase was dried over sodiumsulfate and the solvent removed in vacuo. The residue was dissolved in diethyl ether. 8-Fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester was obtained by crystallization from this solution in a yield of 7%. LC-MS: 1.8 min, 238.0 (MH+), 2.4 min, 238.0 (MH+)
Reaction SMILES: CN1CCOCC1.[C:8]([NH:11][CH:12]([CH:16]=[CH2:17])[C:13]([OH:15])=O)(=[O:10])[CH3:9].C(OC(Cl)=O)C(C)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:8]([NH:11][CH:12]([CH:16]=[CH2:17])[C:13]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])(=[O:10])[CH3:9]
Reactant: C=CC(NC(C)=O)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=CC(NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
4-Methylmorpholine (0.71 g, 6.99 mmol) was added to a suspension of 2-acetamido-2-vinylacetic acid (1.00 g, 6.99 mmol) in THF (325 mL), and the mixture was stirred at room temperature (30 min). The reaction was cooled to -10° to -15° C. and then isobutylchloroformate (1.24 g, 9.08 mmol) was then added dropwise. After stirring (10 min), a solution of benzylamine (0.75 g, 6.99 mmol) in THF (25 mL) was added (15 min). The reaction mixture was allowed to warm to 0° C. The insoluble material was filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on SiO2 gel using 3% MeOH/CHCl3 as the eluant to give 1.00 g (62%) of the desired product: mp 136°-138° C. (recrystallized from EtOAc); Rf 0.24 (3% MeOH/CHCl3); 1H NMR (DMSO-d6) δ 1.88 (s, C(O)CH3), 4.27 (d, J=5.6 Hz, CH2), 4.89-4.94 (dd, J=6.4, 7.8 Hz, α-CH), 5.13-5.30 (m, --CH=CH2), 5.81-5.93 (m, --CH=CH2), 7.20-7.33 (m, 5 PhH), 8.27 (c, J=7.8 Hz, NH), 8.58 (t, J=5.6 Hz, NH); 13C NMR (DMSO-d6) 22.47 (C(O)CH3), 42.05 (CH2), 55.24 (α-CH), 116.44 (CH=CH2), 126.74 (C4'), 127.05 (2C2' or 2C3'), 128.24 (2C2' or 2C3'), 134.76 (CH=CH2), 139.25 (C1'), 168.78 (C(O)CH3), 168.99 (C(O)NH) ppm.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[O:22][B:23](OC)[O:24]C.Cl>C1COCC1.O>[CH2:6]([C:14]1[CH:19]=[CH:18][C:17]([B:23]([OH:24])[OH:22])=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCc1ccc(I)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
n-Butyllithium (BuLi, 1.6 M in hexanes, 2.4 mL, 3.8 mmol) was added dropwise to a stirred solution of p-n-octyliodobenzene (1.0 g, 3.2 mmol) in dry THF (15 mL) at −78° C. under nitrogen. After stirring for 30 minutes and maintaining the temperature at −78° C., trimethylborate (0.4 g, 3.8 mmol) was added dropwise. The system was allowed to return to room temperature after 1 hour and was left stirring under nitrogen overnight. Concentrated HCl (8 mL) and water (15 mL) were then added and stirring was continued for 2 hours. The mixture was extracted with ether (15 3 mL). The ethereal phase was combined and was washed with brine and water (20 2 mL), dried with MgSO4, and the solvent removed in vacuo to give p-n-octylphenylboronic acid as a white solid (0.63 g, 84% yield).
Reaction SMILES: C(OC(=O)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:14]=[C:15]([CH:25]([CH3:27])[CH3:26])[S:16][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[N:19]=2)[C:8]=1[O:28][CH3:29])C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.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>[Cl:24][C:20]1[N:19]=[C:18]([C:17]2[S:16][C:15]([CH:25]([CH3:27])[CH3:26])=[N:14][C:13]=2[C:9]2[C:8]([O:28][CH3:29])=[C:7]([CH:12]=[CH:11][CH:10]=2)[NH2:6])[CH:23]=[CH:22][N:21]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1c(N)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.2 %

Procedure:
To the solution of 2-propen-1-yl[3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate (12.1 g, 22.5 mmol) in DCM (200 mL), acetic acid (3.8 mL, 66.6 mmol), Pd(PPh3)2Cl2 (0.45 g, 0.56 mmol) were added. Then tri-n-butyl tin hydride (8.5 mL, 33 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by added the saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (200 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (500 mL) to afford the title compound of Step G (10 g, 60.8% yield), which was used directly in the next step.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3C=CC(C(N4CCN(C/C=C/C5C=CC=CC=5)CC4)=O)=CC=3)[N:30]=2)=[CH:20][CH:19]=1>>[ClH:15].[ClH:15].[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=2[C:21]([C:29]2[C@H:38]3[C@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([CH2:40][C:36]3[CH:37]=[CH:38][C:33]([C:32]([N:4]4[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][N:9]5[CH2:10][CH2:11][O:12][CH2:13][CH2:14]5)[CH2:6][CH2:5]4)=[O:39])=[CH:34][CH:35]=3)[N:30]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Reactant: C1CN(CCN2CCOCC2)CCN1
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)N4CCN(CCN5CCOCC5)CC4)cc3)C(=O)[C@H]3CC=CC[C@@H]23)c2c1OC(C)(C)C2

Procedure:
Prepared from intermediate product A11 and 4-(2-piperazin-1-yl-ethyl)-morpholine as described for compound 8. M.p. 210–211° C.