Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].Cl.[C:20]1([S:26]([N:29]2[C:33]3=[N:34][CH:35]=[C:36]([N+:45]([O-:47])=[O:46])[C:37]([NH:38][CH:39]4[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]4)=[C:32]3[CH:31]=[CH:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([N:41]3[CH2:42][CH2:43][CH2:44][CH:39]([NH:38][C:37]4[C:36]([N+:45]([O-:47])=[O:46])=[CH:35][N:34]=[C:33]5[N:29]([S:26]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)(=[O:28])=[O:27])[CH:30]=[CH:31][C:32]=45)[CH2:40]3)=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
Fmoc-Cl (3.16 g, 12.2 mmol) was added to a solution of crude (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl-amine hydrochloride (5.34 g, 12.2 mmol) and diisopropylethylamine (5.31 ml, 30.5 mmol) in CH2Cl2 (100 ml) at 0° C. The reaction mixture was warmed to 25° C. and stirred for 18 h, then was partitioned between half-saturated NaHCO3 (225 ml) and CH2Cl2 (2×200 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 0 to 70% EtOAc in heptanes) to afford 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (7.09 g, 93%) as a yellow solid. This material was used in the next step below without additional characterization or purification.
Reaction SMILES: C(N1CCC(=O)CC1)(=[O:8])C1C=CC=CC=1.COC(C=[P:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>C1(C)C=CC=CC=1>[C:34]1([P:21](=[O:8])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Under N2, a mixture of 1-benzoyl-4-piperidone (10.2 g, 0.05 mol), methyl (triphenylphosphoranylidene) acetate (25 g. 0.074 mol) in toluene (100 ml) was heated at reflux for 7 hours. After stirring at room temperature overnight, the solid was filtered off to yield 13.9 g (100%) of triphenylphosphine oxide. The mother liquor was concentrated to dryness and the residue was treated with acetic acid (42 ml), H2O, (6 ml) and 12 N HCl (6 ml). The mixture was heated at 80°-85° C. with stirring for 15 hours. The reaction was then concentrated to dryness and the residue was partitioned between saturated Na2CO3 and ethyl acetate. The aqueous layer was further extracted with ethyl acetate (1×), neutralized to pH 3 with 6 N HCl and extracted with ethylacetate (4×). The organic layer was dried, filtered and concentrated to dryness to yield 7.2 g (59%) of title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:16])([CH:14]=[CH2:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([CH:14]=[CH2:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C=CC1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: C=CC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Temperature: 25 °C

Procedure:
2-Chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one, 4-amino-3-methoxy benzoic acid (1.2 equivalent), i-PrOH and conc. HCl (30 drops) were heated to 95° C. for 18 hours. A this time the reaction was cooled to room temperature and filtered to reveal the product as a tan solid in good yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.75 (m, 6H) 1.85 (m, 2H) 3.29 (s, 3H) 3.73-3.97 (m, 2H) 3.93 (s, 3H) 4.94 (m, 1H) 5.40-5.54 (m, 2H) 6.05 (m, 1H) 7.48-7.65 (m, 2H) 8.09 (d, J=8.34 Hz, 1H) 8.23 (s, 1H) 9.51 (br. s., 1H). [M+H] calculated for C23H26FN5O4, 456. found 456.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:28][C:29]1[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=1[CH2:31][C:32]1[O:33][C:34]([CH3:38])=[C:35]([CH3:37])[CH:36]=1>CN(C)C=O.C(Cl)Cl>[Br:28][C:29]1[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=1[CH2:31][C:32]1[O:33][C:34]([CH3:38])=[C:35]([CH3:37])[C:36]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11]
Reactant: Cc1cc(Cc2ccccc2Br)oc1C
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(Cc3ccccc3Br)oc(C)c2C)cc1C1CCCC1
Yield: 66.4 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (2.00 g, 9.08 mmol, RN-59216-82-9), oxalyl chloride (0.871 mL, 9.99 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (1.17 mL, 4.58 mmol) and 2-(2-bromo-benzyl)-4,5-dimethyl-furan (2.41 g, 9.08 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 4% EtOAc/pet. ether gave 2.82 g (66%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ 1.40-1.44 (m, 2 H), 1.57-1.73 (m, 4 H), 1.79 (s, 3 H), 1.87-1.93 (m, 2 H), 2.16 (s, 3 H), 3.21 (quintet, 1 H), 3.86 (s, 3 H), 3.93 (s, 2 H), 7.04 (d, 1 H), 7.11-7.18 (m, 2 H), 7.29 (t, 1 H), 7.51 (dd, 1 H), 7.54-7.60 (m, 2 H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl-].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][Zn+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=2)[C:11]=1[CH3:12]
Reactant: COc1cccc(C[Zn+])c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cccc(Cc2nc3cc(F)cc(F)c3c(Cl)c2C)c1

Procedure:
Prepared according to procedure Z using 2,4-dichloro-5,7-difluoro-3-methylquinoline (350 mg, 1.41 mmol), Pd(PPh3)4 (163 mg, 0.14 mmol), 3-methoxy-benzylzinc chloride (0.5M in THF, 2.96 mL, 1.48 mmol), and THF (3.5 mL). Purification by column chromatography (silica gel, 0-8% EtOAc in hexanes as eluent) gave 4-chloro-5,7-difluoro-2-(3-methoxybenzyl)-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=334.0 (M+1).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH:23]2[N:28]([C:29](=[O:38])[NH:30][C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)[CH:16]=1>>[ClH:1].[ClH:1].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH:23]2[CH2:24][NH:25][CH2:26][CH2:27][N:28]2[C:29]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=2)=[O:38])[CH:16]=1
Reactant: Cc1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2CCc2cccnc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)N2CCNCC2CCc2cccnc2)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 3-(2-(pyridin-3-yl)ethyl)-4-(p-tolylcarbamoyl)piperazine-1-carboxylate TFA salt (133.9 mg, 0.248 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 89.3 mg (90%) of the desired product as a white solid. LC-MS: RT=3.16 min, [M+H]+=325.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[O:13]([C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[O:13]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:28][CH:29]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccccn1
Reactant: BrCCOc1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(Oc2ccc(OCCCc3ccccn3)cc2)cc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a solution of α-picoline (1.0 g, 11 mmol) in dry tetrahydrofuran (20 ml), n-butyl lithium (8 ml, 11 mmol; 1.4 mmol/ml) was added at -50° C. under nitrogen stream until the reaction mixture turned red. After stirring at -50° C. for 30 minutes, 2-(4-phenoxyphenoxy)ethyl bromide (3.0 g, 10 mmol) was dropwise added thereto at -50° C., and stirring was continued at the same temperature for 2 hours and at 20° C. for 12 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give 2-[3-(4-phenoxyphenoxy)propyl]pyridine (1.6 g) as pale yellow oil. nD24.5 1.5861.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](Cl)=O.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:10]([CH2:9][C:8]([CH3:14])([CH3:13])[CH3:7])[O:6][N:5]=1
Reactant: N=C(CCl)NO
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1nc(CCl)no1
Temperature: 130 °C
Reaction time: 5 h
Yield: 8.1 %

Procedure:
2.0 g of 2-chloro-N-hydroxyacetoamidine and 2.6 g of 3,3-dimethylbutyryl chloride were dissolved in 30 ml of N,N-dimethylformamide, and 2.05 g of triethylamine was added dropwise under ice-cooling. After completion of the addition, the mixture was stirred at 130° C. for 5 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 3-(chloromethyl)-5-(2,2-dimethylpropyl)-1,2,4-oxadiazole.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH:6]=[C:7]([NH2:9])[NH2:8])[CH3:3].C(N(CC)CC)C.[C:18](#[N:21])[CH:19]=[CH2:20]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:10])[C:6]([CH2:20][CH2:19][C:18]#[N:21])=[C:7]([NH2:9])[NH2:8])[CH3:3]
Reactant: C=CC#N
Reactant: CCOC(=O)C=C(N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)=C(N)N
Yield: 25 %

Procedure:
The resulting 3,3-diamino-acrylic acid ethyl ester hydrochloride (2.2 g, 13.2 mmol) was suspended in tetrahydrofuran (40 mL) followed by the addition of triethylamine (2 mL, 14.3 mmol) and acrylonitrile (1.2 mL, 19.3 mmol) and refluxing while heating for 6 hours. Following completion of the reaction, the resulting triethylamine hydrochloride was filtered out and the filtrate was concentrated to obtain the title compound (0.6 g, 3.3 mmol, 25%).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:33][C@@H:34]([CH3:38])[C:35](O)=[O:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[OH:33][C@H:34]([CH3:38])[C:35]([N:30]1[CH2:31][CH2:32][CH:27]([C:24]2[N:23]=[C:22]([NH:21][C:9]3[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][C:12]([S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:11][N:10]=3)[S:26][N:25]=2)[CH2:28][CH2:29]1)=[O:36]
Reactant: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](O)C(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio)pyridin-2-amine (Example 39, step C, 0.075 g, 0.16 mmol), (S)-2-hydroxypropanoic acid (0.018 g, 0.19 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.047 g, 0.24 mmol), and N,N-dimethylpyridin-4-amine (0.002 g, 0.016 mmol) were dissolved in CH2Cl2 (5 mL). Triethylamine (0.033 g, 0.32 mmol) was added and the solution was stirred at room temperature for 3 hours. Water was added and extracted with CH2Cl2, dried, filtered, and concentrated. The residue was purified by silica gel (1-2% MeOH in CH2Cl2) to give (R)-2-hydroxy-1-(4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)propan-1-one (0.023 g, 27% yield). 1H NMR (d6-DMSO) δ 12.34 (s, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.66 (dt, 1H), 7.47 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.82 (t, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 4.01 (m, 1H), 3.25-3.04 (m, 2H), 2.84 (m, 1H), 2.02 (d, 2H), 1.81-1.55 (m, 2H), 1.18 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.CCN=C=NCCC[N:21]([CH3:23])C.Cl.C(N(CC)CC)C.N[O:33][CH3:34].Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:21]([O:33][CH3:34])[CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CON
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A mixture of 4-fluorocinnamic acid (16.6 g), EDAC.HCl (23 g), DMAP (12.2 g), triethylamine (28 mL), and NH2OMe.HCl (12 g) in CH2Cl2 (300 mL) was stirred at room temperature for 16 h. The reaction was quenched with water, and the organic layer was washed with brine, dried over MgSO4 and filtered. The filtrated was evaporated in vacuo, and the crude product was purified by silica gel flash chromatography eluting with 33% hexanes in ethyl acetate gave the title compound (20.5 g) as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1.[OH-].[Na+].C1(C)C=CC=CC=1>C(#N)C.O>[Cl:3][CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Br)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: ClCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 134 %

Procedure:
To a mechanically-stirred solution of 78.12 g of thionyl chloride in 450 mL of acetonitrile at 15° C. was added a solution of 160.75 g of 3-hydroxymethyl-6-bromopyridine in 446 mL of acetonitrile over 30 minutes. The temperature rose to 22° C. during the addition, and the reaction mixture was stirred for 15 minutes at room temperature. The mixture was cooled in an ice bath, and a solution of 70 g of NaOH in 1.4 L of water was added at such a rate that the temperature did not exceed 15° C. 603 mL of toluene was added to the mixture and stirred rapidly. The layers were separated. The aqueous phase was reextracted with toluene. The combined organic phase was concentrated in vacuo to give 181.61 g of 3-chloromethyl-6-bromopyridine.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:4]([NH:6]C(=O)OC(C)(C)C)[CH3:5]>C(OCC)(=O)C>[Cl-:1].[OH:2][C@H:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:4]([NH3+:6])[CH3:5]
Reactant: Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H]([NH3+])[C@H](O)Cc1ccccc1
Product: [Cl-]
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
Hydrochloric acid (5 to 6 M in isopropanol, 4 mL) was added to a solution of tert-butyl (2S,3R)-3-hydroxy-4-phenylbutan-2-ylcarbamate (640 mg, 2.41 mmol) in ethyl acetate (4 mL). The mixture was stirred at 50° C. for 2.5 h and then concentrated. The solid was dissolved in warm ethanol (4-5 mL). Diethyl ether (ca 15 mL) was added under stirring to give the subtitle compound as a light lilic precipitate (290 mg, 60%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12](N(C(C)C)CC)(C)[CH3:13].C([Sn](CCCC)(CCCC)C=C)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1)=[CH2:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(Br)ccc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)c(OC)c1
Temperature: 90 °C
Yield: 91.3 %

Procedure:
To a solution of 4-bromo-2-methoxybenzonitrile (−0.5 g, 2.36 mmol, 1.0 eq) in toluene (12 mL) was added diisopropylethylamine (0.61 g, 0.82 mL, 4.72 mmol, 2.0 eq), and tributyl(vinyl)tin (1.12 g, 1.03 mL, 3.54 mmol, 1.5 eq). The reaction mixture was degrassed by bubbling agron through the mixture. Tetrakis(triphenylphosphine)palladium (0.10 g, 0.12 mmol, 0.05 eq) was added and the reaction further degassed before heating to 90° C. for 16 hours. The reaction was cooled and partitioned between EtOAc (100 mL) and NaHCO3 (100 mL). The organics were washed with brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (5→30% EtOAc-hexane) yielded the title compound (0.343 g, 91%) as a white solid; 1H nmr (CDCl3) δ 7.56-7.53 (2H, m, ArH-5, H-6), 6.92 (1H, d, J 9.0 Hz, ArH-2), 6.59 (1H, dd, J 17.5, 11.0 Hz, CH═CH2), 5.63 (1H, d, J 17.5 Hz, CH═CH2 trans), 5.23 (1H, d, J 11.0 Hz, CH═CH2 cis), 3.91 (3H, s, OCH3); m/z 160 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([OH:26])=O)[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1
Reactant: C1COCCN1
Product: O=C(Nc1nccs1)Nc1ccc(CC(=O)N2CCOCC2)cc1C(=O)C1CCCC1
Yield: 68.2 %

Procedure:
1-[2-Cyclopentanecarbonyl-4-(2-morpholin-4-yl-2-oxo-ethyl)-phenyl]-3-thiazol-2-yl-urea (151 mg, 68%) was prepared from [3-cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)-phenyl]-acetic acid (186 mg, 0.5 mmol) and morpholine (44 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[C:15]2[C:2]=1[NH:1][CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]2=[O:19])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCOC(=O)c1c[nH]c2c(C(=O)c3ccccc3)cc(Cl)cc2c1=O
Yield: 45.6 %

Procedure:
2-Amino-5-chlorobenzophenone (3.0 g) and diethyl ethoxymethylenemalonate (3.3 g) were reacted in the same manner as in Experimental Example 1 to give 8-benzoyl-6-chloro-3-ethoxycarbonyl-4(1H)-quinolone (2.1 g). The compound (1.4 g) was dissolved in methanol (24 ml). A 10% aqueous solution of NaOH (16 ml) was added to the solution, and the mixture was heated under reflux for 1 hour. After acidification of the mixture with a 10% aqueous solution of HCl, the precipitate was collected by filtration, washed with water and dried to give a carboxylic acid (1.2 g). The carboxylic acid (1.2 g) was suspended in diphenyl ether (30 ml), and the suspension was heated under reflux under a stream of argon at 280° C. for 3 hours. After the reaction mixture was left to cool, a mixed solvent of ether (50 parts) and n-hexane (50 parts) was added, and the crude crystal thus obtained was collected by filtration and recrystallized from chloroform-methanol-n-hexane to give 8-benzoyl-6-chloro-4(1H)-quinolone (compound 18, 0.6 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]1(B(O)O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[C:30]1([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: OB(O)c1cccc2ccccc12
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3cccc4ccccc34)nc2c1
Yield: 67.8 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, using methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv) and naphthalen-1-yl boronic acid (63 mg, 0.37 mmol, 1.10 equiv) as reactants. Purification via silica gel column (ethyl acetate/petroleum ether (1:20)) afforded 90 mg (69%) of methyl 3-(naphthalen-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH3:11].[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=O)[CH:16]=[N:17][CH:18]=1.[C:21](#[N:25])[CH2:22][C:23]#[N:24]>>[NH2:25][C:21]1[O:1][C:2]2[C:10]([CH:19]([C:15]3[CH:16]=[N:17][CH:18]=[C:13]([CH3:12])[CH:14]=3)[C:22]=1[C:23]#[N:24])=[CH:9][CH:8]=[C:7]1[N:6]([CH3:11])[CH2:5][CH2:4][C:3]=21
Reactant: Cc1cncc(C=O)c1
Reactant: CN1CCc2c(O)cccc21
Reactant: N#CCC#N
Product: Cc1cncc(C2C(C#N)=C(N)Oc3c2ccc2c3CCN2C)c1

Procedure:
The title compound was prepared from 4-hydroxy-2,3-dihydro-1-methylindole (0.025 g, 0.17 mmol), 5-methyl-pyridine-3-carbaldehyde (0.020 g, 0.17 mmol), and malononitrile (0.011 g, 0.17 mmol) similar to Example 22 to yield 0.017 g (32%) of a white solid. 1H NMR (DMSO-d6): 8.31 (d, J=2.2 Hz, 1H), 8.27 (d, J=1.4 Hz, 1H), 7.37 (m, 1H), 6.71 (dd, J=8.0, 0.83 Hz, 1H), 6.25 (dd, J=8.0 Hz, 1H), 6.22 (brs, 2H), 4.68 (s, 1H), 3.36 (t, J=16.8 Hz, 2H), 2.94 (t, J=16.8 Hz, 2H), 2.70 (s, 3H).