Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].B.[NH4+].[Cl-]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(C(=O)O)c1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.2 %

Procedure:
3-Amino benzoic acid (1.05 g, 7.65 mmoles) was dissolved in THF (30 mL) under nitrogen atmosphere. Borane (BH3 1M solution in THF, 24 ml, 24 mmoles) was added, and the resulting solution was stirred at room temperature for 20 hours. The reaction mixture was then poured into a saturated NH4Cl solution (100 mL) and extracted with AcOEt (3×100 mL). The organic layer was dried over Na2SO4 and evaporated to dryness to yield 388 mg of the title compound, which was employed in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][C:15]3[CH2:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:16]=3[N:17]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][C:15]3[CH2:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:16]=3[N:17]=2)[CH2:9]1
Reactant: c1ccc(CN2CCC(c3nc4c(s3)Cc3ccccc3-4)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: c1ccc2c(c1)Cc1sc(C3CCNC3)nc1-2
Yield: 28.7 %

Procedure:
To a solution of 0.86 g of 2-(1-benzyl-3-pyrrolidinyl)-8H-indeno[1,2-d]thiazole in 5 ml of dichloroethane was added 5 ml of 1-chloroethyl chloroformate, followed by heating under reflux for 2 hours. After cooling, the solvent was evaporated and 10 ml of methanol was added to the resulting residue, followed by heating under reflux for 2 hours. After the completion of the reaction, ethyl acetate was added to the reaction mixture, followed by extraction with 1N hydrochloric acid. The extract was neutralized with sodium bicarbonate, followed by the extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated, whereby 0.18 g of 2-(3-pyrrolidinyl)-8H-indeno[1,2-d]thiazole was obtained. The resulting product was dissolved in methanol. Fumaric acid was added to the resulting solution to cause crystallization, and the crystals were recrystallized from acetonitrile-methanol to obtain a fumarate.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:14]1[C:13]([CH3:12])=[CH:17][N:16]=[CH:15]1)[CH:6]=[O:7]
Reactant: Cc1c[nH]cn1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1-n1cncc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 1 %

Procedure:
To a DMF (50 mL) solution of 4-fluoro-3-methoxybenzaldehyde (3.00 g) and 4-methylimidazole (3.307 g), potassium carbonate (4.05 g) was added and the reaction mixture was agitated at 100° C. overnight. The obtained reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system), and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (856 mg) and 3-methoxy-4-(5-methyl-1H-imidazol-1-yl)benzaldehyde (44 mg) were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:13])[CH:10]([CH3:12])[CH3:11]>C(#N)C>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)C(=O)Cl
Solvent: CC#N
Product: CC(C)C(=O)Nc1cccc(O)c1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
3-Aminophenol (1.0 g) was dissolved in acetonitrile (10 ml), the solution was added with isobutyryl chloride (488 mg) under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was crystallized from hexane-ethyl acetate to obtain the title compound (392 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.ClC(Cl)(Cl)C[O:27][C:28](=O)[NH:29][C:30]1[N:31]([C:39]2[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=2)[N:32]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:34]=1.CCN(C(C)C)C(C)C>CS(C)=O.O.CCOC(C)=O>[C:35]([C:33]1[CH:34]=[C:30]([NH:29][C:28]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:16]=[CH:15][N:14]=[C:13]4[C:8]=3[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11](=[O:17])[NH:12]4)=[CH:4][CH:3]=2)=[O:27])[N:31]([C:39]2[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=2)[N:32]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Reactant: Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)cc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Compound 137 (50 mg, 0.16 mmol), (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (80 mg, 0.20 mmol), and DIEA (0.08 mL, 0.49 mmol) were suspended in DMSO (2 mL), and stirred overnight at 60° C. The reaction solution was diluted with H2O/EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 25 to 100% EtOAc in hexanes to provide 230 (22 mg, 24% yield) as a tan solid. LC-MS (M+H=559, obsd.=559).
Reaction SMILES: [ClH:1].Cl.[OH:3][NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16].O(N)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.Cl.Cl.ON(CCSCC1NC=NC=1C)C(N)=NCCSCC1NC=NC=1C>>[ClH:1].[ClH:1].[CH3:18][NH:17][C:5]([NH:4][O:3][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16]
Reactant: NOc1ccccc1
Reactant: CNC(=NCCSCc1[nH]cnc1C)NO
Agent: Cc1nc[nH]c1CSCCN=C(N)N(O)CCSCc1[nH]cnc1C
Agent: Cl
Product: CNC(=NCCSCc1[nH]cnc1C)NOc1ccccc1

Procedure:
Reaction of the isothiourea dihydrochloride produced by Example 1 (i) with phenoxyamine by the procedure of Example 1 (ii) gave the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[CH3:12][C:3]1[C:2]2[C:7]([CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[N:8][C:14](=[O:15])[C:13](=[O:17])[N:1]=2
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc([N+](=O)[O-])cc(N)c1N
Agent: Cl
Product: Cc1cc([N+](=O)[O-])cc2c1=NC(=O)C(=O)N=2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9.3 g (55.63 mmol) of 2,3-diamino-5-nitro-toluene and 14 g of oxalic acid in 93 ml of 6N HCl is heated at reflux for 30 minutes and then stirred at room temperature overnight to complete the reaction. The suspension is filtered and then washed with water, taken up in 250 ml of 2N NaOH and heated at reflux until a homogeneous solution is formed. After cooling, the mixture is acidified to pH 3 and the resulting 5-methyl-7-nitro-quinoxaline-2,3-dione is filtered off.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19][C:20](Cl)=O.B.C1(N(CCCBr)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]1([N:7]([CH2:20][CH2:19][CH2:18][Br:17])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)CCBr
Agent: B
Agent: BrCCCN(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N(CCCBr)c2ccccc2)cc1

Procedure:
3-[N-phenyl-N-(4-nitrophenyl)amino]-1-bromopropane is prepared from N-phenyl-N-(4-nitrophenyl)amine with 3-bromopropionyl chloride, followed by reduction with borane in tetrahydrofuran, by a procedure analogous to the preparation of 3-[N,N-diphenylamino]-1-bromopropane in Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29](I)[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].C([N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].CO>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29]([C:42]5[CH:43]=[N:39][NH:40][CH:41]=5)[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(I)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncc(-c2cn[nH]c2)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
A mixture of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (142 mg, 0.267 mmol), 1-Boc-pyrazol-4-boronic acid pinacol ester (118 mg, 0.401 mmol), and PdCl2(dppf)-CH2Cl2 adduct (13 mg, 0.016 mmol) in 1,4-Dioxane (3 mL) and saturated aqueous sodium bicarbonate (0.80 mL, 0.800 mmol) was degassed with Nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120° C. in the microwave for 30 min. LCMS showed complete conversion to the de-Boc product. The mixture was cooled, poured into half-saturated aqueous NaHCO3 (25 mL), and extracted with ethyl acetate (2×25 mL). The extracts were washed with brine (1×25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g SiO2, 50%-100% EtOAc in hexanes gradient over 10 minutes, then EtOAc for 5 minutes, then 0-10% MeOH in EtOAc over 20 minutes) to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1H-pyrazol-4-yl)furo[3,2-c]pyridin-4-amine (121 mg, 0.244 mmol, 91% yield) as a white solid. LC/MS (ES) m/z=472 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=8.34 Hz, 2H), 3.97 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.49 (s, 2H), 7.15-7.30 (m, 3H), 7.33 (d, J=8.08 Hz, 1H), 7.44 (s, 1H), 7.99-8.10 (m, 2H), 8.13 (d, J=8.08 Hz, 1H), 8.17-8.29 (m, 2H), 13.01 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([N:29]=[C:30]=[O:31])[CH:18]=[C:19]([Cl:28])[C:20]=1[O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24]>>[Cl:14][C:15]1[CH:16]=[C:17]([N:29]2[C:7](=[O:8])[N:6]=[C:4]([C:3]3[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=3[F:13])[O:5][C:30]2=[O:31])[CH:18]=[C:19]([Cl:28])[C:20]=1[O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25]
Reactant: O=C=Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Product: O=c1nc(-c2c(F)cccc2F)oc(=O)n1-c1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Temperature: 120 °C

Procedure:
With the exclusion of moisture, 5.4 g of 2,6-difluorobenzoylisocyanate are added with stirring to 9.1 g of 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenylisocyanate. The temperature is maintained at 120° C. for 14 hours, with stirring being continued until the reaction mixture commences to congeal. When the resultant crystalline slurry has cooled to room temperature, it is triturated with hexane and subsequently filtered with suction. The residue is recrystallised from toluene, affording the title compound of the formula ##STR9## as a white powder with a melting point of 170°-172° C. (compound 1.2.1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=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.CCOC(C)=O.C(O)C.O>[CH3:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[N:20]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccnc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 365.3 %

Procedure:
A 20 mL microwave vial was charged with 4-(trifluoromethyl)phenylboronic acid (813 mg, 4.28 mmol), 2-chloro-4-methylpyrimidine (500 mg, 3.89 mmol), bis(triphenylphosphine)palladium(II) chloride (136 mg, 0.194 mmol), and K2CO3 (1075 mg, 7.78 mmol), followed by the addition of DME (9.0 mL), water (3.86 mL) and ethanol (2.57 mL). The mixture was microwaved at 120° C. for 10 minutes. The reaction was repeated for three more batches. To the combined reaction mixtures was added 300 mL EtOAc, washed with 300 mL water and 300 mL brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 80 g column, eluted with 0-40% EtOAc in Hexanes (35 mL/min) to obtain the title compound (3.385 g, 14.21 mmol, 91% yield) as a light yellow solid. MS (ESI+) m/z 239.2 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.81 (d, J=5.1, 1H), 8.59 (d, J=8.1, 2H), 7.89 (d, J=8.3, 2H), 7.42 (d, J=5.1, 1H), 2.58 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23](O)=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[S:37]([NH2:41])([NH2:40])(=[O:39])=[O:38]>>[F:35][C:2]([F:36])([F:1])[C:3]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23]([NH:40][S:37](=[O:39])(=[O:38])[NH2:41])=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O
Reactant: NS(N)(=O)=O
Product: NS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-sulfamoylacetamide was prepared from {5-[1-(2,4-bis-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}acetic acid (Example 59) and sulfamide following General Procedure L.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[OH2:26]>>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[O:26]1[CH:2]=[CH:3][CH:19]=[C:18]1[C:20]([O-:22])=[O:21]
Reactant: O
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Product: O=C([O-])c1ccco1

Procedure:
By repeating the preceding example, there are obtained 8.2 g of the salt from 6.73 g (2.10-2 moles) of apovincamine and 2.24 g (2.10-2 moles) of furan-2-carboxylic acid. The product has a melting point of about 120° C. is insoluble in water and soluble in alcohol; the apovincamine content thereof is 66%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:12]([C:14]1[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=1)=[O:13])C#N.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=1)=[O:13]
Reactant: COc1ccc(C(=O)C(C#N)c2ccc(Cl)cc2Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cc1ccc(Cl)cc1Cl)c1ccc(=O)[nH]c1
Temperature: 80 °C
Reaction time: 21 h
Yield: 70.4 %

Procedure:
To a solution of 2-(2,4-dichloro-phenyl)-3-(6-methoxy-pyridin-3-yl)-3-oxo-propionitrile (1.358 g) in 1,4-dioxane (6 ml) was added concentrated aqueous HCl (11.5 ml). The mixture was stirred for 21 h at 80° C. The solvent was evaporated and the residue was suspended in water (30 ml). The pH was adjusted to 7 using concentrated aqueous NaHCO3 solution. The solid was filtered off, washed with water and dried to give the title compound as a colorless solid (0.84 g). MS (m/e, ISP neg. ion)=281.1 [M−H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.C(OCC)(OCC)OCC.[CH:19]1[CH:24]=CC(C2C=CC=CC=2)=C[CH:20]=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[N:3]1[C:4]2[C:5](=[N:8][CH:20]=[CH:19][CH:24]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(Cl)nc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(OCC)OCC
Product: c1cnc2cccnc2c1

Procedure:
The 2-chloro-5-aminopyridine A is converted by heating in the presence of ester B and triethyl orthoformate to the condensation product C as a mixture of olefin isomers (Scheme 1). Various esters that are commercially available, known in the literature or prepared using known literature procedures are applicable to the reaction. Intermediate C is added to hot Dowtherm™ A to facilitate the ring closure and to afford the 1,5-naphthyridine D. Treatment of D with phosphorus oxychloride affords the key intermediate E (Scheme 1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:24](=[O:27])[CH2:25][CH3:26])[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>ClCCl>[CH2:21]([NH:20][C:18]([NH:17][C:15]1[S:16][C:12]2[C:11]([C:24](=[O:27])[CH2:25][CH3:26])=[CH:10][C:9]([OH:8])=[CH:23][C:13]=2[N:14]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C(=O)CC)c2s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)cc(C(=O)CC)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-(benzyloxy)-7-propionylbenzo[d]thiazol-2-yl)-3-ethylurea (5.50 g, 14.34 mmol) in dichloromethane (50 mL) was added methanesulphonic acid (18.6 mL, 286.8 mmol) at rt. The mixture was stirred for 1 h at rt. After reaction completion (by TLC), was added ice-cold water (100 mL) at 0° C. followed by extraction with EtOAc (3×100 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 M, 5% MeOH-DCM) to obtain the desired product as an off white solid (4.30 g, 64%). 1H NMR (DMSO-d6): δ 10.95 (br s, 1H), 9.80 (br s, 1H), 7.43 (s, 1H), 7.25 (s, 1H), 6.80 (br s, 1H), 3.15-3.20 (m, 2H), 3.08-3014 (m, 2H), 1.07-1.14 (m, 6H). LCMS: 294.20 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([C:25]1[CH:49]=[CH:48][C:28]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:33]=2[CH3:47])=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:21]([C:25]1[CH:49]=[CH:48][C:28]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([F:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:33]=2[CH3:47])=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)nc(Nc2ccc(F)c([N+](=O)[O-])c2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(F)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A mixture of 5-bromo-3-(4-fluoro-3-nitro-phenylamino)-1-methyl-1H-pyrazin-2-one (1) (8.8 g; 25.7 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (11.1 g; 28.3 mmol), tetrakis(triphenylphosphine)palladium (1.48 g; 1.28 mmol), 1N sodium carbonate (77 mL; 77 mmol), and 1,2-dimethoxyethane (100 mL) was heated at 100 degrees in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, filtered, and the residue washed with water (3×60 mL). The solid was slurried with ethyl acetate for 1 hr, filtered, and washed with diethyl ether to give 4-tert-butyl-N-{3-[6-(4-fluoro-3-nitro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (2) as a dull yellow solid (13 g).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][OH:26])[S:22][C:23]=1[CH3:24]>CO>[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][O:26][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[S:22][C:23]=1[CH3:24]
Reactant: Cc1sc(CO)cc1Br
Reactant: C1=CCOC=C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1sc(COC2CCCCO2)cc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.6 ml of 1,2-dihydropyrane and 0.2 g of p-toluene sulfonic acid were added to 5.4 g of 4-bromo-2 hydroxymethyl-5-methylthiophene 9 in 40 ml of methanol. The reaction mixture was stirred at room temperature for 24 hours. Methanol was distilled under vacuum and the remainder was distilled by an oil pump. The yield was 6.82 g of the product 10 (90%), Tmelt=125-130° C. (5 mm Hg), nd165=1.5610. Mass-spectrum, m/z: 291, [M]+. 1H NMR spectrum (CDCl3, δ, ppm, J/Hz): 1.45-1.95 (m, 6H, 3×CH2), 2.37 (s, 3H, CH3), 3.50-3.65 (m, 1H, CH), 3.80-4.0 (m, 1 H), 4.55-4.85 (m, 3H), 6.82 (s, 1 H, CH). The results found (%): C, 45.43; H, 5.20; S, 10.92. C11H15BrO2S. The results calculated (%): C, 45.37; H, 5.19; S, 11.01.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1.[C:14]1([C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:21]2[CH:25]=[C:24]([CH:26]=[O:27])[N:23]=[CH:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[CH:12]=[CH:13][C:2]([CH:26]([C:24]3[N:23]=[CH:22][N:21]([C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:25]=3)[OH:27])=[CH:3][C:4]=2[CH2:9][O:8]1
Reactant: CC1(C)OCc2cc(Br)ccc2O1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC1(C)OCc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2O1
Yield: 54.5 %

Procedure:
Starting from 6-bromo-2,2-dimethyl-4H-1,3-benzodioxin and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The temperature of the reaction mixture does not exceed 40° C. Yield: 54.5% of theory; M.P.: 155°-162° C. (recrystallized from acetonitrile).