Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:11]([O:10][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CC[O-]
Reactant: OCc1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1ccc(CO)cn1
Temperature: 95 °C
Reaction time: 36 h

Procedure:
A mixture of (6-chloropyridin-3-yl)methanol (1.4 g, 0.010 mol, Aldrich, Cat. 536016) and sodium ethoxide (3.0 g, 0.044 mol) in ethanol (30 mL) was stirred at 95° C. for 36 hours. The reaction mixture was cooled to r.t., diluted with ethyl acetate, washed with water and brine successively, dried with MgSO4, and concentrated to afford the desired compound. The crude product was directly used in the next step without further purification. LCMS (M+H)+: m/z=154.3.
Reaction SMILES: [C:1]([N:4]([C:10](=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[CH:5]([C:7]([OH:9])=O)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:32][CH:33]([C:35]([OH:37])=[O:36])[CH3:34]>O1CCCC1.[OH-].[Na+]>[C:1]([N:4]([C:10](=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13])[CH:5]([C:7]([NH:32][CH:33]([C:35]([OH:37])=[O:36])[CH3:34])=[O:9])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)c1ccccc1O)C(C)C(=O)O
Reactant: CC(N)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(C(=O)c1ccccc1O)C(C)C(=O)NC(C)C(=O)O
Reaction time: 6 h

Procedure:
Acetylsalicyloyl-(DL)-alanine (2.5 g) was dissolved in dry tetrahydrofuran (15.0 ml) and dry triethylamine (1.36 ml) was added. The reaction mixture was brought to -5° C. and ethyl chloroformate (0.96 ml) was added dropwise over a period of 10 min. (DL)-Alanine (0.89 g) dissolved in aqueous sodium hydroxide (1 M, 10.0 ml) was added. The reaction was allowed to proceed at 0° C. for 6 hrs., and the solvent was then removed at 30° C. under reduced pressure. The residual solution was acidified to pH 2-3 using aqueous hydrochloric acid (3 M). The whole was extracted with ethyl acetate (50.0 ml), and the extract was dried (anhydrous sodium sulphate). The bulk of the ethyl acetate was removed under reduced pressure to leave a small volume of solution.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[NH:13][C:12]([CH3:20])=[C:11]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:41]1([CH:47]=[CH:48][CH:49]=[CH:50][CH2:51][OH:52])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:15]([C:16]([O:52][CH2:51][CH:50]=[CH:49][CH:48]=[CH:47][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:17])=[C:14]([CH3:19])[NH:13][C:12]([CH3:20])=[C:11]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OCC=CC=Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC=CC=Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 93 %

Procedure:
346 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-3-ethoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid, 226 mg (1.1 mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 192 mg (1.2 mM) of 5phenyl-2,4-pentadien-1-ol were dissolved in 10 ml of dichloroethane, and refluxed for 2 hours. Thereafter, the reaction mixture was treated in the same manner as Example 48, and 454 mg of ethyl 5-phenyl-2,4-pentadienyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained (yield 93%).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[C:20]([F:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:7]1)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C.CCOC(C)=O>[N:33]([CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[N:27]([CH:28]([CH3:30])[CH3:29])[C:26]([CH3:31])=[N:25][CH:24]=4)[C:20]([F:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:7]1)=[N+:34]=[N-:35]
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(OS(C)(=O)=O)C4)cc3)ncc2F)n1C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(N=[N+]=[N-])C4)cc3)ncc2F)n1C(C)C
Temperature: 80 °C
Yield: 50.2 %

Procedure:
To a solution of 1-(4-{[5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}phenyl)azetidin-3-yl methanesulfonate (Example 138; 876 mg, 1.90 mM) in dry DMF (7.3 ml), sodium azide (619 mg, 9.5 mM) was added. The reaction was stirred and heated at 80° C. under nitrogen for 18 hours. The reaction mixture was diluted with EtOAc and the solution extracted with water (twice), saturated sodium chloride and then dried with anhydrous sodium sulphate filtered and evaporated. The crude product was purified by silica chromatography eluting with MeOH:DCM (2:98) to give the title compound as a brown foam (389 mg, 50%). NMR 1.4 (d, 6H), 2.53 (s, 3H+DMSO), 3.65 (m, 2H), 4.1 (m, 2H), 4.44 (m, 1H), 5.4 (m, 1H), 6.44 (d, 2H), 7.33 (m, 3H), 8.35 (d, 1H); m/z 408.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2([CH2:22][CH2:23][CH2:24][N:25]([CH3:35])CCC3C=CC(C)=CC=3)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][S:13]2(=[O:21])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>CC(C)=O.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2([CH2:22][CH2:23][CH2:24][NH:25][CH2:35][CH2:23][CH2:22][CH2:12][C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)[S:13](=[O:20])(=[O:21])[CH2:14][CH2:15][CH2:16][S:17]2(=[O:19])=[O:18])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2(CCCN(C)CCc3ccc(C)cc3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(CCCCNCCCC2(c3ccc(OC)c(OC)c3)S(=O)(=O)CCCS2(=O)=O)cc1OC

Procedure:
2-(3,4-dimethoxyphenyl)-N-methyl-N-(p-methylphenethyl)-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride of melting point 169°-171° C (from acetone/ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1CC1(NS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-4-amino-4-(2-methylbenzyl)piperidine (305 mg, 1.0 mmol), methane-sulfonyl chloride (0.31 ml, 4.0 mmol), and pyridine (0.1 ml, 1.2 mmol) in CH2Cl2 (2 mL) is stirred at room temp. overnight. Then concentrate the reaction mixture in vacuo and purify the residue by column chromatography on silica to afford the product.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2].[NH:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
To a stirring suspension of EtSO2—D—Phe—OH (257 g, 100 mmol), Pro—OBn.HCl (26.6 g, 110 mmol), HOBT (13.5 g, 100 mmol) and N,N-diisopropylethylamine (43.5 mL, 250 mL) in THF (1 L) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23 g, 120 mL). After stirring for 20 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1 N citric acid. The organic phase was washed twice with 1 N KHCO3, twice with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of hexanes through 50% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 29 g (65%) of a clear, thick oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11].P>C1(C)C=CC=CC=1.C(Cl)C=CC1C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)c2ccccc2)cc1
Yield: 78.4 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methoxyphenyl chloride (142.2 mg, 1.0 mmol), acetophenone (302.1 mg, 2.5 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (18.4 mg, 0.045 mmol), K3PO43H2O (664.0 mg, 2.5 mmol) in 3 mL dry toluene at 110° C. for 16.7 h. 2-(4′-Methoxyphenyl)-1-phenyl-1-ethanone (177.3 mg) was obtained with a yield of 79% as solid. m.p.: 94.1-94.4° C. (n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.07-8.00 (m, 2H, ArH), 7.60-7.51 (m, 1H, ArH), 7.51-7.42 (m, 2H, ArH), 7.25-7.17 (m, 2H, ArH), 6.92-6.86 (m, 2H, ArH), 4.24 (s, 2H, CH2), 3.78 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ 197.8, 158.3, 136.4, 132.9, 130.3, 128.45, 128.41, 126.3, 113.9, 55.0, 44.4; IR (KBr) v (cm−1) 3056, 2998, 2954, 2934, 2905, 2835, 1691, 1612, 1596, 1579, 1514, 1463, 1447, 1411, 1335, 1301, 1245, 1218, 1204, 1178, 1107, 1035; MS (70 eV, EI) m/z (%): 227 (M++1, 3.58), 226 (M+, 21.25), 121 (100).
Reaction SMILES: C(#N)C.Cl.[CH3:5][N:6](/[C:8](=[CH:12]\[CH3:13])/C(O)=O)[CH3:7].C(Cl)(=O)[C:15]([Cl:17])=[O:16]>CN(C=O)C>[CH3:7][N:6]([CH2:8]/[CH:12]=[CH:13]/[C:15]([Cl:17])=[O:16])[CH3:5]
Reactant: C/C=C(/C(=O)O)N(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of acetonitrile (20 mL) and DMF (0.05 mL) under N2 was added N,N-dimethylamino crotonic acid hydrochloride (0.47 g, 2.8 mmol). After 10 min this solution was cooled to 0-5° C. Oxalyl chloride (0.44 g, 3.5 mmol) was added and the reaction mixture was maintained at 0-5° C. for 30 min. It was allowed to warm to rt and stirring was continued for 2 h. It was then heated to 40° C. for 5 min and again brought to rt and stirred for 10 min to get a light greenish colored solution of dimethylaminocrotonyl chloride that was used as such for next step. To a stirred solution of N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (0.2 g, 0.7 mmol) in NMP (10 mL) was added dropwise under N2 atmosphere at 0° C. the solution of dimethylaminocrotonyl chloride. The reaction mixture was maintained at this temperature for 30 min and was warmed to rt and stirred for 2 h. The mixture was quenched with sodium bicarbonate solution (1 mL) and was extracted with EtOAc (2×35 mL). The combined ethyl acetate extract was washed with water (20 mL) and brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, product was eluted at 4-6% methanol in chloroform) to give (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) as a yellowish solid. 1H NMR (DMSO-d6) δ ppm: 2.24 (s, 6H), 3.13 (d, J=5.76 Hz, 2H), 6.56 (d, J=15.52 Hz, 1H), 6.80 (d, J=15.36 Hz, 1H), 6.95 (t, J=7.36 Hz, 1H), 7.11 (t, J=1.16 Hz, 1H), 7.29 (t, J=7.56 Hz, 2H), 7.58 (s, 1H), 7.65-7.7 (m, 4H), 8.31 (d, J=2.44 Hz, 1H), 9.23 (s, 1H), 9.68 (s, 1H), 10.16 (s, 1H); LCMS: m/e 390.3 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[ClH:7].Cl.Br[C:10]1[CH:11]=[C:12]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].Cl.[NH2:28][C:29]1[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([O:38][C@@H:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[CH3:40])[CH:30]=1>O>[ClH:7].[ClH:7].[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:12]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([NH:28][C:29]3[S:33][C:32]([C:34]([O:36][CH3:37])=[O:35])=[C:31]([O:38][C@@H:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]([F:50])([F:48])[F:49])[CH3:40])[CH:30]=3)[CH:11]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Br)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 27.5 °C
Yield: 173 %

Procedure:
K2CO3 (100 g) was dissolved in water (225 mL) and the resulting solution was cooled to 25-30° C. 1-[(3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine dihydrochloride (50.0 g), methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate hydrochloride (53.7 g) and 2-methyl THF (250 mL) were added and the mixture was stirred until complete dissolution had taken place. The layers were separated, retaining the organic phase. 2-Methyl tetrahydrofuran (40 mL) was added and the mixture was distilled under reduced pressure to a volume of 350-400 mL. Xantphos (2.32 g, 3 mol %) was added, followed by cesium carbonate (48.0 g) and tris(benzylideneacetone)dipalladium(0) (1.84 g, 1.5 mol %). The reaction mixture was heated to 70-75° C. until judged complete by HPLC and then cooled to 20° C. Water (250 mL) was added and the mixture stirred to dissolve the inorganics. The mixture was filtered through celite, then the phases allowed to separate. The aqueous phase was discarded. The celite was washed with MeOH (200 mL). The MeOH wash was added to the previous organic phase. The mixture was slowly added to 5 M aqueous HCl over approximately 40 minutes. The resulting crystalline slurry was stirred overnight at room temperature, then filtered, washing with MeOH (100 mL, cooled to 0° C.) and dried under reduced pressure to give the title compound (72.8 g, 87% th) as orange to red crystalline sold.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=3[F:23])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([C:24]([OH:26])=O)[CH2:3]1.CN.[CH3:29][N:30](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:29][NH:30][C:24]([C@@H:4]1[CH2:3][C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=3[F:23])=[CH:9][CH:8]=2)[CH2:5]1)=[O:26]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cc(F)cc3F)cc2)C1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3c(F)cc(F)cc3F)cc2)C1

Procedure:
In an analogous manner to that described in Example 24f), the condensation of the (R)-5-oxo-1-[4-(2,4,6-trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent yields the (R)-5-Oxo-1-[4-(2,4,6-Trifluoro-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=379 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(NC(C)C)(C)C.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)#[CH:18]>C1COCC1.[Cu]I.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>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:18]#[C:17][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Reactant: CSc1nccc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1nccc(C#Cc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
4-Iodo-2-(methylthio)pyrimidine (39.7 g, 0.157 mol) and diisopropylamine (44.2 mL, 0.315 mol) were dissolved in dry THF (720 mL) and argon gas was bubbled through the solution for 20 min. Copper(I) iodide (2.99 g, 14.3 mmol) and bis(triphenylphosphine)palladium dichloride (5.51 g, 7.85 mmol) were added and then 1-ethynyl-3-nitrobenzene (25.4 g, 0.173 mol) in dry THF (100 mL) was added dropwise over about 30 min with the temperature being maintained at about 25° C. Following complete addition, the mixture was stirred at rt overnight. The mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure. The residue was washed with EtOAc/MeOH to give pale-yellow solid (42 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[N:26]=[C:25](I)[C:24]([NH2:28])=[CH:23][CH:22]=1.[CH2:29]([O:31][C:32](=[O:39])[C:33]([CH3:38])([CH3:37])[CH2:34][C:35]#[CH:36])[CH3:30]>CCN(CC)CC.Cl[Pd]Cl.[Cu]I>[CH2:29]([O:31][C:32](=[O:39])[C:33]([CH3:38])([CH3:37])[CH2:34][C:35]#[C:36][C:25]1[C:24]([NH2:28])=[CH:23][CH:22]=[C:21]([Cl:20])[N:26]=1)[CH3:30]
Reactant: Nc1ccc(Cl)nc1I
Reactant: C#CCC(C)(C)C(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)CC#Cc1nc(Cl)ccc1N

Procedure:
PdCl2 (0.200 g, 1.13 mmol), CuI (0.214 g, 1.13 mmol), and PPh3 (0.590, 2.25 mmol) were suspended in NEt3 (150 mL) and stirred under N2. 6-Chloro-2-iodo-pyridin-3-ylamine (5.7 g, 2.24 mmol) was added, followed by 2,2-dimethyl-pent-4-ynoic acid ethyl ester (5.2 g, 3.37 mmol), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.O>CO.[BH4-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[C:6](=[O:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]2[OH:10]
Reactant: CC(C)CN1C(=O)c2ccc(Br)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)c2ccc(Br)cc2C1O
Temperature: 20 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
5-Bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-dihydroinsoindol-1-one are prepared as described in Example 1, starting with 23.6 g of 4-bromo-N-isobutylphthalimide in 200 cm3 of methanol and 4.5 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then cooled to a temperature in the region of 0° C. and 175 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C. The aqueous phase is extracted 3 times with 200 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 23.7 g of 5-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder (Rf=0.79, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.S(=O)(=O)(O)O.[CH3:20]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:20])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1
Reactant: O=C(O)c1cc(Cl)cc2c1OCCN2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc2c1OCCN2

Procedure:
A mixture of 12 g of 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid, 200 ml of methanol, and 10 ml of concentrated sulfuric acid was heat-refluxed for 24 hours with stirring. The liquid reaction mixture was concentrated in vacuo. To the residue were added an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the resulting organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was clitilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether and ethanol to give 9.2 g of methyl 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate. Melting point: 60°-61° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)(=O)C.CO>O>[CH3:17][C:14]1([CH3:18])[O:13][C@@H:12]([CH2:11][OH:10])[CH2:16][O:15]1
Reactant: CC(=O)OC[C@H]1COC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@H](CO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Then potassium carbonate (66.96 g, 0.485 mol) was added to a mixture of (R)-4-acetoxymethyl-2,2-dimethyl-1,3-dioxolane (56.32 g, 0.323 mol) and methanol (400 ml) and resulting mixture was stirred for 8 hours at 25° C. After completion of the reaction the salt was filtered off and the filtrate was condensed in vacuo. Water was added to the residue and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 38.27 g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 87%, b.p. 65° C. at 3 mmHg, optical purity 97.5% e.e., specific rotation [α]D20+ 10.87°(c=1,MeOH)).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH:24]=O.N1CCCCC1>C(O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH:24]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 82.6 %

Procedure:
A mixture of 5-aminosulfonyl-2-oxindole (106 mg) (prepared as described in Compound IN-02), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (4 mg) in ethanol (2 mL) was heated in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 140 mg (83% yield) of 3-(1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide as an orange solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])(=O)[CH3:2].O.[NH2:17][NH2:18]>CO.O>[CH3:15][O:14][C:12]1[CH:13]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[NH:18][N:17]=[C:1]2[CH3:2]
Reactant: COC(=O)c1ccc(OC)cc1C(C)=O
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)[nH]nc(C)c2c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To a solution of methyl 2-acetyl-4-methoxybenzoate (5) (2.47 g, 11.86 mmol) in methanol (14.5 mL) is added hydrazine monohydrate (1.78 g, 35.60 mmol). The mixture is stirred at 95° C. under argon for 6 h, the cooled to room temperature, diluted with H2O (50 mL), and extracted with CHCl3 (2×100 mL) and ethyl acetate (100 mL, 2×50 mL, and 2×40 mL). The extracts were washed (brine) and dried. After solvent removal at reduced pressure, the residue is suspended in ethyl acetate (30 mL), heated, cooled, and filtered to give 2.13 g (94%) of 6 as a white solid, mp 252-254° C. IR 3298, 2941, 1732, 1055 cm−1; 1H NMR (CDCl3) δ 2.58 (s, 3H, CH3), 4.00 (s, 3H, CH3O), 7.12 (d, J=1.6 Hz, 1H, 5-PhthH), 7.35 (dd, J=5.6, 1.6 Hz, 1H, 7-PhthH), 8.41 (d, J=5.6 Hz, 1H, 8-PhthH), 10.12 ppm (s, 1H, NH).