Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].C(OC(=O)C)(=O)C.I.[PH2](O)=O.[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([CH3:30])[C:26]=1[C:27](=[O:29])[CH3:28]>O>[CH3:21][C:22]1[NH:23][C:24]([CH:1]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[C:25]([CH3:30])[C:26]=1[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(=O)c1ccccc1
Agent: I
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1c(C)[nH]c(C(C)c2ccccc2)c1C
Reaction time: 48 h

Procedure:
A solution of 0.6 ml of acetophenone of 5 ml of acetic anhydride was slowly added to a stirred mixture of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of hypophosphorous acid containing 548 mg of 2,4-dimethyl-3-acetyl pyrrole. The mixture was allowed to stand for two days at room temperature then poured into water. The crude product which separated was recrystallized from acetone (thimble) as nearly colourless rhombic plates (75%), mp. 146°-148.5° C. Anal. Calc. For C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.47: H, 7.78; N, 5.79.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([OH:7])=[O:6].C([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[NH:16]C2C(C=1)=CC=CC=2)(O)=O.CC(CCCC(Cl)=O)C(Cl)=O>>[C:5]([C:4]1[NH:16][C:15]2[C:2]([CH:3]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)([OH:7])=[O:6]
Reactant: O=C(O)CCCCc1cc2ccccc2[nH]1
Reactant: O=C(O)C=CCBr
Agent: CC(CCCC(=O)Cl)C(=O)Cl
Product: O=C(O)c1cc2ccccc2[nH]1

Procedure:
Refer to 32(a) using 4-bromo-2-butenoic acid as the alkylating agent. Preparation of 2-(4-carboxy-n-butyl) indole: Refer to Example 3 using methyl adipyl chloride as the acid chloride. The methyl ester was hydrolyzed in the cyclization workup to provide the product carboxyindole. In the alternative, refer to Example 32b) using 2-(4-carboxy-3-buten-1-yl) indole as the starting material.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]([C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)=O.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[O:9]=[C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:11]([C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[NH:10]1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: NC(=O)c1ccccc1N
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: O=C(O)COc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Yield: 73 %

Procedure:
2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid was synthesized from anthranilamide and 4-formyl phenoxy acetic acid, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)phenoxy) acetic acid (800 mg, 73%) was isolated as a white solid. Selected data: MS (m/z): 296.98; MP 285-287° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:9](=[O:11])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:13])[CH3:12])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 79 was prepared from 2-(4-chlorophenyl)-2-methyl propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 2H), 7.34–7.25 (m, 6H), 6.95 (d, 1H, J=7.2 Hz), 6.65 (br s, 1H), 3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.92 (d, 2H, J=12.0 Hz), 2.45 (m, 1H), 2.36 (t, 2H, J=6.0 Hz), 2.20 (s, 3H), 1.94 (t, 2H, J=12.4 Hz), 1.78 (d, 2H, J=13.2 Hz), 1:65 (m, 2H), 1.57 (s, 6H), 1.55–1.46 (m, 2H); ESMS m/e: 456.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12](OCC3C=CC([N+]([O-])=O)=CC=3)[C@H:11]([C:25]([OH:27])=O)[CH2:10]2)=[CH:5][CH:4]=1.[N+:30]([C:33]1[CH:51]=[CH:50][C:36]([CH2:37][O:38][C:39]([NH:41][C:42]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[NH:43])=[O:40])=[CH:35][CH:34]=1)([O-:32])=[O:31]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:39]([O:38][CH2:37][C:36]3[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:51][CH:50]=3)=[O:40])[C@H:11]([C:25]([N:47]3[CH2:46][CH2:45][N:44]([C:42](=[NH:43])[NH:41][C:39]([O:38][CH2:37][C:36]4[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:51][CH:50]=4)=[O:40])[CH2:49][CH2:48]3)=[O:27])[CH2:10]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCNCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=N)NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.6 %

Procedure:
740 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxy)pyrrolidine-2-carboxylic acid was dissolved in 7.4 ml of dry acetonitrile, and 330 mg of N,N'-carbonyldiimidazole were added to the resulting solution, after which the mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 525 mg of 1-(4-nitrobenzyloxycarbonylamidino)piperazine [prepared as described in step (c) above] dissolved in 10 ml of acetonitrile was added to the resulting mixture, and the mixture was left to stand overnight under the same conditions. The reaction mixture was then diluted with ethyl acetate, after which it was washed with an aqueous solution of sodium hydrogencarbonate, with water and with an aqueous solution of sodium chloride, in that order, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted first with ethyl acetate alone and then with a 4:1 by volume mixture of ethyl acetate and acetonitrile, in that order. The fractions containing the desired compound were concentrated by evaporation under reduced pressure, to obtain 890 mg of the title compound, as a powder.
Reaction SMILES: C[N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([C:5]1[C:6](=[O:17])[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[F:24]C1C=CC(N)=CC=1.CCCCCCC>C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:2][C:3]([C:5]2[C:6](=[O:17])[N:7]([CH3:16])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:4])=[CH:19][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CN(C(=O)c1c(O)c2ccccc2n(C)c1=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cn1c(=O)c(C(=O)Nc2ccc(F)cc2)c(O)c2ccccc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A solution of N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (15 mg, 0.050 mmol) and 4-fluoro-aniline (0.100 mmol) in toluene (0.5 mL) was stirred at 100° C. for 1 h. Heptane (1.5 mL) was added and the solution was allowed to cool to room temperature. The crystallized product was separated from the solution and washed with heptane to give the title compound (12 mg, 79%).
Reaction SMILES: [Br-].[CH2:2]([Al+2])[C:3]#[CH:4].[Br-].C(Br)C#C.[Al].CO[CH:14]([O:20][CH3:21])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.O1CCCC1>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:14]([O:20][CH3:21])[CH2:4][C:3]#[CH:2]
Reactant: C#CC[Al+2]
Reactant: COC(OC)c1ccco1
Agent: C#CCBr
Agent: [Al]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCC(OC)c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of propargyl aluminum bromide, prepared from 52.9 g of 80% propargyl bromide in toluene, 6.41 g of aluminum splutters activated with 70 mg of mercuric choride and 80 ml of tetrahydrofuran, was added dropwise a solution of 42.2 g of furfural dimethyl acetal [J. Org. Chem., 40, 1478 (1975)] in 30 ml of tetrahydrofuran during a 15 minute period while maintaining a temperature of. 25° to 30° C. The mixture was stirred for 20 minutes at 25° C., then partitioned with ether and ice-water. The organic layer was separated, washed with water, then aqueous sodium bicarbonate, finally with brine and dried. After evaporation the residue was distilled, giving 39.8 g of the desired compound, bp 68°-69° C. (11 mm).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][C@@H:17]([C:19]2[CH:30]=[CH:29][C:22]3[O:23][C:24]([CH3:28])([CH3:27])[O:25][CH2:26][C:21]=3[CH:20]=2)[O:16][C:15]1=[O:31].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:27][C:24]1([CH3:28])[O:23][C:22]2[CH:29]=[CH:30][C:19]([C@H:17]3[O:16][C:15](=[O:31])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:3][CH2:2][CH2:1][OH:4])[CH2:18]3)=[CH:20][C:21]=2[CH2:26][O:25]1
Reactant: OCCO
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCBr)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of ethylene glycol (5.00 ml) in DMF (40 ml) under nitrogen at 0° was treated portionwise with sodium hydride (60% dispersion in mineral oil, 1.292 g) and the mixture was stirred at 0° for 15 min A solution of (5R)-3-(6-bromohexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (7.40 g) in DMF (10 ml) was added. The mixture was stirred at 0° for 0.5 h then at 20° for 3 h. Phosphate buffer solution (pH 6.5, 40 ml) and water (160 ml) were added and the mixture was extracted with EtOAc (2×100 ml). The combined extracts were washed with water (2×150 ml), brine (50 ml) and were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. Elution with MeOH-EtOAc (1:9) gave the title compound (4.10 g). LCMS RT=2.90 min, ES+ve 394 (MH)+.
Reaction SMILES: [CH3:1][N:2]([C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=O)=[N:10][N:11]=2)[N:8]=1.[NH3:25]>>[CH3:1][N:2]([C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([NH2:25])=[O:14])=[N:10][N:11]=2)[N:8]=1
Reactant: CCOC(=O)c1nnc2ccc(N(C)[C@@H](C)c3ccccc3)nn12
Reactant: N
Product: C[C@@H](c1ccccc1)N(C)c1ccc2nnc(C(N)=O)n2n1
Yield: 92 %

Procedure:
A solution of compound (S)-ethyl 6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (0.5 g, 1.5 mmol) in 5 mL of methanolic ammonia (7N) was stirred for 0.5 h at room temperature. The mixture was concentrated in vacuum to give product (S)-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide as a yellow solid (0.42 g, 92%). LRMS (M+H+) m/z: calcd 297.15; found 297. 1H NMR (300 MHz, CDCl3): δ 8.11 (br, 1H), 8.05-8.02 (d, J=9 Hz, 1H), 7.40-7.29 (m, 5H), 7.13-7.10 (d, J=9 Hz, 1H), 6.47 (br, 1H), 5.57-5.55 (q, 1H), 2.97 (s, 3H), 1.71-1.69 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cl
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(=O)OCC
Yield: 91 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.10 gm, 0.29 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl-7-chlorobenzofuran, mp. 99°-100° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([C:22]([F:25])([F:24])[F:23])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH2:21])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])O.[Na+]>O>[C:1]1([CH2:7][O:8][CH:9]([C:22]([F:25])([F:23])[F:24])[CH2:10][CH:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[C:18]([NH:21][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:19]=[CH:20][C:13]=3[O:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc2c(c1)CCC(CC(OCc1ccccc1)C(F)(F)F)O2

Procedure:
A solution of 3.6 g (10 mmol) of 2-(2-phenylmethoxy-3,3,3-trifluoropropyl)-6-amino-3,4-dihydro-2H-1-benzopyran in 34 ml of a 9/1 mixture of tetrahydrofuran and water is reacted for 20 min with 1.1 ml (11 mmol) of ethyl chloroformate and 1.3 g (15 mmol) of sodium hydrogencarbonate. The mixture is then diluted with water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using a 20/80 mixture of cyclohexane and dichloromethane, 4.2 g of product are obtained.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH:33]([C:36]#[N:37])[CH2:34][CH3:35])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-:39].[K+].[K+].OO>CS(C)=O>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH:33]([C:36](=[O:39])[NH2:37])[CH2:34][CH3:35])=[CH:28][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCC(C#N)CCOc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(CCOc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 67.6 %

Procedure:
The nitrile prepared in example 108 (0.40 g, 0.80 mmol) and potassium carbonate (0.24 g, 1.70 mmol) were slurried in DMSO (5 mL) and cooled to 0° C. in an ice bath. Aqueous hydrogen peroxide (30%, 1.0 mL) was added slowly, and the reaction stirred at room temperature for 48 hours. The reaction was quenched by pouring into water, and extracting the aqueous layer with ethyl acetate. The combined organic layers were dried (MgSO4), and concentrated in vacuo to a light tan oil. The material was purified by flash chromatography over silica gel eluting with EtOAc/hexanes/10% NH4OH in MeOH (5:4:1) to provide 0.28 g (67%) of a colorless oil. MS (FD+) 518.07 (MH+). NMR.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9](Cl)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1)(=[O:23])=[O:22].C(N(CC)CC)C>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[C:9]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)(=[O:22])=[O:23])=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cnc(Cl)nc1Cl
Reactant: NCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cnc(Cl)nc1NCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 19 h

Procedure:
A solution of 0.95 g (3.83 mmol) of 2,4-dichloro-pyrimidine-5-carboxylic acid-tert-butylamide in 6 ml of THF is mixed at room temperature while being stirred with a suspension that consists of 1.00 g (3.86 mmol) of N-(3-amino-propyl)-3-nitro-benzenesulfonamide in 9 ml of THF/0.55 ml of triethylamine. After 19 hours, the precipitate that is formed is suctioned off and washed with ethyl acetate. The filtrate is spun in, and the residue that is formed is purified by chromatography (hexane/ethyl acetate 2:1, Flashmaster II). 0.79 g (1.67 mmol, corresponding to 44% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([S:46][CH3:47])=[CH:42][CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[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>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](/[C:40]2[CH:45]=[CH:44][C:43]([S:46][CH3:47])=[CH:42][CH:41]=2)\[C:20]2[CH:21]=[CH:22][C:17]([C:3]#[C:2][CH2:1][N:4]3[CH:8]=[CH:7][CH:6]=[N:5]3)=[CH:18][CH:19]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC)cc2)cc1C
Reactant: C#CCn1cccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2ccc(SC)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpyrazole (0.530 g, 5.0 mmol) and diisopropylamine (1.6 mL, 11.7 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-methylsulfanylphenyl)allyloxy]-2-methylphenoxy]acetate (1.40 g, 2.5 mmol; prepared as described in example 40) in tetrahydrofuran (35 mL). The mixture was degassed and copper(I) iodide (38.0 mg, 0.2 mmol) and bis(triphenylphosphine)palladium(II) dichloride (87.5 mg, 0.12 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-phenoxy]acetate as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[N:46][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[CH:44][C:45]([N:48]5[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]5)=[N:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc32)cc1
Yield: 69 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.286 mmol) was coupled with tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (intermediate 69C) (167 mg, 0.429 mmol) in sodium carbonate (76 mg, 0.715 mmol), Pd(PPh3)2Cl2 (10 mg, 0.014 mmol), DME/water (5/1 mL). This afforded 140 mg (69.0% yield) after purification by column chromatography (60-120 silica gel) using 2% methanol in DCM as eluent. MS: m/z=708.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20]>>[OH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[CH:24]=[CH:23][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Product: COc1ccc(C(=O)C#Cc2ccc(C(=O)O)c(O)c2)cc1C(C)(C)C
Yield: 85.1 %

Procedure:
Following the basic procedure of Example 1(b), by reacting 4.2 g (0.02 mol) of 3-tert-butyl-4-methoxybenzoyl chloride with 5 g (0.02 mol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate, 6 g (81%) of the expected compound were obtained, after purification by chromatography on a silica column eluted with dichloromethane, in the form of a brown oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.O>O1CCCC1>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8]
Reactant: BrCCCCBr
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCN1CCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride(555 mg/13.9 mmol) in tetrahydrofuran (50 ml) was added 2-pyrrolidinone (0.7 ml/9.26 mmol) at ice-cooling temperature. The mixture was stirred for 1 h at ambient temperature, and then 1,4-dibromobutane (10 g/46.3 mmol) was added at the same temperature. The resulting mixture was stirred overnight. Water (10 ml) was added to the mixture and the mixture was extracted with ethyl acetate (50 ml×2). The combined extracts were washed with water and brine succesively, then dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (80g/dichloromethane:methanol=100:0-100:5-100:10) to give a colorless oil(2.0 g/90%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccncc4)cc3)cc21
Yield: 72.3 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), isonicotinoylchloride (142 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (306 mg).
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[C:14](=[O:15])[C:13]2[C:12]([N+]#N)=[C:11]3[O:18]C[O:20][C:10]3=[CH:9][C:8]=2[N:7]([CH2:21][CH3:22])[N:6]=1)([OH:4])=[O:3].S(=O)(=O)(O)O>O>[Cl:1][C:12]1[C:11]([OH:18])=[C:10]([OH:20])[CH:9]=[C:8]2[C:13]=1[C:14](=[O:15])[C:5]([C:2]([OH:4])=[O:3])=[N:6][N:7]2[CH2:21][CH3:22]
Reactant: [Cl-]
Reactant: CCn1nc(C(=O)O)c(=O)c2c([N+]#N)c3c(cc21)OCO3
Agent: O=S(=O)(O)O
Solvent: O
Product: CCn1nc(C(=O)O)c(=O)c2c(Cl)c(O)c(O)cc21
Yield: 90.3 %

Procedure:
A solution of 3-Carboxy-1-ethyl-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-5-diazonium chloride (1.85 g, 5.68 mmol) in sulfuric acid (19.98 ml, 187 mmol) was heated at 95° C. for 20 h. Water was added, the precipitates were collected to provide 5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (1.46 g, 5.13 mmol, 90% yield). LCMS: (M+H)+: 285.2