Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1OC1C.CCOCC>C(COC)OC>[Cl:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]1[N:3]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=1
Reactant: Nc1ccc2c(Cl)cccc2n1
Reactant: CCOC(=O)C(=O)CBr
Agent: CC1CO1
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)c1cn2c(ccc3c(Cl)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
140 mg of 2-amino-5-chloroquinoline were dissolved in 2.5 ml of dimethoxyethane and then a mixture of 170 mg of ethyl bromopyruvate and 30 mg of propylene oxide was added. The mixture was stirred at room temperature for 2 hours and 2 ml of ether were added. Then, the mixture was cooled in ice and the precipitated quaternary salt was filtered off, was dissolved in 5 ml of ethanol and the solution was heated at reflux for 2 hours. Then, the solvent was removed under vacuum and the residue was partitioned between sodium bicarbonate solution and chloroform. The chloroform solution was dried over magnesium sulfate and was evaporated to dryness. The residue was chromatographed over silica with chloroform as eluent and the purified product was recrystallized from ethyl acetate/petroleum ether to obtain colorless needles of ethyl 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 193°-194° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH2:1]([O:4][C:5]1[C:13]([Br:14])=[CH:12][C:8]([C:9]([N:18]([O:19][CH3:20])[CH3:17])=[O:11])=[C:7]([Cl:15])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(C(=O)O)cc1Br
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCOc1cc(Cl)c(C(=O)N(C)OC)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.6 %

Procedure:
To a suspension of 4-(allyloxy)-5-bromo-2-chlorobenzoic acid 21 (5.0 g, 17.2 mmol) in CH2Cl2 (50 mL) were added N,O-dimethylhydroxylamine HCl (2.1 g, 20.6 mmol), EDCI (4.9 g, 25.8 mmol), HOBT (4.7 g, 34.4 mmol) and NMM (9.5 mL, 86.0 mmol). The reaction mixture was stirred at rt for 15 hours and evaporated in vacuo to remove volatiles. The mixture was extracted with EtOAc/H2O (100 mL/100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexane (100 mL) and stirred at r.t. for 30 min. The solid was precipitated, filtered, washed with hexane (50 mL) and dried under high vacuum to obtain the desired product (5.5 g, 95%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH:5]([OH:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:3]#[C:4][CH:5]([OH:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(O)CCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 1-trimethylsilyl-l-decyn-3-ol (2.07 g, 9.13 mmol) in tetrahydrofuran (11 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([NH2:16])[N:3]=1.[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1>[NH2:16][C:4]1[N:3]=[C:2]([NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][N:5]=1
Reactant: Nc1ncc(CCc2ccccc2)c(Cl)n1
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)ncc1CCc1ccccc1
Reaction time: 8.5 h
Yield: 79.7 %

Procedure:
A mixture of 4-chloro-5-phenethylpyrimidine-2-ylamine (234 mg, 1 mmol), amylamine (0.58 ml) and dioxane (2 ml) was kept at 95-100° C. for 8.5 hours. The procedure according to pro-treatment of Example 27 was carried out to give the object compound (227 mg, 79.7%).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:12]=[C:13]([NH2:25])[C:14]3[N:15]([N:17]=[C:18]([C:20]4[O:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:16]=2)[CH:6]=1)C.[Li+].[OH-]>CO.C1COCC1>[NH2:25][C:13]1[C:14]2[N:15]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:16]=[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:26])=[O:3])[N:12]=1
Reactant: CCOC(=O)c1cccc(-c2cn3nc(-c4ccco4)nc3c(N)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(-c2cccc(C(=O)O)c2)cn2nc(-c3ccco3)nc12
Temperature: 70 °C

Procedure:
A mixture containing 3-(8-amino-2-furan-2yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-benzoic acid ethyl ester (100 mg; see Ex. 141 below, which was prepared according to Example 4 above), LiOH (2 M, 1 mL), and MeOH (a few drops) in THF (10 mL) was heated (at around 70° C.) for 1 hour. The solvent was removed in vacuo, and the residue was taken up in water and acidified, resulting in a precipitate, which was filtered off as the desired product with an appearance of a light brown solid (60 mg, 65 %). 1H NMR (300 MHz, DMSO-d6) δ 6.76 (dd, J=3.4, 1.8Hz, 1H), 7.18 (dd, J=3.4, 0.8, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.68 (br. s, 2H), 7.96 (dd, J=1.8, 0.8 Hz, 1H), 8.00 (dt, J=7.8, 1.8 Hz, 1H), 8.30 (dt, J=7.8, 1.8 Hz, 1H), 8.72 (t, J=1.8, 1H), 8.91 (s, 1H), 13.09 (br. s, 1 H). MS: m/z 322 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5]CC)=O.O.[OH-].[Na+].Cl[C:12]1[C:17]([NH2:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1>CCO>[Cl:19][C:15]1[CH:14]=[N:13][C:12]2[S:1][CH2:2][C:3](=[O:5])[NH:18][C:17]=2[CH:16]=1
Reactant: CCOC(=O)CS
Reactant: Nc1cc(Cl)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CSc2ncc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of ethyl 2-mercaptoacetate (2.0 mL, 18.4 mmol) in water (5.03 mL, 12.27 mmol) was added NaOH (0.491 g, 12.27 mmol). The reaction was stirred at rt for 10 min. After this time a solution of 2,5-dichloropyridin-3-amine (2.0 g, 12.27 mmol) in EtOH (20 mL) was added and the reaction was heated at reflux for 4 days and cooled to rt. The resulting precipitate was filtered and washed with hexanes (50 mL) and MeOH (5 mL) to give 7-chloro-1H-pyrido-[2,3-b][1,4]thiazin-2(3H)-one as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (1H, d, J=0.6 Hz), 8.15 (1H, d, J=2.2 Hz), 7.31 (1H, d, J=2.3 Hz), 3.59-3.74 (2H, m). Mass Spectrum (ESI) m/e=201.0 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:38])[C@H:7]([CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[NH:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(OC(C)(C)C)=O)=[CH:13][C:12]=1[N+:25]([O-:27])=[O:26])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][NH:8][C@H:7]([C:6]([OH:38])=[O:5])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])=[C:12]([N+:25]([O-:27])=[O:26])[CH:13]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(=O)NN[C@@H](CCC(=O)O)C(=O)O)c([N+](=O)[O-])c1

Procedure:
To a solution of di-tert.-butyl-N-(4-(tert-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate in 53 ml dichloromethane were added 53 ml of trifluoroacetic acid at 0° C. under argon. After 1 hour at room temperature the mixture was concentrated to dryness to give 3.54 g of N-(4-amino-2-nitrobenzamido)-L-glutamic acid as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15].[C:16]1([CH:23]=CC(O)=[CH:19][CH:18]=1)O.C=CC=C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:19][CH:18]=[CH:16][CH2:23][C@H:10]2[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Reactant: Oc1ccc(O)cc1
Agent: C=CC=C
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Temperature: 160 °C
Reaction time: 144 h

Procedure:
50.0 g of 3,4-dimethoxy-ω-nitrostyrene and 1.0 g (9.1 mmol) of hydroquinone are suspended in 200 ml of abs. toluene and treated at −70° C. with 55.0 g (1.02 mol) of liquid 1,3-butadiene. The mixture is stirred at 160° C. for 6 days in an autoclave and then cooled. Some of the solvent is removed on a rotary evaporator, and the resulting precipitate is filtered off with suction and recrystallized in ethanol. M.p.: 113.5-115.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:11])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.C(Cl)(Cl)Cl.CO>O.[Sn]>[OH:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)=[O:11]
Reactant: O=C(C(=O)c1cccc(O)c1)c1cccc(O)c1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1cccc(O)c1)C(O)c1cccc(O)c1
Reaction time: 1 h

Procedure:
To a hot stirred solution of 3,3'-dihydroxybenzil (5 g.) in water (200 ml) and tin (30 mesh) was slowly added concentrated hydrochloric acid (10 ml.). Heating on a steam bath with efficient mechanical stirring was continued for 1 hour. Thin layer chromatography on Silica AR 7GF plates (Mallinckrodt) with chloroform-methanol (9:1) showed the reaction was largely complete after 15 minutes. The mixture was filtered, while hot, through Celite and the filtrate was evaporated to smaller volume. The resulting crystals (4.60 g.), m.p. 159°-162° were recrystallized from hot water with decolorization to give white crystals, m.p. 173°-175°, M+ 244 (E. I. mode), pmr (DMSO-d6) δ 5.97 [s, --CH(OH)].
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:42]12[CH2:49][CH2:48][CH:45]([CH2:46][CH2:47]1)[C@@H:44](O)[CH2:43]2>C1COCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:10][C@@H:44]1[CH:45]2[CH2:48][CH2:49][N:42]([CH2:47][CH2:46]2)[CH2:43]1)=[O:9]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccccc1)N1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
A mixture of 2-(2-oxopyrrolidin-1-yl)-2-phenylacetic acid (345 mg, 1.57 mmol), DCC (649 mg, 3.15 mmol), HOBT (425 mg, 3.15 mmol) and (R)-quinuclidin-3-ol (400 mg, 3.15 mmol) in dry THF (15.7 ml) was stirred at room temperature for 24 hours. The yellow suspension was filtered washing the white solid with THF. The yellow solution was evaporated and the crude was purified by flash chromatography (DCM/MeOH=96/4+0.4% NH4OH) to collect the title compound (482 mg, 93% yield) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH:23](O)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:25])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2C(O)C1C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=c1[nH]c2ccccc2cc1C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 63 %

Procedure:
3-(1-Benzylpiperidin-4-yl)-4-hydroxy-3,4-dihydroquinolin-2(1H)-one (550 mg, 1.6 mmol) was suspended in benzene (10 mL). p-Toluenesulfonic acid monohydrate (370 mg, 1.9 mmol) was added to the mixture. The reaction was heated to reflux and held there for 1 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in 10% ethanol/dichloromethane (50 mL) and washed with aqueous sodium bicarbonate (2×). The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to give a solid which was filtered, washed with diethyl ether, and dried in vacuo. The title compound was obtained as off-white solid in 63% yield. 1H NMR (300 MHz, DMSO-d6): δ 11.72 (s, 1H), 7.72 (s, 1H), 7.62 (d, J=6.95, 1H), 7.47-7.38 (m, 1H), 7.35-7.30 (m, 4H), 7.29-7.20 (m, 2H), 7.14 (t, J=7.50, 1H), 3.49 (s, 3H), 2.92 (d, J=11.34, 2H), 2.83-2.69 (m, 1H), 2.04 (t, J=10.61, 2H), 1.78 (d, J=12.08, 2H), 1.71-1.47 (m, 2H). Mass spec.: 319.3 (MH)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1[C:9]2[N:10]=[CH:11][NH:12][C:13](=[O:14])[C:8]=2[NH:7][CH:6]=1.[CH2:15]=O>O>[OH:2][CH2:1][CH2:3][NH:4][CH2:15][C:5]1[C:9]2[N:10]=[CH:11][NH:12][C:13](=[O:14])[C:8]=2[NH:7][CH:6]=1
Reactant: O=c1[nH]cnc2cc[nH]c12
Reactant: C=O
Reactant: NCCO
Solvent: O
Product: O=c1[nH]cnc2c(CNCCO)c[nH]c12
Temperature: 85 °C
Yield: 64.9 %

Procedure:
A mixture of ethanolamine (78 μl, 0.96 mmol), 9-deazahypoxanthine (100 mg, 0.74 mmol) and 37% aq formaldehyde (72 μl, 0.96 mmol) in water (5 ml) was stirred and heated in stoppered flask at 85° C. overnight. The solution was evaporated to dryness and the residue was chromatographed on silica (DCM-MeOH-cNH3 6:3.5:0.5) to give 7-((2-hydroxyethylamino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (100 mg, 0.48 mmol, 65% yield) as a pale brown solid. 1H NMR (300 MHz, CD3OD) 2.80 (2H, t, J 5.5 Hz), 3.68 (2H, t, J 5.5 Hz), 3.97 (2H, s), 7.42 (1H, s), 7.88 (1H, s); 13C NMR (75 MHz, MeOD+DCl) 42.0, 50.7, 58.43, 105.2, 120.5, 133.8, 135.0, 147.1, 153.0
Reaction SMILES: [CH3:1]N(CN(C)C)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=[O:18].C(OC(=O)C)(=O)C>>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=[CH2:1])[C:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=[O:18]
Reactant: CN(C)CN(C)C
Reactant: CSc1ccc(C(=O)Cc2ccc(F)cc2F)cn1
Solvent: CC(=O)OC(C)=O
Product: C=C(C(=O)c1ccc(SC)nc1)c1ccc(F)cc1F
Yield: 50.2 %

Procedure:
N,N,N',N'-Tetramethyldiaminomethane (5.2 ml, 38 mmol) was added to a stirred mixture of the product of part (iii) (7.2 g, 26 mmol) and acetic anhydride (3.6 ml, 38 mmol) and the reaction temperature was moderated by use of water bath at ambient temperature. After 1 hour at room temperature the yellow solution was poured onto ice and the mixture extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with dilute hydrochloric acid (0.2M, 50 ml) followed by saturated sodium bicarbonate solution (50 ml), then dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica by elution with ether/hexane (1:4) to give the title compound as a yellow solid, (3.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:12][C:13]([OH:15])=[O:14])#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: O=C(O)CC(=O)O
Product: N#Cc1cccc(C=CC(=O)O)c1

Procedure:
3-Cyanobenzaldehyde was reacted with malonic acid by the method described in Example 2(a) to give the title product, m.p. ca 240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[C:29]([C:32](O)=[O:33])[C:28](=[O:35])[N:27]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O.O>[OH:21][C:19]([CH3:22])([CH3:20])[CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:23]=[CH:24][C:2]([NH:1][C:32]([C:29]4[C:28](=[O:35])[N:27]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:26]([CH3:25])[C:30]=4[CH3:31])=[O:33])=[CH:3][CH:4]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3)ccnc2c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC(C)(C)O)ccc34)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To a solution of 1-((4-(4-aminophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (3.75 g, 11.6 mmol) in DCM (31 mL) was added 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.7 g, 11.8 mmol), HOAT (0.32 g, 2.32 mmol), EDCI (2.7 g, 13.9 mmol). The reaction mixture was refluxed for 3 hours, then cooled to 45° C. and continued to stir for 4 hours. Additional EDCI (0.4 eq., 0.90 g, 4.64 mmol) was added and the reaction was stirred overnight at 45° C. The mixture was cooled to room temperature and diluted with a mixture of EtOAc (30 mL) and water (30 mL). After stirring at room temperature for 2 hours, the mixture was filtered. The solid was stirred in 95% EtOH (15 mL) at −5° C. for 5 hours. The solid was collected through filtration, dried in vacuo at 50° C. overnight to give the title compound as a gray-white solid (3.04 g, 48.87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([OH:10])[CH:3]=1.[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: BrC1CCCC1
Reactant: CSc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Br)cc1OC1CCCC1
Temperature: 60 °C

Procedure:
A stirred solution of 4-bromo-2-hydroxythioanisole (15.9 g) and cyclopentyl bromide (16.05 g) in dry dimethylformamide (170 mL) is treated with anhydrous potassium carbonate (14.7 g) and the mixture is heated at 60° C. for 1 day. After cooling, the solution is diluted with water (250 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are dried over magnesium sulfate and concentrated. The residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (5:95 v/v), to give 4-bromo-2-cyclopentyloxy-1-(methylthio)benzene, in the form of an oil (17.2 g). [NMR (DMSO): 7.14-7.03(m,3H),4.93(m,1H), 2.33(s,3H),2.0-1.53(m,8H)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11](=[O:20])(=[O:19])[NH:12][CH2:13][C:14](OCC)=O)=[CH:6][CH:5]=1.C[O-:23].[Na+]>CO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C:13](=[O:23])[NH:12][S:11]2(=[O:20])=[O:19])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CNS(=O)(=O)Nc1ccc(C(=O)OC)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(N2CC(=O)NS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Compound 102 was dissolved in 5 mL of methanol and cooled to 0° C. A solution of freshly prepared NaOMe in methanol was added, and the solution was warmed to room temperature and stirred overnight. TLC (70:30 hexanes/ethyl acetate) showed no starting material. The reaction was acidified with Dowex resin, filtered, and concentrated to a white solid. The compound 103 was recrystallized from ethyl acetate/hexanes.
Reaction SMILES: Cl.[CH:2]([O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[O:19]=[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37](O)=[O:38])[CH:32]=2)=[N:22][NH:21]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:3][CH:2]([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:37]([C:33]2[CH:32]=[C:31]([CH2:30][C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20](=[O:19])[NH:21][N:22]=3)[CH:36]=[CH:35][N:34]=2)=[O:38])[CH2:8][CH2:7]1)[CH3:4]
Reactant: CC(C)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
A solution of 4-isopropoxypiperidine hydrochloride (192 mg, 1.07 mmol) and triethylamine (0.327 mL, 2.35 mmol) in N,N-dimethylformamide (3 mL) was added in one portion to a stirred solution of 4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)picolinic acid (5)(300 mg, 1.07 mmol), triethylamine (0.327 mL, 2.35 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (607 mg, 1.60 mmol) in DMF (3 mL) at 25° C. The resulting solution was stirred at 25° C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired compound as a solid (257 mg, 59.3%); 1H NMR (400.132 MHz, DMSO) δ 1.08 (6H, dd), 1.28-1.46 (2H, m), 1.65-1.74 (1H, m), 1.78-1.87 (1H, m), 3.12 (1H, ddd), 3.23-3.31 (1H, m), 3.42-3.51 (1H, m), 3.62 (1H, m), 3.69 (1H, quintet), 3.91-4.00 (1H, m), 4.40 (2H, s), 7.39 (1H, dd), 7.49 (1H, d), 7.83-7.97 (3H, m), 8.28 (1H, dd), 8.46-8.49 (1H, m), 12.60 (1H, s); m/z (LC-MS, ESI+), RT=1.54 (M+H 407).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]([N:18]=[C:19]=[O:20])=[O:17]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:19]([NH:18][C:16]([O:15][CH3:14])=[O:17])=[O:20])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)N=C=O
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)NC(=O)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 79.1 %

Procedure:
To 4-nitrobenzenesulfonamide (2.1 grams, 0.01 mole) in 100 milliliters dry toluene was added 1.2 grams (0.012 mole) methoxycarbonyl isocyanate. Three drops of pyridine were added. The mixture was refluxed for four hours. After cooling the precipitate was filtered off and washed with toluene. The solid material was dried. There was obtained 2.4 grams of the title compound, m.p. 150°-158° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[Cl:20])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:21](P(=O)(OCC)OCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[Si:3]([O:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][C:13]=1[Cl:20])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(/C=C/c2ccccc2)cc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Sodium hydride (70% in mineral oil, 81 mg) was added to a mixture of 4-((tert-butyldimethylsilyloxy)methyl)-3-chlorobenzaldehyde (571 mg) and diethyl benzylphosphonate (502 mg) in N,N-dimethylformamide (2 ml) under a nitrogen atmosphere at room temperature and the mixture was stirred at 40° C. for 2 hr. Water was added to the reaction mixture and the resulting product was extracted three times with ether. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=50/1) to give the objective compound (448 mg) as a colorless oil.