Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:37][C:38]([F:42])([F:41])[CH2:39]O>C(Cl)Cl>[F:37][C:38]([F:42])([F:41])[CH2:39][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1
Reactant: CCOC(=O)c1cnc2ccc(CO)cn12
Reactant: OCC(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnc2ccc(COCC(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (59) (460 mg, 2.2 mmol) and DIEA (0.78 mL, 4.4 mmol) in DCM (5 mL) was added MsCl (303 mg, 2.64 mmol). The mixture was stirred at room temperature for 10 minutes then subjected to standard aqueous work up to give a residue. The crude product was dissolved in 2,2,2-trifluoroethanol (2 mL) and was added K2CO3 (608 mg, 4.4 mmol). The reaction mixture was heated at 80° C. for 2 hours. Once complete, the reaction mixture was diluted and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford a residue which was purified by silica chromatography to yield ethyl 6-((2,2,2-trifluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (97). 1H NMR (400 MHz, CDCl3) δ 9.33 (m, 1H), 8.32 (s, 1H), 7.76 (dd, J=0.8, 9.2 Hz, 1H), 7.47 (dd, J=2.0, 9.2 Hz, 1H), 4.76 (s, 2H), 4.44 (q, J=7.2 Hz, 2H), 3.92 (q, J=8.4 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H). MS m/z 303.1 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].Cl.[CH2:17]1[C:22]2[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:21]=2[CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:17]1[C:22]2[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:21]=2[CH2:20][CH2:19][N:18]1[S:12]([CH2:11][C:5]1([C:3]([OH:2])=[O:4])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:14])=[O:13]
Reactant: c1ccc2c3c(sc2c1)CNCC3
Reactant: COC(=O)C1(CS(=O)(=O)Cl)CCOCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(O)C1(CS(=O)(=O)N2CCc3c(sc4ccccc34)C2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
4-Chlorosulfonylmethyl-tetrahydro-pyran-4-carboxylic acid methyl ester (520 mg) was added to a solution of 1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine hydrochloride (450 mg) and triethlyamine (1.0 ml) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 18 h then water (5 ml), methanol (5 ml) and lithium hydroxide monohydrate (400 mg) were added and the reaction heated to reflux for 3 h. The mixture was evaporated under reduced pressure and the aqueous residue washed with diethyl ether (2×10 ml), acidified with 1M hydrochloric acid and the precipitate collected by filtration to give the title compound (200 mg, 25%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:23][CH3:24])=[C:11]([CH:13]3[C:19](=[O:20])[CH:18]4[CH2:21][CH:15]([CH2:16][CH2:17]4)[C:14]3=[O:22])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:23][CH3:24])=[C:11]([C:13]3[C:14](=[O:22])[CH:15]4[CH2:21][CH:18]([CH2:17][CH2:16]4)[C:19]=3[O:20][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C2CCC(C2)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C(C)(C)C)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of the 3-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]bicyclo[3.2.1]octane-2,4-dione (100 mg, 0.28 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added pivaloyl chloride (123 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethylpropionic acid 3-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]-4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (101 mg)
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[C:5]2[S:12][CH:13]=[CH:14][C:4]=2[N:3]=1.C([O-])=O.[NH4+]>CCO.[Pd]>[S:12]1[C:5]2[C:6]3[CH2:7][CH2:8][NH:9][CH2:10][C:11]=3[CH:2]=[N:3][C:4]=2[CH:14]=[CH:13]1
Reactant: Clc1nc2ccsc2c2c1CNCC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1cc2ncc3c(c2s1)CCNC3
Temperature: 80 °C

Procedure:
A mixture of 5-Chloro-6,7,8,9-tetrahydrothieno[3,2-c]-2,7-naphthyridine (3.22 g, 14.33 mmol), 10% Pd on C (500 mg) and ammonium formate (8.13 g, 128.97 mmol) in EtOH (125 ml) was heated at 80° C. for 24 hours. Analytical data (TLC, MS) confirmed complete removal of chlorine to give both the title compound along with the N-formyl analog. Upon cooling, the catalyst was filtered off (celite) and the filtrate was treated with NaOH(aq.) until pH ˜14. The alkaline reaction mixture was refluxed for 33 hours, cooled, filtered and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 9:1 EtOAc:7M NH3 in MeOH) gave the title compound as a viscous yellow oil which crystallized on standing (1.96 g, 72%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH2:9][N:8]([C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:40]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)(=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc(C3CN(C(=O)c4ccccc4)CC3C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 10 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
A stirred solution of 1-benzoyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (5 g, Reference Example 7) in ethanol (60 ml), at 23° C., was treated dropwise with sodium hydroxide solution (16 ml, 1N). After stirring for 24 hours the mixture was evaporated (40° C. and 2.7 kPa) and the residue was treated with water (300 ml). The mixture was cooled to 10° C, then treated with hydrochloric acid (25 ml, 1N) and then stood at 23° C. for 20 hours. The resulting white precipitate was filtered, then dried under reduced pressure (40° C. and 2.7 kPa) for 45 minutes and then recrystallised from aqueous ethanol (40 ml) affording the title compound (3.25 g) as a white crystalline powder, m.p. 248° C. TLC: RF=45/78 (on silica eluting with a mixture of dichloromethane and methanol, 90:10). 1H-NMR [500 MHz, (CD3)2SO at 373°K.]: δ 2.29 (s, 3H); 3.26 (m, 1H); 3.50 to 3.65 (m, 2H); 3.61 (s, 2H); 3.76 (m, 1H);3.85 to 4.00 (m, 2H); 3.91 (s, 3H); 6.88 (d, J=8 Hz, 1H); 6.99 (t, J=7.5 Hz, 1H); 7.03 (bs, 1H); 7.14 (t, J=7.5 Hz, 1H); 7.18 (d, J=7.5 Hz, 1H); 7.26 (d, J=8.5 Hz, 2H); 7.45 (m, 3H); 7.55 (m, 4H); 7.70 (d, J=7.5 Hz, 1H); 8.01 (d, J=8 Hz, 1H); 8.10 (bs, 1H); 8.26 (bs, 1H); 9.64 (bs, 1H); 11.50 to 12.30 (b, 1H). MS [FAB (meta-nitrobenzylalcohol)]: 607 [M+H]+.
Reaction SMILES: CCN([CH2:6][CH3:7])CC.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[PH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:9]1[P:17]([C:12]1[CH2:11][C:10]2[C:7]([CH:6]=1)=[CH:15][CH:16]=[CH:8][CH:9]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1=C(Pc2ccccc2)Cc2ccccc21
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C1=C(P(C2=Cc3ccccc3C2)c2ccccc2)Cc2ccccc21
Temperature: 25 °C

Procedure:
To 4.00 g (0.021 mol) of 2-bromo-1-indene and 0.46 g (0.40 mmol) of Pd(PPh3)4 in 20 ml of toluene, 3.2 ml (2.32 g, 0.023 mol) of Et3N and, then, 4.52 g (0.020 mol) of 17 were added. This mixture was refluxed for 13 hours, cooled to room temperature, and passed through short column with Silica Gel using 150 ml of toluene as eluent. The resulted solution was evaporated to dryness. The crude product was crystallized from ethanol. Yield 1.63 g (28%) of white crystals of 16.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([N:28]1[C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=[N:29]1)[CH3:27].CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:33]([C:32]4[N:28]([CH:26]([CH3:25])[CH3:27])[N:29]=[CH:30][CH:31]=4)=[O:35])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CC(C)n1nccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.17 h

Procedure:
To a solution of HATU (0.253 g) in DMF (3 ml) was added 1-(1-methylethyl)-1H-pyrazole-5-carboxylic acid (0.102 g) and DIPEA (0.211 ml) and the mixture was left to stand for 10 min. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (0.075 g) dissolved in DMF (3 ml) was added and the solution was left to stand at RT for 18 h. DMF was removed by blow down (not to dryness) and the residue was dissolved in chloroform (1 ml) and loaded onto an aminopropyl SPE (2 g) (pre-conditioned with methanol (6 ml) and chloroform (6 ml)). The mixture was left on the column for 2 h then eluted with ethyl acetate:methanol (1:1, 10 ml). The solvent was blown down to dryness and the residue was dissolved in DMSO:methanol (1 ml, 1:1) and purified by MDAP (method K). The solvent was removed in vacuo and dried in an vacuum oven (50° C.) overnight to give title compound, 18 mg.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[N-:22]=[N+]=[N-].[Na+]>ClCCl>[CH:6]1[C:19]2[C:18](=[O:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:21])[NH:22][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of concentrated sulfuric acid (25.2 mL) and DCM (dichloromethane) (8.4 mL) was cooled to 0° C., anthraquinone (1) (5 g, 24 mmol) was added, then sodium azide (1.84 g, 28.3 mmol) was added in small portions over a 1 h period at 0-5° C. The reaction mixture stirred overnight at room temperature and then poured into ice water (300 mL). The product was filtered off, washed with water till acid-free and dried to give 5H-dibenzo[b,e]azepine-6,11-dione (2) as a white solid (5.3 g, 100%). Data: (m/z)=224 (M+H)+.
Reaction SMILES: [H+].[B-](F)(F)(F)F.[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])C=CC=CC=1>CO>[O:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:7]1
Reactant: Oc1ccccc1Nc1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CO
Product: c1ccc2ocnc2c1
Reaction time: 0.5 h
Yield: 172.7 %

Procedure:
Hydrogen tetrafluoroborate (6.79 mL, 48% w/w) was added drop wise to a solution of 2-(phenylamino)phenol (9 g, 48.6 mmol) in 30 mL methanol. After 30 minutes of stirring, the solvent was removed under vacuum and (EtO)3CH (30 mL) was added. The resulting solution was stirred at room temperature under N2 overnight to give a white suspension. The solid was filtered and washed with diethyl ether to give 10 g of product (72%).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]1[C:13](=[O:14])[C@H:12]2[CH2:15][CH2:16][CH2:17][C@H:11]2[N:10]([C:18](=[O:31])[CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[C:9]2[CH:32]=[CH:33][CH:34]=[CH:35][C:8]1=2.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(OCC)C>[C:39]([NH:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]1[C:13](=[O:14])[C@H:12]2[CH2:15][CH2:16][CH2:17][C@H:11]2[N:10]([C:18](=[O:31])[CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[C:9]2[CH:32]=[CH:33][CH:34]=[CH:35][C:8]1=2)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Br
Solvent: CCOCC
Product: O=C(Nc1cccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1)c1ccccc1
Yield: 56 %

Procedure:
Using (3aR*,10aS*)-9-(3-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one hydrobromide and benzoyl chloride, the title compound was synthesized in otherwise the same manner as Example 20. Yield 56%, m.p. 244°-246° C. (diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([CH:19]([CH3:21])[CH3:20])=[N:17][N:18]=3)[CH:15]=2)O)=[CH:4][CH:3]=1>[Zn].C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([CH:19]([CH3:20])[CH3:21])=[N:17][N:18]=3)[CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nnc2ccc(C(O)c3ccc(F)cc3)cn12
Agent: [Zn]
Solvent: O=CO
Product: CC(C)c1nnc2ccc(Cc3ccc(F)cc3)cn12
Temperature: 105 °C
Yield: 31.5 %

Procedure:
A mixture of (4-fluoro-phenyl)-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-methanol (591.3 mg, 2.07 mmol), Zn (1 g), and formic acid (3 mL) was heated at 105° C. for 4 days. The reaction was cooled, concentrated in vacuo, and quenched with saturated Na2CO3. The reaction mixture was extracted with ethyl acetate, the extracts dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 10% methanol/ethyl acetate), followed by ethyl acetate precipitation (following addition of HCl in dioxane). The crude precipitate was recrystallized from MeOH/EtOAc to give the title compound (175.6 mg, 21%).
Reaction SMILES: COC(N[C@@H](C(C)C)C(O)=O)=O.Cl.C(OC(=O)[C@@H]1CCCN1)C1C=CC=CC=1.[CH2:29]([O:36][C:37]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:44](=[O:60])[C@H:45]([NH:52][C:53]([O:55][C:56](C)(C)C)=[O:54])[C:46]1[CH:51]=CC=C[CH:47]=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:44](=[O:60])[C@@H:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:46]([CH3:51])[CH3:47])=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: Cl
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C

Procedure:
Compound 2b was synthesized from compound 1 (2 mmol) and L-proline benzyl ester hydrochloride (2.2 mmol), following the procedure as described for compound 2a.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:14]=[C:15](O)[CH:16]=[CH:17][CH:18]=1>>[F:11][C:8]1[CH:9]=[N:10][C:2]([O:1][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Oc1cccc(F)c1
Reactant: O=C(O)c1cc(F)cnc1O
Product: O=C(O)c1cc(F)cnc1Oc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 & 2 of Example 1 from 2-hydroxy-5-fluoronicotinic acid and 3-fluorophenol; 1H-NMR (DMSO-d6) δ 8.37 (1H, m), 8.23–8.15(1H, m), 7.49–7.35 (1H, m), 7.10–6.90 (3H, m).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[CH:25]2)[CH2:6]1)(=O)C.[OH-].[K+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[CH:25]2)[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cnc5ccccc54)=CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cnc4ccccc43)=CC[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
The acetate 4 (1.3 g 3.02 mmol) was dissolved in methanol (20 mL) under an inert Ar atmosphere, and the resulting solution treated with 10% methanolic KOH (8 mL). The mixture was stirred at room temperature for 1.5 h, and then concentrated under reduced pressure at approx. 40° C. to a volume of 10 mL. This solution was poured into ice water (300 mL), and the resulting white precipitate was filtered, washed with water and dried. Crystallization from EtOAc/MeOH gave 5 (1.10 g, 94%), mp 189-190° C.; IR(CHCl3) 2934, 2339, 1609, 1490, 1453, 1291, 1040, 837, 808, 705, 663, 608, 578, 550, 517 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.02 (s, 3H, 18-CH3), 1.07 (s, 3H, 19-CH3), 3.55 (m, 1H, 3α-H), 5.41 (br s, 1H, 6-H), 5.99 (s, 1H, 16-H), 7.30 (m, 2H, aromatic-Hs), 7.54 (s, 1H, aromatic-H), 7.80 (s, 1H, aromatic-H), and 7.96 (s, 1H, 21-H). HRMS calcd 411.2407 (C26H32ON2.Na+). found 411.2396.
Reaction SMILES: [OH:1][CH2:2][C@:3]([OH:20])([CH3:19])[C:4](=[O:18])[C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH:7]([CH3:9])[CH3:8].Cl[S:22]([C:25]1[C:42]([CH3:43])=[CH:41][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[CH:27][C:26]=1[CH3:44])(=[O:24])=[O:23].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:11]([NH:10][C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4](=[O:18])[C@@:3]([OH:20])([CH3:19])[CH2:2][O:1][S:22]([C:25]1[C:26]([CH3:44])=[CH:27][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])=[CH:41][C:42]=1[CH3:43])(=[O:24])=[O:23])=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)Cl
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)[C@](C)(O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 34.7 %

Procedure:
Referring to FIG. 37, to a solution of the tert-butyl ((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)carbamate (0.72 g. 2.5 mmol) in DCM (30 mL) were added benzyl 2-(4-(chlorosulfonyl)-3,5-dimethylphenoxy)acetate (1.1 g, 3 mmol), Et3N (0.52 mL, 3.7 mmol) and DMAP (63 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 7 h (TLC analysis showed some starting material was left). DCM (50 mL) was added and the resulting mixture was washed with HCl solution (1 N, 30 mL) and saturated aqueous NaHCO3 (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=10:1) to give product as a white powder (540 mg, 34.8%). LC-MS analysis confirmed the structure.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]([CH3:29])=[CH:17]3)=[CH:10][CH:9]=1.Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]([CH3:29])=[CH:17]4)=[CH:10][CH:9]=2)=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CCOC(=O)c1nc2ccc(-c3ccc(O)cc3)cc2cc1C
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2cc1C
Reaction time: 18 h
Yield: 44 %

Procedure:
Cesium carbonate (71.7 mg, 220.1 μmol) was added to ethyl 6-(4-hydroxyphenyl)-3-methyl-2-quinolinecarboxylate (61.5 mg, 200.1 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (67.0 mg, 220.1 μmol) in N,N-dimethylformamide (4 mL) at room temperature. The resulting suspension was stirred for 18 hours, then water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 50.7 mg (44%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-methyl-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.32 (s, 1H), 8.14 (s, 1H), 8.08-8.01 (m, 2H), 7.72 (s, 1H), 7.70 (s, 1H), 7.63 (d, J=8 Hz, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.93 (d, J=9 Hz, 2H), 4.89 (s, 2H), 4.41 (q, J=7 Hz, 2H), 3.48 (septet, J=7 Hz, 1H), 2.55 (s, 3H), 1.36 (t, J=7 Hz, 3H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:20])=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.[C:21]([O:25][C:26]([C@@H:28]1[CH2:32][C@@H:31](O)[CH2:30][C@H:29]1[C:34](=[O:46])[NH:35][C@:36]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:38][C@H:37]1[CH:39]=[CH2:40])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([CH:28]1[CH2:32][CH:31]([O:20][C:7]2[C:6]3[C:11](=[C:12]([CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:30][CH:29]1[C:34](=[O:46])[NH:35][C:36]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:38][CH:37]1[CH:39]=[CH2:40])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc2c(O)nc(-c3ccccc3)nc2c1C
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccccc3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 75.8 %

Procedure:
Quinazolinol derivative (83) (480 mg, 1.8 mmol) was coupled to compound 15 (0.55 mg, 1.5 mmol) as described in example 16, which gave the title compound (700 mg, 75%)
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:20](=[O:23])[CH2:21][CH3:22])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nc(-c2ccccc2)c(-c2nc(CC)no2)s1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and propionyl chloride.