Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[C:26]1([CH:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([OH:35])=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:42][O:43][C:44]([C@H:46]1[NH:51][CH2:50][C:49]2[N:52]=[CH:53][N:54]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[C:58]([CH3:65])[CH:57]=3)[C:48]=2[CH2:47]1)=[O:45]>C(#N)C>[CH3:42][O:43][C:44]([C@H:46]1[N:51]([C:33](=[O:35])[CH:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:50][C:49]2[N:52]=[CH:53][N:54]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[C:58]([CH3:65])[CH:57]=3)[C:48]=2[CH2:47]1)=[O:45]
Reactant: COC(=O)[C@@H]1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)[C@@H]1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105.5 %

Procedure:
Acetonitrile (16 ml) was added to a mixture of N,N'-dicyclohexylcarbodiimide (DCCI) (2.1080 g, 0.01022 mol), 1-hydroxybenzotriazole (HBTA) (1.3806 g, 0.01022 mol), and diphenylacetic acid (2.1685 g, 0.01022 mol), followed by stirring at room temperature for 20 minutes. A solution of (S)-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid methyl ester (VI-2) (2.7000 g, 0.00817 mol) in acetonitrile (14 ml) was added to the suspension, and the mixture was stirred at room temperature for 21 hours. An insoluble portion in the reaction mixture was filtered out and washed with acetonitrile, and then the filtrate and washings were joined and concentrated. The residue was dissolved in methylene chloride (40 ml), washed with a 10% sodium carbonate solution and a saturated brine, then dried over sodium sulfate and concentrated to obtain an orange oily material (4.5203 g). This crude oily material was purified by silica gel column chromatography (Kieselgel 60, 270 g, chloroform/methanol=60/11) to obtain the objective compound (V-2) (2.8250 g; yield: 65.9%) as colorless crystals (top: 174.5°-177° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][C:27]=2[Cl:28])[O:21][CH:22]=1>>[Cl:28][C:27]1[CH:26]=[CH:25][S:24][C:23]=1[C:20]1[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2sccc2Cl)n1
Product: Clc1ccsc1-c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3-chloro-2-thienyl)oxazole to give 2-(3-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 69-70° C.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)C=CC=CC=1.C([Li])CCC.CCCCCC.O=[CH:58][CH2:59][C@H:60]([NH:68][C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70])[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62].[Cl-].[Na+]>O1CCCC1>[C:73]1([CH2:72][O:71][C:69]([NH:68][C@@H:60]([CH2:59]/[CH:58]=[CH:9]/[C:10]2[N:11]=[CH:12][N:13]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:14]=2)[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:70])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: CC(C)(C)OC(=O)[C@H](CC=O)NC(=O)OCc1ccccc1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)[C@H](C/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
50.93 g (820 mmol) of triphenyl[[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]phosphonium chloride in solution in 333 ml of tetrahydrofuran are introduced, under argon, into a three-necked round-bottomed flask. 51.2 ml of a 1.6M solution of n-butyllithium in hexane (820 mmol) are added dropwise, at -70° C. After stirring for 30 minutes at -70° C., the reaction mixture is quickly poured into 270 ml of a 0.253M solution, cooled to -70° C., of 1,1-dimethylethyl (S)-4-oxo-2-[[(phenylmethoxy)carbonyl]amino]butanoate in tetrahydrofuran (683 mmol). The mixture is allowed to return to room temperature overnight. The mixture is hydrolysed with 280 ml of a saturated aqueous sodium chloride solution. The aqueous phase is separated from the organic phase and extracted with 2 times 140 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated to dryness. Purification is carried out by chromatography on a column of silica gel, the eluent being a hexane/ethyl acetate gradient.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](C(O)=O)=[CH:6]2.N1C2C(=CC=CC=2)C=CC=1>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1[N+](=O)[O-]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: c1ccc2ncccc2c1
Product: COc1ccc2[nH]ccc2c1[N+](=O)[O-]
Temperature: 225 °C
Reaction time: 0.67 h
Yield: 22 %

Procedure:
The crude 5-methoxy-4-nitroindole-2-carboxylic acid (720 mg, 3.05 mmol), quinoline (9 ml) and copper chromite (180 mg) were stirred together. Nitrogen was gently bubbled through the mixture for 5 minutes, then the mixture was heated quickly to 225° C., and stirred at this temperature for 40 minutes under an atmosphere of nitrogen. The mixture was cooled to ambient temperature diluted with ethyl acetate (80 ml) and the insoluble material filtered off. The filtrate was extracted twice with aqueous hydrochloric acid (2M) and then with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried (MgSO4), evaporated and the residue purified by silica column chromatography eluting with dichloromethane to give 5-methoxy-4-nitroindole (129 mg, 22%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: Cc1ccnc(Br)c1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4cc(C)ccn4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 2-bromo-4-methylpyridine
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:9]([OH:20])[CH2:10][NH:11][CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:46][C:41]=2[O:40][CH2:39]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@H:9]([OH:20])[CH2:10][N:11]([S:47]([C:45]1[CH:44]=[CH:43][C:42]2[O:38][CH2:39][O:40][C:41]=2[CH:46]=1)(=[O:48])=[O:49])[CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Yield: 57.9 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.099 g, 0.25 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.066 ml, 0.38 mmol) and Benzo[1,3]dioxole-5-sulfonyl chloride (0.067 g, 0.31 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (1% MeOH in CH2Cl2) gave 0.083 g of a white solid. MS(ES): 574 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([F:45])=[CH:32][C:31]=1[N:46]1[CH2:58][CH2:57][N:49]2[C:50]3[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=3[CH:56]=[C:48]2[C:47]1=[O:59])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:45][C:33]1[CH:34]=[C:35]([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[C:30]([CH2:29][OH:28])=[C:31]([N:46]2[CH2:58][CH2:57][N:49]3[C:50]4[CH2:51][CH2:52][CH2:53][CH2:54][C:55]=4[CH:56]=[C:48]3[C:47]2=[O:59])[CH:32]=1
Reactant: CN1CCN(c2ccc(Nc3cc(Cl)nn4ccnc34)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)nn4ccnc34)nc2)CC1
Temperature: 130 °C
Yield: 20.1 %

Procedure:
A sealed tube was charged with 104b (340 mg, 0.8 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101l (400 mg, 0.8 mmol), Pd2(dba)3 (72 mg, 0.1 eq., 0.08 mmol), PCy3 (68 mg, 0.3 eq., 0.24 mmol), cesium carbonate (520 mg, 2 eq., 1.6 mmol), dioxane (15 mL), and water (1 mL). After three cycles of vacuum/argon flash, the mixture was heated at 130° C. for 14 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/-methanol (20:1) to afford 104 (100 mg, 16%). LCMS: [M+H]+ 622. 1H NMR (500 MHz, DMSO) δ 9.95 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=2.0, 1H), 7.67 (s, 1H), 7.43-7.46 (m, 3H), 7.34-7.36 (m, 1H), 6.52 (s, 1H), 4.67 (t, J=5.0, 1H), 4.34-4.41 (m, 2H), 4.13-4.18 (m, 3H), 3.87-3.88 (m, 1H), 3.10-3.12 (m, 4H), 2.57-2.61 (m, 2H), 2.43-2.47 (m, 6H), 2.21 (s, 3H), 1.77-1.79 (m, 2H), 1.68-1.69 (m, 2H)
Reaction SMILES: [Li+].[BH4-].[CH3:3][N:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:13](OCC)=[O:14])[CH:6]=[N:5]1.Cl.C(=O)([O-])[O-].[Na+].[Na+].C1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(NN)C=1>C1COCC1.ClCCl.C(Cl)Cl.C(OCC)(=O)C.O>[CH3:3][N:4]1[C:8]([C:9]([F:10])([F:11])[F:12])=[C:7]([CH2:13][OH:14])[CH:6]=[N:5]1
Reactant: CCOC(=O)c1cnn(C)c1C(F)(F)F
Agent: Cl
Agent: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cn1ncc(CO)c1C(F)(F)F

Procedure:
LiBH4 in THF (2M, 15 ml, 0.03 mole) was added dropwise to a stirred solution of ethyl 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (3.32 g, 0.015 mole) in THF (40 ml) at room temperature under nitrogen. The solution was then stirred under reflux for 18 hrs. After cooling, the cloudy solution was evaporated at room temperature to give an oil. Water was added (heavy ppt. of white solid) and the mixture chilled and treated cautiously with hydrochloric acid (2M) to pH 2 (no solid remaining, to give an oil). The mixture was neutralised with sodium carbonate and the mixture extracted with diethyl ether (3×20 ml). The organic layer was separated and back-washed with brine (3×30 ml). The organic layer was separated, dried (Na2SO4), filtered and evaporated to give an oil. Yield 3 g. An aliquot (150 mg) was dissolved in dichloromethane and purified using an ISCO Companion (4 g silica col. CH2Cl2 to CH2Cl2:ethyl acetate 9:1). The appropriate fractions were combined and evaporated to give an oil, 72 mg. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H) 4.69, 4.48 (d, 2H) 4.00 (s, 3H) 1.70, 1.68, 1.67 (t, 1H). MS (ESI) m/z 181 (M+H)+. LC-MS m/z 181 (M+H) GC-MS FID 100% Cl+ 181 (M+H)+. TLC CH2Cl2:ethyl acetate 9:1 0.25 UV−ve DNPH+ve.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[C:20]=1[CH3:27])C>>[CH:10]([S:9][C:4]1[C:3]([CH2:2][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:28])=[O:15])=[C:20]([CH3:27])[C:21]=2[CH3:26])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CC(C)Sc1ncccc1CCl
Product: Cc1c(CCC(=O)O)ccc(OCc2cccnc2SC(C)C)c1C
Yield: 78.8 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (25 mg, 0.12 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-2,3-dimethyl-phenyl)-propionic acid ethyl ester (30 mg, 0.13 mmol) obtained in Step D of Preparation Example 43 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (34 mg, 85%).
Reaction SMILES: O=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[NH2:21][C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>C(O)(=O)C>[OH:31][C:25]1[CH:24]=[CH:23][C:22]([N:21]2[C:5]3[CH2:6][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:4]=3[CH:3]=[C:2]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:30][C:26]=1[CH:27]([OH:29])[OH:28]
Reactant: O=C(CC1C(=O)CCc2ccccc21)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: Oc1ccc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)cc1C(O)O
Yield: 50.2 %

Procedure:
A mixture of 3 (2.41 g, 9.1 mmol), 5-aminosalicylic acid (1.40 g, 9.1 mmol) and glacial acetic acid (9 mL) was heated under reflux for 2 hours. After cooling, the precipitate was filtered and washed with acetic acid and water. The solid was recrystallized from acetic acid to afford 1.75 g (50% yield) title product as a yellow solid; MS m/z 380 (M−−H) 9.92 min; 1H NMR (DMSO-d6) δ 2.63 (t, 2H), 2.94 (t, 2H), 4.89 (s, 1H), 7.16 (m, 13H).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:37]1[N:42]=[CH:41][C:40]([C:43]2[O:44][C:45]3[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:46]=3[N:47]=2)=[CH:39][CH:38]=1.[F:54][CH2:55][CH2:56][OH:57]>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:54][CH2:55][CH2:56][O:57][C:37]1[N:42]=[CH:41][C:40]([C:43]2[O:44][C:45]3[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:46]=3[N:47]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc2nc(-c3ccc(Br)nc3)oc2c1
Reactant: OCCF
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2nc(-c3ccc(OCCF)nc3)oc2c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Toluene (1 mL) was added to Pd(OAc)2 (6.4 μmol), 2-(di-t-butylphosphino)-1,1′-binaphtyl (racemic, 8.0 μmol), Cs2CO3 (0.24 mmol) and 2-(6-bromopyridin-3-yl)-6-methoxy-1,3-benzoxazole under Ar. 2-Fluoroethanol (0.16 mmol) was added and the reaction was stirred 1 h at 120° C. Additional Pd(OAc)2 (8.0 μmol), 2-(di-t-butylphosphino)-1,1′-binaphtyl (racemic, 8.0 μmol) and 2-fluoroethanol (0.16 mmol) was added and the mixture was again stirred 1 h at 120° C. The reaction mixture was cooled to r.t., diluted with EtOAc, filtered through celite and concentrated. The crude product was subjected to reverse phase HPLC to afford the title compound as an off white solid (10.1 mg). 1H NMR (400 MHz, Chloroform-d) δ ppm 8.95 (d, 1H) 8.36 (dd, 1H) 7.62 (d, 1H) 7.12 (d, 1H) 6.91-6.99 (m, 2H) 4.82-4.88 (m, 1H) 4.69-4.76 (m, 2H) 4.61-4.66 (m, 1H) 3.89 (s, 3 H); MS m/z (M+H) 289.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].[OH-].[Na+].[Cl-].[Na+]>CS(C)=O>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NCCc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A solution of 17.1 g. (0.1 m.) of benzyl bromide in 100 ml. of dimethylsulfoxide is added slowly to a stirred mixture of 18.2 g. (0.1 m.) of 4-hydroxy-3-nitrophenethylamine in 1 l. of dimethylsulfoxide and 60 ml. of 2N sodium hydroxide at 85°C. After addition is complete the reaction mixture is stirred at 85°C. for an additional two hours, poured into ice-water, saturated with sodium chloride and extracted with ethyl acetate. The organic extract is dried and concentrated to give 4-benzyloxy-3-nitrophenethylamine. The latter (2.72 g., 0.01 m.) in 50 ml. of toluene is rfluxed azeotropically with 1.27 g. (0.012 m.) of benzaldehyde until water formation is completed (about one hour). Solvent is removed by distillation to leave the crude imine. Sodium borohydride (0.38 g., 0.01 m.) is then added to a solution of the above imine in 30 ml. of methanol over a period of 30 minutes and after stirring for an additional hour the reaction mixture is evaporated. The residue is treated with 2N hydrochloric acid and ether. The solid obtained is filtered and washed to give N-benzyl-4-benzyloxy-3-nitrophenethylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[S:10][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)=[CH:12][N:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8].Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C:3]1([C:9]2[S:10][C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)=[CH:12][N:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8]
Reactant: NO
Reactant: COC1(c2ncc(Sc3ccc(C(C)=O)cc3)s2)CCOC1C
Agent: Cl
Product: COC1(c2ncc(Sc3ccc(/C(C)=N/O)cc3)s2)CCOC1C
Yield: 98 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'-{2-[(2RS,3RS)-3-methoxy-2-methyltetrahydrofuran-3-yl]thiazol-5-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{2-[(2RS,3RS)-3-methoxy-2-methyltetrahydrofuran-3-yl]thiazol-5-ylthio}acetophenone oxime in 98% yield as a gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:37]C(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]([C:26](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH3:37])=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(NC(=O)c3ccccc3)cc2)cs1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C(=O)c1ccccc1)c1ccc(OCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
2-[(4-{2-[4-(Benzoylamino)phenoxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (500 mg) synthesized in Example 54-1 and methyl iodide (170 mg) were dissolved in N,N-dimethylformamide (6 mL), potassium tert-butoxide (135 mg) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (290 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14]([C:16]1[CH:37]=[CH:36][C:19]([O:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]([C:31]([O-:33])=[O:32])[CH2:26][CH2:27][O:28]4)=[CH:23][C:22]=3[C:34]#[N:35])=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2.O[Li].O.O1CCOCC1.Cl>C1COCC1>[C:34]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:21]=1[O:20][C:19]1[CH:18]=[CH:17][C:16]([C:14](=[O:15])[NH:13][CH:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:9]3)=[CH:37][CH:36]=1)[O:28][CH2:27][CH2:26][CH:25]2[C:31]([OH:33])=[O:32])#[N:35]
Reactant: COc1ccc2c(c1)CCC(NC(=O)c1ccc(Oc3cc4c(cc3C#N)C(C(=O)[O-])CCO4)cc1)C2
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)CCC(NC(=O)c1ccc(Oc3cc4c(cc3C#N)C(C(=O)O)CCO4)cc1)C2
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.6 %

Procedure:
7-(4-((6-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (29.5 mg, 0.0576 mmol) was dissolved in THF (3 ml) and 1M solution of LiOH—H2O (115 μl, 0.115 mmol) was added. The mixture was stirred for 17 hours at ambient temperature. The mixture was quenched with 4M HCl dioxane (43.2 μL, 0.173 mmol). The crude mixture was purified on silica gel (MeOH in dichloromethane with 1% acetic acid gradient) to provide 28.9 mg of the title compound as a thin film (100%). MS (apci) m/z=499.1 (M+H).
Reaction SMILES: O=[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2c([nH]c1=O)CCCC2
Product: N#Cc1cc2c(nc1Cl)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To 2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (6.0 g, 34.4 mmol) was added phosphorus oxychloride (20 mL), this mixture was stirred at RT for 1 h, and then refluxed for 12 h. Excess phosphorous oxychloride was distilled off, and the residue was poured into ice cooled water. The aqueous solution was basified with saturated sodium bicarbonate solution, and the precipitate that formed was filtered off. The precipitate was purified by column chromatography eluting with 2% ethyl acetate and petroleum ether to afford 2-chloro-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (5.00 g), yield: 75%.