Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5](=[S:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>CN(C)C=O>[CH3:17][C:16]1[C:2]2[S:12][C:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:4][C:3]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(NC(=S)c2ccccc2)c1Cl
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: CN(C)C=O
Product: Cc1cccc2nc(-c3ccccc3)sc12

Procedure:
91.6 g (0.35 mol) of the compound from Example VI in 1 l of dimethylformamide were boiled under reflux with 64 g (0.42 mol) of diazabicycloundecane for 3 h. The mixture was concentrated, the residue was taken up in methylene chloride/water, and the solution was rendered weakly acidic, washed with water, dried and concentrated. Yield: 70 g (89% of theory) M.p.: 53°-54° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[CH3:23][O:24][C:25]([C:27]1[C:28]([CH3:35])=[N:29][O:30][C:31]=1[C:32](O)=[O:33])=[O:26]>ClCCl.C(OCC)(=O)C>[N:1]1([C:32]([C:31]2[O:30][N:29]=[C:28]([CH3:35])[C:27]=2[C:25]([O:24][CH3:23])=[O:26])=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C)noc1C(=O)O
Reactant: C1CCNCC1
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)noc1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
At -5° C., 3.0 g (35.1 mmol) of piperidine, 10.1 g (100.0 mmol) of methylmorpholine, 1.1 g (9 mmol) of dimethylaminopyridine and 22.9 g of a 50% strength solution of propanephosphonic anhydride in dichloromethane (36.0 mmol) were added one after the other to 5.0 g (27.0 mmol) of 4-methoxycarbonyl-3-methyl-isoxazole-5-carboxylic acid in 100 ml of dichloromethane, and the mixture was stirred for 12 hours at room temperature. The solvent was stripped off under reduced pressure, and the residue was taken up in 200 ml of ethyl acetate and extracted twice with saturated sodium bicarbonate solution and once with 5% strength citric acid solution and once with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 90%, 1H-NMR (250 MHz; CDCl3): δ=1.65 ppm (m; 6H), 2.49 ppm (s; 3H), 3.18 ppm (m; 2H), 3.73 ppm (m; 2H), 3.87 ppm (s; 3H).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].[C:21](O)(=[O:23])[CH3:22]>>[C:14]([N:5]1[C:4]2=[N:3][N:2]=[CH:1][N:9]2[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]1[C:21](=[O:23])[CH3:22])(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)NNc1nncn1-2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccccc2-n2cnnc2N1C(C)=O
Yield: 91 %

Procedure:
7.0 g (0.04 mole) of 4,5-dihydro-s-triazolo[3,4-c]-benzo-as-triazine are added to a mixture of 35 ml of glacial acetic acid and 35 ml of acetic anhydride, and the reaction mixture is refluxed for 6 hours. At the end of the reaction the mixture is cooled, the product is precipitated with ether and filtered off. 9.4 g of the title compound are obtained; yield: 91%; m.p.: 186°-188° C.
Reaction SMILES: [I-:1].[CH3:2][N:3]([CH3:29])[C:4]1[CH:13]=[CH:12][C:11]2[N+:10]3[CH:14]=[C:15]4[CH:24]=[CH:23][C:22]5[CH:21]=[C:20]([C:25](C)(C)[CH3:26])[CH:19]=[CH:18][C:17]=5[N:16]4[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:5]=1>CO.CCOCC>[I-:1].[CH3:2][N:3]([CH3:29])[C:4]1[CH:13]=[CH:12][C:11]2[N+:10]3[CH:14]=[C:15]4[CH:24]=[CH:23][C:22]5[CH:21]=[C:20]([CH2:25][CH3:26])[CH:19]=[CH:18][C:17]=5[N:16]4[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: CN(C)c1ccc2c(ccc3n4c(ccc5cc(C(C)(C)C)ccc54)c[n+]23)c1
Agent: [I-]
Solvent: CCOCC
Solvent: CO
Product: CCc1ccc2c(ccc3c[n+]4c5ccc(N(C)C)cc5ccc4n32)c1

Procedure:
3-Dimethylamino-10-(1,1-dimethylethyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium Iodide; m.p. 360° C., from methanol/ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][NH2:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][NH:12][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NCCc1ccc2[nH]ccc2c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCCc1ccc2[nH]ccc2c1
Reaction time: 0.33 h

Procedure:
A mixture of 1H-indole-5-ethanamine (1.00 g), methane sulphonylchloride (0.69 ml), 8% sodium bicarbonate solution (100 ml) and ethyl acetate (100 ml) were stirred vigorously for 20 min. The organic phase was separated and the aqueous phase extracted with ethyl acetate (50 ml). The combined organic phases were dried and evaporated in vacuo to give the title compound as an oil (1.50 g). T.l.c. SiO2, EtOAc Rf 0.8
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[S-:20][C:21]#[N:22].[K+].O1CCCC1>O>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:6]=[C:7]([S:20][C:21]#[N:22])[C:3]([CH3:2])=[N:4]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1SC#N

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole (9.55 g), potassium thiocyanate (1 g) and tetrahydrofuran (50 ml) were heated under reflux for 3 hours. The mixture was poured into water, solid collected and recrystallised from ethyl aceteate/hexane to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-thiocyanato-methyl-2H-1,2,3-triazole, m.p. 115°-117°. (Compound 23)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28](I)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:42]([N:50]1[CH:54]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH:52]=[N:51]1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:53]5[CH:52]=[N:51][N:50]([CH2:42][CH2:43][C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=6)[CH:54]=5)=[CH:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(I)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(CCc5ccccc5)c3)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Yield: 15.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 50) (150 mg, 0.215 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (76 mg, 0.258 mmol) using sodium carbonate (68 mg, 0.645 mmol) and Pd(PPh3)2Cl2 (8 mg, 0.0107 mmol) in toluene/ethanol/water (5/5/2 ml) to afford 25 mg (15.7% yield) of titled compound after purification by preparative TLC (Silicagel-1000 micron) using 1% methanol in DCM as eluent. MS: m/z=742.4 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.C([N:21]([CH2:34][CH3:35])[C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]C)[C:24]=1[CH2:31]C)C.[CH2:36]([N:43]1[CH2:47]C[CH:45](C#N)[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([N:43]1[CH2:44][CH2:45][CH:35]([C:34]2[NH:21][C:22](=[O:33])[C:23]3[C:24]([CH:31]=2)=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)[CH2:47]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCc1cccc(C(=O)N(CC)CC)c1CC
Reactant: N#CC1CCN(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(C3CCN(Cc4ccccc4)C3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 107.9 %

Procedure:
A solution (400 mL) of diisopropylamine (26.9 g) in tetrahydrofuran was cooled to −5° C. and 1.57 M n-butyllithium hexane solution (154 ml) was added dropwise to the solution. After stirring at 0° C. for 30 min, the mixture was cooled to −78° C. and a solution (50 mL) of N,N-diethyl-2,3-diethylbenzamide (45.1 g) in tetrahydrofuran was added dropwise. After stirring at −78° C. for 1 hr, a solution (50 mL) of 1-benzyl-3-cyanopyrrolidine (37.18 g) in tetrahydrofuran was added dropwise. After Completion of the dropwise addition, the reaction mixture was heated to room temperature and the mixture was stirred overnight at room temperature. The mixture was further stirred under reflux for 1 hr and the reaction mixture was concentrated to about half. Water and methylene chloride were added and the organic layer was partitioned washed with water, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (ethyl acetate) to give (±)-3-(1-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (66.38 g).
Reaction SMILES: C[C@H]1CCC[C@@H](C)N1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](N)CC3)C=CC2=NN=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([CH3:37])[N:32]1[C:38]1[N:42]2[CH:43]=[C:44]([O:47][C@H:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[C@@H:51]([NH:58][C:59](=[O:81])[NH:60][C:61]4[N:65]([C:66]5[CH:67]=[N:68][N:69]([CH2:71][CH2:72][O:73]S(C)(=O)=O)[CH:70]=5)[N:64]=[C:63]([CH:78](C)[CH3:79])[CH:62]=4)[CH2:50][CH2:49]3)[CH:45]=[CH:46][C:41]2=[N:40][N:39]=1>>[CH3:37][C@H:33]1[CH2:34][CH2:35][CH2:36][C@@H:31]([CH3:30])[N:32]1[C:38]1[N:42]2[CH:43]=[C:44]([O:47][C@H:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[C@@H:51]([NH:58][C:59]([NH:60][C:61]4[N:65]([C:66]5[CH:67]=[N:68][N:69]([CH2:71][CH2:72][OH:73])[CH:70]=5)[N:64]=[C:63]([CH2:78][CH3:79])[CH:62]=4)=[O:81])[CH2:50][CH2:49]3)[CH:45]=[CH:46][C:41]2=[N:40][N:39]=1
Reactant: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Agent: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: CCc1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCO)c2)n1

Procedure:
The title compound was prepared starting from Intermediate 3 (900 mg, 2.27 mmol), and Intermediate Cb (889 mg, 2.27 mmol) by using an analogous procedure to that described for Intermediate A step d. LCMS (Method 3): Rt 3.30 min, m/z=639 [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:25]1([CH2:24][NH:31][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[O:8][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[CH2:10][C:3]=23)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(CNc2ccnc3c2CC2(CN4CCC2CC4)O3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
A solution of 97 mg (0.387 mmol) of 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in 5 mL of benzylamine was heated to reflux under a nitrogen atmosphere and stirred for 18 hours. Upon cooling to ambient temperature, the diluted with 40 mL of water, basicified with 2 mL of saturated aqueous sodium carbonate and extracted with chloroform (3×25 mL). The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo, and flash chromatographed on neutral silica gel using a 9:1 mixture of ammoniated chloroform/methanol to provide 42 mg (34%) of the title compound as a white solid: electrospray MS (m/z, relative intensity) 322 ([MH]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClC1C=CC=CC=1Cl>[C:17]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:12])[NH:10]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccc2cccc(O)c2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
8-Hydroxy-(1H)-quinolin-2-one (32.24 g, 200 mmol, 1.0 eq) is suspended in 1,2-dichloro benzene (300 mL). The suspension is maintained at 20-25° C. and aluminium chloride (93.3 g, 700 mmol, 3.5 eq.) is added in portions (30 minutes, IT max. 25 IC). Acetic anhydride (21.4 g, 210 mmol, 1.05 eq.) is slowly added (30 minutes, IT max. 20° C.) and the addition funnel is rinsed with a small amount of 1,2-dichlorobenzene. The suspension is stirred for 30 minutes at 20-25° C. HPLC control reveals complete conversion to 8-acetoxy-(1H)-quinolin-2-one. The mixture is heated to IT=80 IC while purging the head-space with a stream of nitrogen. HCl evolution is noticed upon reaching IT=40° C. The reaction mixture is stirred for 1 hour at IT=80° C. HPLC control reveals almost complete conversion to 5-acetyl-8-hydroxy-(1H)-quinolin-2-one (1.8% O-acetyl intermediate, 7.2% ortho-isomer). The reaction mixture is heated to IT=90° C. and poured hot (90 ° C.) over water (645 mL). Water (100 mL) is added in the reaction vessel and brought to reflux temperature. After 15 minutes at reflux temperature, the suspension is added to the previous quench suspension. The mixture is maintained for 15 minutes at IT=80° C. and is hot filtered. The yellow product is rinsed with water (2×200 mL, 50° C.). The crude product (70.1 g) is suspended in acetic acid (495 mL) and the suspension is heated to reflux temperature for 30 minutes. The suspension is cooled down to IT=20° C. and then filtered. The product is washed with acetic acid/water 1/1 (60 mL) and washed with water (5×100 mL) before being dried at 70° C. under vacuum to yield the title compound in 75% yield (31.48 g) and with 99.9% purity.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=O)[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:10]1[OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C)S(C(F)(F)F)(=O)=O.[CH2:38]([NH2:41])[CH2:39][CH3:40]>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[N:15]=[C:16]([NH:41][CH2:38][CH2:39][CH3:40])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:10]1[OH:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](O)[C@@H](COCc3ccccc3)C[C@@H]2O1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCNC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](O)[C@@H](COCc3ccccc3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
To a solution of (3aS,4R,5R,6R,7aS)-4-(benzyloxy)-6-((benzyloxy)methyl)-5-hydroxyhexahydrobenzo[d]oxazol-2(3H)-one (60 mg, 0.16 mmol) in dry DCM (2 mL) under N2 at 0° C. was added methyl triflate (0.035 mL, 0.32 mmol) dropwise. The mixture was stirred at room temperature for 18 h, cooled to 0° C. and n-propylamine (0.131 mL, 1.6 mmol) was added. The mixture was further stirred at 0° C. for 5 h. The mixture was diluted with aqueous satd. NaHCO3 (15 mL) and extracted with DCM (2×15 mL). The extracts were dried (Na2SO4) and concentrated to give the crude product (75 mg). This was purified by silica gel chromatography, eluted with 92:6:2 DCM-MeOH—NH4OH to give the product (3aS,4R,5R,6R,7aS)-4-(benzyloxy)-6-((benzyloxy)methyl)-2-(propylamino)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (21 mg, 30.6%). 1H NMR (600 MHz, CDCl3) δ 7.35-7.27 (m, 10H), 4.94 (d, J=11.6, 1H), 4.85 (m, 1H), 4.71 (d, J=8.2, 1H), 4.53 (s, 2H), 4.02 (t, J=6.8, 1H), 3.68 (m, 3H), 3.50 (t, J=6.4, 1H), 3.75 (m, 2H), 2.18-2.15 (dt, J=14.8, 3.0, 1H), 1.98-1.94 (m, 1H), 1.80-1.78 (m, 1H), 1.62-1.58 (m, 2H), 0.98 (t, J=7.2, 3H).
Reaction SMILES: C1COCC1.[CH3:6][C@H:7]([OH:10])[CH2:8][CH3:9].C(N(CC)CC)C.[C:18]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CCOCC>[CH3:6][CH:7]([O:10][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:28][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:37][CH:36]=1)[CH2:8][CH3:9]
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Reactant: CC[C@H](C)O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(C)OC(=O)c1ccc(OC(=O)OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 17.4 %

Procedure:
A THF solution of 0.1 mole of (S)-(+)-2-butanol and 0.1 mole of triethylamine was stirred at 0° C., and a THF solution of 0.12 mole of 4-carbobenzoxyoxybenzoic acid chloride was added dropwise. The temperature was returned to the room temperature slowly, and stirring was carried out for 8 hours. After the reaction, the reaction solution was ether extracted, dried, concentrated, and purified by column chromatography, to obtain 5.7 g of 4-carbobenzoxyoxybenzoic acid 1-methylpropyl ester. (yield: 18%)
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:15][C:14]=1[CH3:36])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+].Cl>O1CCCC1.CO.O>[Br:35][C:27]1[C:28]2[S:29][C:30]([CH3:34])=[C:31]([CH3:33])[C:32]=2[C:20]([C:16]2[CH:15]=[C:14]([CH3:36])[C:13]([O:12][C@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3]([OH:37])=[O:2])=[C:18]([CH3:19])[CH:17]=2)=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1O[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid methyl ester (3.1 g, 5.4 mmol) in tetrahydrofuran (125 mL) and methanol (41 mL) at room temperature was added dropwise aqueous potassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol). After 1.5 h at room temperature the reaction mixture was placed in the freezer for 18 h. The reaction was removed from the freezer and allowed to stir at room temperature. More aqueous potassium hydroxide (19.5 mL of a 1N solution, 19.5 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 9.5 h. Concentration under reduced pressure gave a residue which was diluted with water (1 L). The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1, and extracted with diethyl ether (700 mL). The diethyl ether layer was washed twice with water (500 mL), and then dried (Na2SO4). Concentration under reduced pressure and chromatography on silica gel (treated with 2% phosphoric acid in methanol) with petroleum ether:ethyl acetate (90:10, then 86:14) gave the title compound as a white solid foam (1.9 g, 64%): Opt. Rot. [a]25/D=+33.380 (10.035 mg/mL, MeOH); NMR (DMSO-d6): δ 12.90 (broad singlet, 1H), 8.17 (d, 1H), 7.63 (ddd, 1H), 7.50-7.43 (m, 2H), 7.36-7.23 (m, 5H), 6.97 (s, 2H), 4.71 (t, 1H), 3.25 (d, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.54 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 558/560; Anal. Calc. for C31H27BrO3S: C, 66.55, H, 4.86, N, 0.00. Found: C, 65.91, H, 5.05, N, 0.09; Analytical HPLC indicates a major component (99.5%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:13]I.S(=O)(=O)(O)O>CC(O)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([I:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: II
Reactant: COC(=O)c1ccc(C)cc1Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(C)cc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a round-bottom flask was added a mixture of methyl 2-bromo-4-methylbenzoate (2.00 g, 7.86 mmol, 1.00 equiv) in AcOH (20 mL). I2 (2.45 g, 9.65 mmol, 1.10 equiv), NaIO4 (950 mg, 4.42 mmol, 0.50 equiv), and sulfuric acid (0.1 mL, 0.15 equiv) were added and the resulting mixture was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction was carefully quenched with Na2S2O3 (aq., sat.). The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to yield 2.50 g (81%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([C:14]#[N:15])([CH3:13])[CH3:12].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[C:33]=1[C:45]#[N:46]>O1CCCC1.C(OCC)(=O)C>[C:40]([NH:39][C:37]1[S:38][C:34]2[C:33]([C:45]#[N:46])=[C:32]([O:31][C:30]3[CH:29]=[C:28]([NH:27][C:6](=[O:8])[C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:4]=4)[CH:49]=[CH:48][CH:47]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4ccc(Cl)c(C(C)(C)C#N)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of 4-chloro-3-(1-cyano-1-methylethyl)benzoic acid (83 mg, 0.370 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (40 μL, 0.462 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (100 mg, 0.308 mmol) produced in Example 12(ii) was added to the solution, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (108 mg, 66%) as a white powder.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([OH:10])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][O:10][C:7]1[N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]2=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2cc[nH]c2n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridin-6-ol (1.52 g, 11.4 mmol) and potassium carbonate (7.86 g, 57 mmol) in acetone (100 mL) was stirred under nitrogen at room temperature for 1 h. Iodomethane (2.6 g, 18.2 mmol) was added and the resulting mixture stirred at 56° C. for 12 h. The mixture was filtered, and the filtrate was concentrated to half its volume, diluted with water, and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 20% ethyl acetate/hexanes) to afford 6-methoxy-1H-pyrrolo[2,3-b]pyridine (0.5 g, 30%): LC/MS m/e calcd for C8H8N2O [M+H]+ 149.17, observed 149.1.