Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[I-].[NH2:24][N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[K+].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)[CH:5]=[CH:4][N:3]=1
Reactant: N[n+]1ccccc1
Reactant: O=C(Nc1cccc(C#Cc2ccnc(Cl)n2)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Yield: 63.5 %

Procedure:
N-[3-(2-Chloro-pyrimidin-4-ylethynyl)-phenyl]-2,2,2-trifluoro-acetamide (9.14 g, 28.1 mmol), N-aminopyridinium iodide (6.24 g, 28.1 mmol), KOH (1.57 g, 28.9 mmol) and K2CO3 (7.76 g) were heated in DMSO (175 mL) were reacted according to earlier examples to afford, after workup, 7.45 g of the title compound, Rf=0.2 (2:1 Hex/EtOAc).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:10][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([O:12][CH3:11])[CH2:14][CH2:15]2)[C:5]=1[NH2:9]
Reactant: CO[C@H]1CC[C@H](N)CC1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CO[C@H]1CC[C@H](Nc2nc(N)nc(Cl)c2N)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,5-diamino-4,6-dichloropyrimidine (6 g, 33.5 mmol), trans-4-methoxy cyclohexyl amine (4.32 g, 33.5 mmol, 1 equiv.), sodium bicarbonate (9.85 g, 117.2 mmol, 3.5 equiv.) and 1-butanol (350 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, gradual elution with 96/4 methylene chloride/methanol to 90/10 methylene chloride/methanol) to give the desired product as a brown solid (69% yield). MS (EI) m/z 272 (MH)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[OH:38][C:39]12[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][C:41]([C:49](O)=[O:50])([CH2:42]3)[CH2:40]1)[CH2:46]2>O1CCCC1.C(OCC)(=O)C>[Cl:8][C:5]1[S:4]/[C:3](=[N:2]\[C:49]([C:41]23[CH2:42][CH:43]4[CH2:44][CH:45]([CH2:46][C:39]([OH:38])([CH2:48]4)[CH2:40]2)[CH2:47]3)=[O:50])/[NH:7][CH:6]=1
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: Nc1ncc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/N=c1/[nH]cc(Cl)s1)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-5-chlorothiazole hydrochloride (Aldrich) (1.00 g, 5.84 mmol) in tetrahydrofuran (50 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.12 g, 5.84 mmol), 1-hydroxybenzotriazole (0.79 g, 5.84 mmol), triethylamine (2.04 mL, 14.6 mmol), and 3-hydroxyadamantane-1-carboxylic acid (Acros) (1.15 g, 5.84 mmol). The mixture was stirred overnight at room temperature and was diluted with ethyl acetate, washed with 1 M aqueous sodium carbonate, dried (Na2SO4), filtered and concentrated. Purification by column chromatography (SiO2) using a gradient of 0% to 100% ethyl acetate:hexane provided the title compound. MS (ESI+) m/z 313 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:18]=[C:19]([CH3:28])[C:20]([CH2:24][N:25]=[C:26]=[O:27])=[C:21]([CH3:23])[CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH2:24][N:25]2[CH2:2][CH2:3][C:4]([CH2:5][C:6]([CH3:8])=[CH2:7])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:26]2=[O:27])=[C:19]([CH3:28])[CH:18]=1
Reactant: Cc1cc(Br)cc(C)c1CN=C=O
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Product: C=C(C)CC1(c2ccccc2)CCN(Cc2c(C)cc(Br)cc2C)C(=O)O1

Procedure:
The title compound was prepared from 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol and 5-bromo-2-isocyanatomethyl-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Example 96. LC-MS (Method 5): tR=4.95 min; Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.CCN(CC)CC.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:29](=[O:30])[C:28]2[CH:27]=[C:26]([C:25]([F:40])([F:39])[F:24])[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cc(F)cnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-chloro-5-fluoro-[3,4′]bipyridinyl-3′-yl)-methyl-amine (80 mg, 0.34 mmol) in CH2Cl2 (10 mL) were added Et3N (0.187 mL, 1.35 mmol) and 3,5-bis(trifluoromethyl)-benzoyl chloride (0.061 mL, 0.34 mmol, CAS RN 1271-19-8) at 25° C. and the resulting reaction mixture was stirred for 4 hours at 25° C. The mixture was diluted with CH2Cl2 (20 mL), the organic layer was washed with saturated aqueous NaHCO3 solution (2×20 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude product which was purified using preparative HPLC. Off-white solid (22 mg, 14%). MS (ESI): m/z=478.4 [M+H]+.
Reaction SMILES: CS([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=O)=O.P(Br)(Br)([Br:25])=O>>[Br:25][C:13]1[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[C:10]2=[N:11][C:6]([OH:5])=[CH:7][CH:8]=[C:9]2[N:14]=1
Reactant: CS(=O)(=O)Oc1ccc2nc(O)n(-c3ccccc3Br)c2n1
Reactant: O=P(Br)(Br)Br
Product: Oc1ccc2nc(Br)n(-c3ccccc3Br)c2n1

Procedure:
From 3-(2-bromophenyl)-2-hydroxy-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate and phosphoryl tribromide, prepared in a similar manner as the one described in Example 1.136, the title compound was obtained. LCMS m/z=368.10 [M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 6.70 (d, J=8.6 Hz, 1H), 7.57-7.64 (m, 3H), 7.90 (d, J=8.0, 1H), 7.94 (d, J=8.6 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.36 g) and benzyl bromide (0.18 mL) as starting materials, 5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.34 g) was obtained.
Reaction SMILES: C(O[C:6]([NH:8][C:9]([CH2:17]O)([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])(C)(C)C.[NH2:19][CH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:21]12([CH2:20][N:19]3[CH2:17][C:9]([CH2:10][OH:12])([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:8][C:6]3=[O:7])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: CC(C)CC(CO)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC12CC3CC(CC(C3)C1)C2
Product: CC(C)CC1(CO)CN(CC23CC4CC(CC(C4)C2)C3)C(=O)N1

Procedure:
The title compound was prepared following procedures analogous to those described in Example 27 using (±)-2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)-4-methylpentanoic acid and 1-(aminomethyl)adamantane. MS m/z=321.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:48]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 200 mg (1 mmole) of lauric acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 202 mg (Yield: 43%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: C1CC(=O)C2C(=CC=CC=2)C1.[CH2:12]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CC.C1C=CC=CC=1>O>[C:12]1(=[N:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: CCCCCCCCCCCCNc1ccccc1
Agent: O=C1CCCc2ccccc21
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(N=C2CCCc3ccccc32)cc1

Procedure:
A solution of α-tetralone (50 ml), dodecyl aniline (80 g) and benzene (150 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was crystallized from ethanol to give N-(1,2,3,4-tetrahydronaphthylidene) aniline (XXVI). XXVI had a melting point of 53° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@@H:13](O)[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13]([Br:25])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@@H]1C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 73.7 %

Procedure:
The alcohol 34 (5.34 g, 16.7 mmol) and CBr4 (16.6 g, 50 mmol) were dissolved in 100 mL dichloromethane and solid triphenylphosphine (13.1 g, 50 mmol) was added over a 10 min period. This solution was allowed to stir for 18 h then worked up and purified as for the synthesis of 4a. This gave 4.73 g (74% yield) of the title compound. This material crystallized on standing to give material of m.p.=87°-88° C. (Et2O/hexane). 1H NMR (CDCl3) δ 1.35/1.46 (2s, 9H), 2.41 (m, 1H), 2.58 (m, 1H), 3.90 (m, 2H), 4.48 (m, 2H), 5.19 (m, 2H), 7.34 (s, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][S:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:32](=[O:36])[C@@H:33]([CH3:35])[NH2:34]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:34][C@@H:33]([C:32]([N:31]([CH2:30][CH2:29][CH2:28][S:27][CH3:26])[CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])[CH3:35])=[O:24])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: CSCCCN(CCCc1ccccc1)C(=O)[C@@H](C)N
Agent: Cl
Product: CSCCCN(CCCc1ccccc1)C(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
By the method of part B of Example 8, N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine (1.50 g.) was condensed with N-[3-(methylthio)propyl]-N-(3-phenylpropyl)-D-alaninamide hydrochloride (1.470 g.), affording N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl-N-[3-(methylthio)propyl]-N-(3-phenylpropyl)-D-alaninamide as a viscous oil (2.716 g.). ##STR21##
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[O:14][C:15]4[C:20]([C@@:21]5([CH2:25][O:24][C:23]([NH2:26])=[N:22]5)[C:10]=3[CH:9]=2)=[CH:19][C:18]([C:27]2[C:28]([O:33]C)=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:17][CH:16]=4)[CH:5]=[CH:4][N:3]=1.COC1C(B(O)O)=CC=CN=1.FC1C=C(B(O)O)C=CN=1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C>[NH2:26][C:23]1[O:24][CH2:25][C@:21]2([C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=4)[N:13]=[CH:12][C:11]=3[O:14][C:15]3[C:20]2=[CH:19][C:18]([C:27]2[C:28]([OH:33])=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:17][CH:16]=3)[N:22]=1
Reactant: COc1ncccc1-c1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(-c3ccnc(F)c3)ncc1O2
Agent: COc1ncccc1B(O)O
Agent: C[Si](C)(C)Cl
Agent: OB(O)c1ccnc(F)c1
Solvent: CC#N
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3O)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of (S)-3-(2-fluoropyridin-4-yl)-7-(2-methoxypyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.075 g, 0.17 mmol, prepared as described in BB41 and AA1 using 2-methoxypyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid) and sodium iodide, anhydrous (0.077 g, 0.51 mmol) in acetonitrile (6.0 mL) was treated chlorotrimethylsilane (0.070 mL, 0.55 mmol) and the resulting mixture was stirred at room temperature for 16 h. The reaction was concentrated to dryness on the rotary evaporator, the resulting residue was taken up in dichloromethane (25 mL), water (15 mL), and formation of insoluble solids was observed. The solids were collected by filtration. The solid was dissolved in DMSO (1.5 mL) and loaded on the AGILENT MASS-TRIGGERRED HPLC system for purification using a MeCN/Water/0.1% TFA gradient and PHENOMENEX Gemini Axia-5 C-18 column (150×30 mm). The solvent was removed from the pure fractions in the GENEVAC and the resulting product was dissolved in methanol (1.5 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge (0.36 mmol loading; 500 mgs), and the filtrate was concentrated under high vacuum to yield the product (S)-3-(2′-amino-3-(2-fluoropyridin-4-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazole]-7-yl)pyridin-2-ol as an amorphous off-white solid [MS: m/z=442.1 (M+H)].
Reaction SMILES: C[C@@]12C(=O)CC[C@H]1[C@H]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3CC1)[CH2:4]C2.N[CH2:22][C:23]([OH:25])=[O:24].[OH-].[Na+]>>[CH3:4][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=2[O:25][C:23](=[O:24])[CH:22]=1
Reactant: NCC(=O)O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)oc2cc(O)ccc12

Procedure:
4-Methylumbelliferyl sulfate (final concentration 0.3 mmol/L), recombinant human estrone sulfatase (7.8 ng/well) and an estra-1,3,5(10)-triene derivative of each test concentration (the estra-1,3,5(10)-triene derivative was dissolved in 0.001 mL of DMSO) were added to a phosphate buffer (pH 7.5, final volume 0.1 mL) containing 0.28 mol/L of sucrose and 0.04 mol/L of nicotinamide, and the mixture was subjected to enzymatic reaction at 37° C. for 1 hour. The recombinant human estrone sulfatase used herein was prepared from CHO (Chinese hamster ovary) cells, which were transfected with a human estrone sulfatase gene, after partial purification. After the enzymatic reaction, an aqueous solution of 2 mol/L glycine-sodium hydroxide (pH 10.3, 0.13 mL) was added thereto followed by stirring. Using a fluorescent plate reader (Cyto Fluor II), the fluorescent intensity of 4-methylumbelliferone formed in the system was measured. The measurement was carried out at one time by duplication, and the assay fluctuation was 10% or less. The enzymatic reaction in the absence of the test compound was also carried out simultaneously. The inhibitory activity against estrone sulfatase of the test compound of each concentration was calculated according to the equation shown below. Inhibitory Activity against Estrone Sulfatase (%)=100−[100×(A/B)] wherein;
Reaction SMILES: II.N1C=CC=CC=1.[I:9][C:10]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:11]=1[C:12](=S)[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1COCC1.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>[I:9][C:10]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[CH:14][N:13]=1
Reactant: Cc1cccc(C(=S)NCc2ccccn2)c1I
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cccc(-c2ncc3ccccn23)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Iodine (0.827 g, 3.26 mmol) and pyridine (0.263 mL, 3.26 mmol) were added to 2-iodo-3-methyl-N-(pyridin-2-ylmethyl)benzothioamide (0.40 g, 1.086 mmol) in THF (2.2 mL) at 0° C. The solution was allowed to warm to RT and stirred 15 min. The reaction mixture was diluted with saturated sodium bicarbonate and aq. sodium sulfite and extracted with EtOAc. The combined organic extracts were washed with saturated sodium bicarbonate, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:1.5 EtOAc in hexane to provide 3-(2-iodo-3-methylphenyl)imidazo[1,5-a]pyridine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([F:12])[F:11])=[C:4]([NH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OCCCO2)=[C:17]([F:27])[C:16]=1[O:28][CH3:29].[F-].[Cs+].O>COCCOC.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>[Cl:8][C:6]1[C:5]([O:9][CH:10]([F:12])[F:11])=[C:4]([NH2:13])[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([O:28][CH3:29])[C:17]=2[F:27])[N:7]=1
Reactant: Nc1cc(Br)nc(Cl)c1OC(F)F
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COc1c(Cl)ccc(-c2cc(N)c(OC(F)F)c(Cl)n2)c1F
Yield: 84.2 %

Procedure:
6-Bromo-2-chloro-3-(difluoromethoxy)pyridin-4-amine (368 mg, 1.346 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (395 mg, 1.615 mmol), PdCl2(PPh3)2 (47.2 mg, 0.067 mmol), and CsF (409 mg, 2.69 mmol) were combined in DME (2 mL) and H2O (2 mL) and heated in a Biotage microwave reactor at 110° C. for 15 min. The cooled reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried, concentrated onto silica gel, and purified by flash chromatography (SiO2, EtOAc/hexane gradient). This process yielded the title compound as a white solid (0.4 g, 84%): mp 152-154° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.63-7.50 (m, 1H), 7.42 (dd, J=8.7, 1.6, 1H), 7.16 (d, J=1.8, 1H), 7.02 (t, J=73.4, 1H), 6.70 (s, 2H), 3.93 (d, J=0.8, 3H); ESIMS m/z 354 ([M+H]+), 352 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].[Cl:24][C:25]1[CH:34]=[C:33]([CH:35]=O)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:24][C:25]1[CH:34]=[C:33]([CH2:35][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][N:5]([C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])[CH2:12][CH2:11]2)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc(C=O)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 2-chloro-4-formylbenzoate (73.0 mg, 0.368 mmol) and sodium triacetoxyborohydride (104 mg, 0.490 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water (4 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes, then 0 to 10% MeOH/EtOAc) to give 35 mg of product as off-white solid. MS: (M+H)+=509.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.28-1.78 (m, 7H), 1.81-1.94 (m, 1H), 2.09-2.21 (m, 2H), 2.39-2.54 (m, 1H), 2.89-3.01 (m, 2H), 3.10-3.22 (m, 1H), 3.41-3.67 (m, 4H), 3.90-3.95 (m, 3H), 7.12-7.42 (m, 6H), 7.53 (s, 1H), 7.81 (d, J=8.08 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:3]=1[NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[CH2:9][CH2:8]1.[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>O1CCCC1>[CH3:30][O:29][C:27]1[CH:26]=[CH:25][C:3]2[N:4]([CH2:5][CH2:6][N:7]3[CH2:12][CH2:11][N:10]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([C:21]([F:22])([F:24])[F:23])[CH:14]=4)[CH2:9][CH2:8]3)[C:31](=[O:32])[NH:1][C:2]=2[CH:28]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(NCCN2CCN(c3ccc(OC)c(C(F)(F)F)c3)CC2)c(N)c1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[nH]c(=O)n2CCN1CCN(c2ccc(OC)c(C(F)(F)F)c2)CC1
Reaction time: 24 h

Procedure:
2-Amino-4-methoxy-N-{2-[4-(4-methoxy-3-trifluoromethyl-phenyl)piperazin-1-yl]-ethyl}-aniline (2.5 g, 6 mmol) is dissolved in 30 ml tetrahydrofurane; 1.5 g (9 mmol) carbonyldiimidazole is added portionwise to the resulting solution. The mixture is left at room temperature under stirring for 24 h. After evaporation to dryness, the residue is purified by silicagel chromatography (methylene chloride/methanol/32% aqueous ammonia 95:5:0.5). The crude title compound is triturated with ethylether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH3:24])=[N:11][C:12]([CH3:23])=[CH:13][C:14]=2[O:15]CC2C=CC=CC=2)=[CH:5][CH:4]=1)#[N:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH3:23])[NH:11][C:10]=2[CH3:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(OCc2ccccc2)c(-c2ccc(C#N)cc2)c(C)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(=O)c(-c2ccc(C#N)cc2)c(C)[nH]1
Reaction time: 2 h
Yield: 38 %

Procedure:
A mixture of compound D (240 mg), ammonium formate (120 mg) and 10% palladium on charcoal catalyst (40 mg) in methanol (5 ml) was stirred for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was partitioned between dichloromethane (10 ml) and water (10 ml). The aqueous phase was separated and further extracted with dichloromethane (3×10 ml). The combined extracts were dried and the solvent was removed by evaporation. The residue was triturated with ether to give 3-(4-cyanophenyl)-2,6-dimethyl-4-(1H)-pyridone (E) (65 mg), as a non-crystalline solid; NMR (CDCl3): 2.1(s,3H), 2.25(s,3H), 6.2(s,1H), 7.4(d,2H), 7.7(d,2H), 11.2(br s, 1H).