Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Reactant: NN1CCOCC1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NN2CCOCC2)[nH]n1
Yield: 94 %

Procedure:
As described for example 17e, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (50 mg, 0.15 mmol) was converted, using 4-aminomorpholine instead of 2,2,2-trifluoroethylamine, to the title compound (57 mg, 94%) which was obtained as a colorless oil. MS: m/e=403.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:8]([C:18]([F:21])([F:20])[F:19])[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=2.O.N#N.[CH3:33][N:34]1C(=O)CCC1>CC(OC)(C)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[C:33]([C:7]1[C:8]([C:18]([F:21])([F:20])[F:19])=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])#[N:34]
Reactant: Cc1[nH]c2ccc(OS(=O)(=O)C(F)(F)F)c(C(F)(F)F)c2c1C(=O)OC(C)(C)C
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: N#N
Agent: [C-]#N
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1[nH]c2ccc(C#N)c(C(F)(F)F)c2c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 2-methyl-4-(trifluoromethyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-indole-3-carboxylate (20.2 g, 45.2 mmol) in NMP (150 mL) was added deionized water (8 mL) and N2 was passed through the solution for 10 min with the aid of a glass pipette. 1,1′-Bis(diphenylphosphino)ferrocene (2.49 g, 4.49 mmol) and tris(dibenzylidineacetone)dipalladium(0) (2 g, 2.18 mmol) were added and the solution was stirred under N2 atmosphere at rt for 15 min. Zinc cyanide (3.95 g, 33.6 mmol) was added and the mixture was stirred an additional 10 min at rt. The reaction mixture was gradually heated to 80° C. (internal temperature) and maintained at this temperature for 3 h. After cooling to 35° C., the mixture was diluted with MTBE (100 mL) and washed with water (100 mL). The aqueous layer was back extracted with MTBE (2×100 mL) and the combined MTBE layers were washed with water (4×125 mL) and dried over MgSO4. The organic phase was filtered through a glass fritted funnel and the MTBE filtrate was stirred over decolorizing charcoal for 15 min. The charcoal mixture was filtered through a plug of silica gel (75 g) and the filtrate was concentrated at reduced pressure. Remaining material was triturated with hot MTBE, then diluted with i-octane, cooled to −15° C. and filtered to afford 1,1-dimethylethyl 5-cyano-2-methyl-4-(trifluoromethyl)-1H-indole-3-carboxylate as a beige solid (12.5 g, 85% yield): 1H NMR (DMSO-d6) δ 12.54 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 2.50 (s, 3H), 1.49 (s, 9H); MS (ES): m/z 323 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(5-methyl-2-thienyl)-2-naphthalenyl]ethynylbenzoate acid (Compound 33) (35.0 mg, 0.082 mmol) in 2 ml of EtOH and 1 ml THF at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was stirred at room temperature overnight and then acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.03 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 7.5-7.48 (3H, m), 6.89 (1H, m), 6.18 (1H, t, J=4.7 Hz), 2.49 (3H, s), 2.35 (2H, d, J=4.7 Hz), 1.32 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]=[O:19])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.[O-:26]Cl=O.[Na+].P([O-])(O)(O)=O.[Na+].Cl>C1COCC1.C(O)(C)(C)C.O>[C:1]([O:5][C:6]([CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]([OH:26])=[O:19])=[CH:9]1)=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(C=O)c2cc(Cl)ccc21
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-chloro-3-formyl-indol-1-yl)-acetic acid tert-butyl ester (902 mg, 2.92 mmol) in THF (12 mL) and tert-butanol (4.80 mL) were added successively 2-methyl-2-butene (9.27 mL, 88.0 mmol), a solution of NaClO2 (2.64 g, 29.2 mmol) and sodium dihydrogen phosphate (2.80 g, 23.3 mmol) in water (4.80 mL), followed by stirring at RT for 18 h. The reaction mixture was acidified with 0.1N HCl (pH 2 to 3) and extracted with EtOAc (3×). The combined organics were dried (Phase separator) and concentrated in vacuo. The residue was triturated with diethyl ether, the solid was filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a white solid. MS (LC/MS): 310 [M+H]+; tR (HPLC conditions b): 5.16 min.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O.CCOCC>N1C=CC=CC=1>[C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCC/C=C/c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC/C=C/Cc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
To a solution of 7.5 g of (E)-8-phenyl-7-octen-1-ol dissolved in 60 ml of pyridine, 9.1 g of p-toluenesulfonyl chloride was added at 0° C. After stirring at 10° C. for 5 hours, 10 ml of water was added and the mixture was stirred for 30 minutes, followed by addition of 200 ml of ether. The mixture was washed with 10% aqueous hydrochloric acid, water and saturated saline water. The organic layer was dried, and the solvent was removed under reduced pressure. The pale yellow oily product obtained was purified by silica gel column chromatography (solvent: hexane-ethyl acetate=5:1) to give 12 g of (E)-1-phenyl-8-p-toluenesulfonyloxy-2-octene as an oily product.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:24])[C:11]3[C@@H:15]([CH2:16][C:17]([O:19]CC)=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1.C1COCC1.O[Li].O.Cl>O.CO>[NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:24])[C:11]3[C@@H:15]([CH2:16][C:17]([OH:19])=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2nnc(N)s2)cc2c1[C@@H](CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution (R)-ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (30 g, 86 mmol) in a mixed solution of THF (750 mL) and methanol (100 mL) was added a solution of LiOH.H2O (12.63 g, 301 mmol) in water (750 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hrs and then acidified to pH=2 with diluted hydrochloric acid at 0° C. After removal of the volatile organics, the residue was dissolved in EtOAc. The aqueous phase was separated and concentrated in vacuo, and the residue was neutralized to pH=6.5˜7.0 using saturated aq. sodium bicarbonate. The precipitated solid was filtered and stirred with EtOAc for 1 hr. The solid was filtered, washed with cold EtOAc and water then dried to give the product (R)-2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid (21 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ12.31 (1H, s), 9.26 (1H, s), 7.33 (1H, m), 7.16 (1H, m), 7.06 (2H, s), 5.50 (1H, m), 3.03 (1H, m), 2.29 (3H, s), 2.10 (1H, m). ESI-MS m/z 322 (M+H+, positive); [α]25D=−91.395°±0.305° (C=1.0017 g/100 ml diluted with 2M HCl, L=0.5 dm).
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:10][CH2:11][CH3:12])([CH3:9])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].[CH:13]([N:16]=[C:17]=[N:18][CH:19]([CH3:21])[CH3:20])([CH3:15])[CH3:14].N=C=N>>[CH2:11]([O:10][Si:4]([O:3][CH2:1][CH3:2])([CH3:9])[CH2:5][CH2:6][CH2:7][NH:8][C:17]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:16][CH:13]([CH3:15])[CH3:14])[CH3:12]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCO[Si](C)(CCCN)OCC
Agent: N=C=N
Product: CCO[Si](C)(CCCNC(=NC(C)C)NC(C)C)OCC

Procedure:
A mixture of 28.94 g of 3-(diethoxy(methyl)silyl)propylamine (0.151 mol, 20% excess) and of 15.9 g of diisopropylcarbodiimide (0.126 mol) was heated for 9 h at 80° C. (carbodiimide conversion of 97.3%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O>[Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:18])=[CH:19][CH:20]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Nc2nc(Br)cn3ccnc23)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Product: O=C(c1ccc(Nc2nc(Br)cn3ccnc23)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (7) (0.16 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (0.16 mmol), and N′N-diisopropylethylamine (0.48 mmol) is stirred at room temperature for 20 min. under N2. Morpholine (0.48 mmol) is added and the mixture is stirred at room temperature for 16 hr. Water (10 mL) is added and the mixture extracted with ethyl acetate (2×70 mL). The extracts are subsequently washed with water (2×30 mL) and brine (1×30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is triturated with diethyl ether to give [4-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-morpholin-4-yl-methanone (8) as a cream solid.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:15][C:2]1[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]2=[N:16][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)[nH]c2c1
Reactant: Nc1ccccn1
Product: Cc1c(-c2ccc3oc(=O)[nH]c3c2)nc2ccccn12
Yield: 33.9 %

Procedure:
5-(3-Methylimidazo[1,2-a]pyridin-2-yl)-2-benzoxazolinone (0.9 g) was prepared in substantially the same manner as that of Example 30 from 5-(2-bromopropionyl)-2-benzoxazolinone (2.7 g) and 2-aminopyridine (2.8 g). mp. 296°-298° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2N4CC3)c(OC)c1

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl (±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (143 mg, 0.32 mmol) and corresponding 2,4-dimethoxyphenylboronic acid (115 mg, 0.63 mmol), to afford after chromatographic purification the title compound (92 mg, 66%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.15-7.18 (m, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 6.40-6.60 (m, 2H), 3.75-4.00 (m, 7H), 3.60-3.70 (m, 1H), 3.00-3.50 (m, 7H), 2.70-2.90 (m, 1H), 1.70-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 437 (base, M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=1>CN(C=O)C.C(O)=O>[OH:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[CH:51][CH:52]=1
Reactant: NCc1ccc(O)cc1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1sc(C(=O)NCc2ccc(O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μL, 1.65 mmol) in DMF (15 mL) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-phenol hydrochloride (88 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μL, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-benzylamide (45 mg) as a colourless oil. LC-MS: tR=0.96 min, [M+1]+=328.17.
Reaction SMILES: [F:1][C:2]1[C:22]([F:23])=[C:21]([Si](C)(C)C)[CH:20]=[C:19]([CH3:28])[C:3]=1[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].CCN(CC)CC.C(O)=O>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([CH3:28])[C:3]=1[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:7]1)=[O:5]
Reactant: Cc1cc([Si](C)(C)C)c(F)c(F)c1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(F)c1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h
Yield: 60.1 %

Procedure:
To a solution of (R)-tert-butyl 3-(2,3-difluoro-6-methyl-4-(trimethylsilyl)benzoyl)piperidine-1-carboxylate (2 g, 4.9 mmol) in THF (20 mL) was added TEAF (0.22 g, 1.5 mmol) in THF (5 mL) at 0° C. The mixture was stirred for 4 h, after which brine was added, and the mixture was extracted with Et2O. The organic layer was washed with brine and dried over Na2SO4, concentrated. The residue was purified by column chromatography on silica gel to afford (R)-tert-butyl 3-(2,3-difluoro-6-methylbenzoyl)piperidine-1-carboxylate (1 g, 61%). 1H-NMR δ 7.07 (m, 1H), 6.90 (m, 1H), 4.10 (m, 2H), 3.92 (m, 2H), 2.21 (s, 3H), 1.97 (m, 2H), 1.60 (m, 4H), 1.49 (s, 9H), 1.30 (m, 3H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.Br[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH:29]3[N:32]([CH:33]4[CH:40]5[CH2:41][CH:36]6[CH2:37][CH:38]([CH2:42][CH:34]4[CH2:35]6)[CH2:39]5)[C:31](=[O:43])[C:30]3([CH3:45])[CH3:44])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:20]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[CH:24][C:23]([C:26]2([CH:29]3[N:32]([CH:33]4[CH:40]5[CH2:41][CH:36]6[CH2:37][CH:38]([CH2:42][CH:34]4[CH2:35]6)[CH2:39]5)[C:31](=[O:43])[C:30]3([CH3:45])[CH3:44])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)C1C1(c2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)C1C1(c2ccc(-c3ccccc3)cc2)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
A solution of 4-[1-(4-bromophenyl)cyclopropyl]-1-(adamantan-2-yl)-3,3-dimethylazetidin-2-one (12.2 mg, 0.0285 mmol) in 1,4-dioxane (3 mL) prepared in Example 75 was added with tetrakis(triphenylphosphine) palladium (1.6 mg, 1.4 μmol), phenyl boronic acid (7 mg, 0.057 mmol), and potassium phosphate (30 mg, 0.142 mmol) at room temperature, and the resultant was stirred at 100° C. for 20 hours. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using thin-layer chromatography (hexane:ethyl acetate=3:1), and 4-[1-(biphenyl-4-yl)cyclopropyl]-1-(adamantan-2-yl)-3,3-dimethylazetidin-2-one (10.2 mg, 84%) was obtained as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH2:17]([CH:24]([C:30](OCC)=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30]([CH:24]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:31])=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Product: CCOC(=O)C(Cc1ccccc1)C(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Temperature: 160 °C
Reaction time: 24 h
Yield: 45.1 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (10 g) and diethyl benzylmalonate (24 g) was stirred at 160° C. for 24 hours. After cooling, the reaction mixture was purified by column chromatography on silica gel. Elution with chloroform-methanol (100:1, v/v) gave ethyl 2-(p-diethoxyphosphorylmethylphenylaminocarbonyl)-3-phenylpropionate (8.3 g, 45%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless crystals having melting point of 115° to 116° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[C:7]([Br:12])[CH:6]=1>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[CH:8]=[C:7]([Br:12])[CH:6]=1
Reactant: C[O-]
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(Br)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
Sodium methoxide (25 g; WAKO) was added to a DMF (250 mL) solution of 1,3,5-tribromobenzene (75 g; TCI) and the resulting mixture was stirred at 90° C. for 15 minutes. The reaction mixture was concentrated, aqueous ammonium chloride (400 mL) and ethyl acetate (400 mL) were added to extract the reaction mixture, the organic layer was washed with saturated brine (200 mL×2), and the organic layer was dried. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (n-hexane) to give the title compound (39.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[Cl:22]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:7]([Cl:22])[N:6]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3.48 g (11.2 mmol) of 3-methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester [prepared from 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 1A) by reaction with 3-chloro-perbenzoic acid in analogy to the procedure described for the preparation of intermediate 1C] was added at RT while stirring to 20.4 ml=34.25 g (223.3 mmol) of phosphorus oxychloride and the reaction mixture was warmed up to 50° C. After 2 hours, it was cooled down to RT and poured into crashed ice. This solution was carefully neutralized with solid sodium carbonate and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/CH2Cl2 1:1 to 0:1) to give 2.52 g (68%) 6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester as light yellow oil; [MS: 330.0 (MH+, 1Cl)] and 1.10 g (30%) 4-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester as colorless solid. MS: 330.0 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>C(C(C)=O)C(C)C.O.C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17](=[O:18])[CH2:16][O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1COc2cc(Br)ccc2N1
Temperature: 25 °C
Yield: 77 %

Procedure:
Part 2. A solution of 2-amino-5-bromophenol (2.53 g, 18.2 mmol, 1.0 equiv) in 15 mL of isobutylmethyl ketone and 15 mL of water was cooled to 0° C., NaHCO3 (3.67 g, 2.4 equiv) and then chloroacetyl chloride (2.36 g, 1.67 mL, 1.15 equiv) were added. The mixture was heated to reflux overnight, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated in vacuo. Flash chromatography on silica gel gave 7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one in 77% yield. LRMS found for C9H10NO3 (M+H)+: 180.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([OH:13])=O)=[CH:4][C:3]=1[Cl:14].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>CN(C)C=O.ClCCl>[NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][CH2:29][O:28][CH3:27])[CH2:33][CH2:34]2)=[O:13])=[CH:4][C:3]=1[Cl:14]
Reactant: COCCCN1CCC(N)CC1
Reactant: Nc1c(Cl)cc(C(=O)O)c2nccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
To a suspension of the 5-amino-6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 1, METHOD A, Step 4, 210 mg, 0.99 mmol) in N,N-dimethylformamide (5 mL) was added 1,1′-carbonyldiimidazole (177 mg, 1.09 mmol) and stirred at room temperature for 20 min. To this resulting solution was added 1-(3-methoxypropyl)-4-piperidinamine (A. Karasawa et al., WO 9950264, 188 mg, 1.09 mmol) and the mixture was stirred overnight under nitrogen at room temperature. The mixture was concentrated in vacuo, chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% aqueous ammonia (95:5:0.5) to afford a yellow oil, which was dissolved in dichloromethane (300 mL), washed with water (75 mL×3), brine (75 mL) and dried over magnesium sulfate. After treatment with charcoal, removal of solvent gave a cream solid, which was recrystallized from diethyl ether to afford 175 mg (48%) of the title compound as a solid.