Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20]([F:26])=[C:19]([CH3:27])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:34]>O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]([NH2:25])=[O:34])=[CH:21][C:20]([F:26])=[C:19]([CH3:27])[CH:18]=3)=[N:11][CH:10]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc2c(cc1F)c(C#N)c(-c1ccc(S(=O)(=O)NC(C)(C)C)cn1)n2C1CCCC1
Solvent: O
Product: Cc1cc2c(cc1F)c(C(N)=O)c(-c1ccc(S(=O)(=O)NC(C)(C)C)cn1)n2C1CCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Into a solution of N-tert-butyl-6-(3-cyano-1-cyclopentyl-5-fluoro-6-methyl-1H-indol-2-yl)pyridine-3-sulfonamide (90 mg, 0.2 mmol) in TFA (2.0 mL) was added 2 drops of water. The mixture was stirred at 40° C. for 30 min and then evaporated. The residue was purified on silica gel eluting with 5 to 30% ethyl acetate in CH2Cl2 to provide the title compound (19 mg, 20%). MS m/z 473.3 M+H+; 1H NMR (500 MHz, DMSO-d6): δ 9.10 (1H, dd, J=2.0, 1.0 Hz), 8.29 (1H, dd, J=10.5, 2.5 Hz), 7.89 (1H, s), 7.81 (1H, dd, J=8.5, 1.0 Hz), 7.59 (1H, d, J=10.5 Hz), 7.49 (1H, d, J=6.5 Hz), 7.02 (2H, br s), 4.63-4.56 (1H, m), 2.46 (3H, s), 2.16-2.08 (2H, m), 1.96-1.85 (4H, m), 1.60-1.56 (2H, m), 1.17 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1>C(O)C>[ClH:1].[F:30][C:31]1([F:35])[CH2:34][N:33]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[C:12](=[O:13])[C:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][NH:9]3)[CH:3]=2)[CH2:32]1
Reactant: FC1(F)CNC1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(N2CC(F)(F)C2)ncn1
Reaction time: 0.5 h

Procedure:
100 mg (0.4 mmol) of the compound from Example 23, 94 mg (0.7 mmol) of N,N-diisopropylethylamine and 95 mg (0.731 mmol) of 3,3-difluoroazetidine hydrochloride are suspended in 3 ml of ethanol and reacted at 120° C. in a single-mode microwave oven (CEM Explorer) for 40 min. The solvent is then removed, and the residue is taken up in 6 ml of DMSO. Undissolved components are removed by filtration, and the solution obtained is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and concentrated on a rotary evaporator, and the residue is dried under high vacuum. The residue is then stirred in 5 ml of a 4 N solution of hydrogen chloride in dioxane for 30 min. The solid is filtered off, washed with tert-butyl methyl ether and dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12]2)=[C:4](Cl)[N:3]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12]2)=[C:4]([NH:30][CH:27]2[CH2:29][CH2:28]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3CO[C@@H](COC(=O)c4ccccc4)O3)c2n1
Reactant: NC1CC1
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@H]3CO[C@@H](COC(=O)c4ccccc4)O3)c2n1
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
Benzoic acid 4(R)-(2-amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-ylmethyl ester (1266 g, cis/trans:1.9/1), ethanol (20 L), and cyclopropylamine (643 g) were refluxed for 16 hours. The reaction mixture was cooled and concentrated to a residue. The residue was dissolved in dichloromethane (3.6 L) and agitated with an aqueous solution of sodium bicarbonate for 30 minutes. After settling the organic layer was separated and the aqueous was back-extracted with dichloromethane (2×750 mL). The combined organic layers were concentrated to give a yellow-brown foam (1304 g) of material (9) which is suitable for reaction in the subsequent deprotection step in NH3/MeOH.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:34])([F:33])[O:20][C:21]1[CH:22]=[C:23]([C:27]#[C:28][CH2:29][CH2:30][CH2:31]O)[CH:24]=[CH:25][CH:26]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][CH2:30][CH2:29][C:28]#[C:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:33])[F:34])[CH:22]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: OCCCC#Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2cccc(OC(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 14 h
Yield: 38.1 %

Procedure:
To an ice cold solution of 50 mg (0.21 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590), 48 mg (0.21 mmol) 5-(3-trifluoromethoxy-phenyl)-pent-4-yn-1-ol (example 3C]) and 70 μl (0.25 mmol) tributylphosphine (50 19 μmol) in 5 ml tetrahydrofuran were added 43 mg (0.25 mmol) N,N,N′,N′-tetramethyl azodicarboxamide. The cooling bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to obtain 34 mg (80 μmol, 36%) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>C(O)(=O)C>[C:12]([O:15][CH:7]1[CH2:6][C:5](=[O:11])[C:4]([CH2:1][CH:2]=[CH2:3])=[C:8]1[CH3:9])(=[O:14])[CH3:13]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCC1=C(C)C(OC(C)=O)CC1=O
Yield: 390.7 %

Procedure:
In the same apparatus as in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), acetic acid (45 ml) and sodium acetate (2 g) were charged and heated to reflux for 7 hours. After the completion of the reaction, acetic acid was evaporated off under reduced pressure. The residue was extracted with toluene (60 ml) and water (40 ml) and treated as in Example 1 to obtain 4-acetoxy-2-allyl-3-methyl-2-cyclopentenone (18.5 g). Yield, 95.3%. B.P., 100°-110° C./0.1-0.3 mmHg.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:11][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(C(=O)O)c(F)c2)cn1

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part I, but with 4-bromo-2-fluorobenzoic acid and 6-methoxypyridin-3-ylboronic acid hydrochloride as starting materials, and 10 molar equivalents of 0.4M aqueous sodium carbonate. 1H NMR (DMSO) δ 13.30 (br s, 1H), 8.59 (d, 1H), 8.11 (dd, 1H), 7.90 (t, 1H), 7.68-7.57 (m, 2H), 6.91 (d, 1H), 3.88 (s, 3H). ESI MS (M+1)+: 248.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[NH:14][CH3:15].[CH:16](O)=O>>[CH2:8]([N:7]1[C:2]2[N:1]=[CH:15][N:14]([CH3:16])[C:3]=2[C:4](=[O:13])[NH:5][C:6]1=[S:12])[CH:9]([CH3:11])[CH3:10]
Reactant: O=CO
Reactant: CNc1c(N)n(CC(C)C)c(=S)[nH]c1=O
Product: CC(C)Cn1c(=S)[nH]c(=O)c2c1ncn2C
Temperature: 85 °C
Yield: 74 %

Procedure:
6-Amino-1-isobutyl-5-methylamino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.11 g, 0.48 mmol) was dissolved in formic acid (1 mL) and heated at 85° C. for 1 h. The excess of formic acid was evaporated off under reduced pressure. 10% Sodium hydroxide solution (2 mL) was added and the solution was heated at 85° C. for 20 minutes. Water was added and the pH was adjusted to 4 with dilute acetic acid, upon which a white solid precipitated. The white solid was collected by filtration, washed with water and dried to yield the title compound (85 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N:26]=[C:27]=[O:28])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:27]([NH2:26])=[O:28])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cccnc1CN(CCCN)Cc1ncccc1C
Solvent: CC(C)O
Product: Cc1cccnc1CN(CCCNC(N)=O)Cc1ncccc1C

Procedure:
The amine from above was dissolved in i-PrOH (3 mL) and treated with trimethylsilylisocyanate (93 μL, 0.69 mmol) at room temperature for 16 hours. The solution was then concentrated under reduced pressure and dried in vacuo. The crude material was then purified by column chromatography with silica gel (20:1:0.1 CH2Cl2/MeOH/NH4OH) to give {3-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-propyl}-urea as a colorless oil (82 mg, 51% 2 steps). 1H NMR (CDCl3) δ 1.67 (m, 2H), 2.22 (s, 6H), 2.67 (t, 2H, J=7.5 Hz), 3.10 (m, 2H), 3.69 (s, 4H), 4.78 (br, 2H(NH2)), 7.10 (m, 2H), 7.42 (d, 2H, J=6.0 Hz), 8.36 (d, 2H, J=2.8 Hz). Conversion to the HBr salt gave COMPOUND 179 as a white solid. 1H NMR (D2O) δ 1.66 (m, 2H), 2.51 (s, 6H), 2.68 (m, 2H), 2.99 (t, 2H, J=6.5 Hz), 4.32 (s, 4H), 7.87 (t, 2H, J=6.9 Hz), 8.38 (d, 2H, J=7.8 Hz), 8.61 (d, 1H, J=5.4 Hz). 13C NMR (D2O) δ 17.25 (2C), 26.16, 37.79, 52.47, 54.30 (2C), 126.06 (2C), 137.83 (2C), 138.72 (2C), 148.54 (2C), 150.98 (2C), 161.74. ES-MS m/z 328 (M+H). Anal. Calcd. for C18H25N5O.3.0HBr.2.7H2O: C, 34.94; H, 5.44; N, 11.32; Br, 38.74. Found: C, 34.99; H, 5.34; N, 10.92; Br, 38.86.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>>[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: Nc1ccc(I)cc1F
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Product: NS(=O)(=O)c1ccc(NC(=S)Nc2ccc(I)cc2F)cc1

Procedure:
The subject compound was prepared utilizing the procedure described above from 4-isothiocyanatobenzenesulfonamide and 2-fluoro-4-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.77 (s, 1H), 7.86-7.37 (m, 7H), 7.29 (bs, 2H); (M+H)+ (452).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[C:40]([N+:48]([O-:50])=[O:49])[CH:39]=2)[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
A solution of triphenylphosphine (138 mg, 0.53 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol) in small portions. The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (150 mg, 0.44 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-aminothiazole (97 mg, 0.97 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography, (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate), to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide (96 mg, 52%) as a pale yellow solid: mp 121-124° C.; FAB-HRMS m/e calcd for C18H21N3O5S2 (M+H)+ 424.1001, found 424.1000.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH:26]2[CH2:29][O:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:26]2[CH2:29][O:28][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2COC2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4-Bromophenol (2.5 g, 14.5 mmol) and K2CO3 (5.45 g, 39.4 mmol) were added to a solution of oxetan-3-yl 4-methylbenzenesulfonate (3.00 g, 13.1 mmol) in DMF (10 mL) in a sealed tube. The reaction was heated to 100° C. and stirred at this temperature for 24 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound. MS (GCMS) m/z 228. This material was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27](=[O:30])[NH:28][CH3:29])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[B:36]([OH:38])[OH:37].[OH:39][CH2:40][C:41]([CH2:45]O)([CH2:43]O)[CH3:42].CC(C)([O-])C.[K+:52].C1COCC1>C1COCC1>[K+:52].[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27](=[O:30])[NH:28][CH3:29])=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[B-:36]12[O:39][CH2:40][C:41]([CH3:45])([CH2:43][O:37]1)[CH2:42][O:38]2
Reactant: CC(CO)(CO)CO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([B-]45OCC(C)(CO4)CO5)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C

Procedure:
To a stirred solution of (2-chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronic acid (0.0750 g, 0.135 mmol) and 1,1,1-tris(hydroxymethyl)ethane (0.0180 g, 0.148 mmol) in anhydrous THF (6 mL) was added activated 3 angstrom molecular sieves (0.400 g). The resulting mixture was heated to reflux for 4 hours and cooled to RT. The mixture was filtered to remove solids and the filtrate concentrated to dryness at reduced pressure. The residue was dissolved in 5 mL of anhydrous THF and the solution cooled to 0° C. The solution was treated with 1M potassium t-butoxide/THF (135 μL, 0.135 mmol) by dropwise addition. After warming to RT the solution was concentrated to dryness at reduced pressure to afford the title compound as a light yellow solid in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (d, J=4.0 Hz, 1H) 8.09 (s, 1H) 7.98 (dd, J=8.9, 5.5 Hz, 2H) 7.51 (d, J=7.9 Hz, 1H) 7.39 (t, J=8.9 Hz, 2H) 7.07-7.18 (m, 3H) 3.55 (s, 6H) 3.28 (s, 3H) 2.82 (d, J=3.4 Hz, 3H) 2.10-2.23 (m, 1H) 0.73-1.04 (m, 4H) 0.45 (s, 3H).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1CCC(Cc2cc(O)n3nccc3n2)CC1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)C1CCC(Cc2cc(Cl)n3nccc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottom flask was charged ethyl 4-((7-hydroxypyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4f, 2.48 g, 8.19 mmol), N,N-dimethylaniline (4 mL) and POCl3 (40 mL). The resulting solution was allowed to stir at room temperature for 18 hours. After 18 hours, the solvent was removed in vacuo. The residue was cooled to 0° C. in ice bath. The cooled residue was slowly quenched with saturated NaHCO3 (aq), and then extracted with DCM (x3). The combined organic extracts were dried over Na2SO4 and the residue purified via silica gel chromatography to yield the title compound as clear oil. Yield=2.29 g.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([N:24]2[CH:28]=[N:27][N:26]=[CH:25]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([N:24]2[CH:25]=[N:26][N:27]=[CH:28]2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: Nc1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1

Procedure:
0.28 Milliliter of acetic anhydride was added to ml of a pyridine solution containing 0.35 g of 4-[N-(4-aminophenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole at room temperature and the mixture was stirred for about minutes. After reaction, the solvent was removed by distillation under reduced pressure, and a proper amount of an aqueous sodium hydrogen carbonate solution was added to the resulting residue, which was then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 0.33 g of 4-[N-(4-acetylaminophenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (50/1) eluate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1>C1(C)C=CC=CC=1>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([C:3](=[O:4])[CH2:2][N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]2)=[CH:6][CH:7]=1)#[N:10]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)C[C@H]1CCCNC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CCCN(CC(=O)c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.1 %

Procedure:
To a mixture of 4-(2-bromoacetyl)benzonitrile (5.5g, 24.55 mmol) in toluene was added (R)-ethyl 2-(piperidin-3-yl)acetate (4 g, 23.36 mmol). The reaction mixture was stirred for 4 days at room temperature and then stirred from one day at 50° C. Solvents were removed in vacuo. The resulting solids were triturated with EtOAc. The solid material was filtered and washed with EtOAc. The solid material was collected and dried to yield 5 g of (R)-ethyl 2-(1-(2-(4-cyanophenyl)-2-oxoethyl)piperidin-3-yl)acetate. MS (M+1)=314. HPLC Peak RT=0.77 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([C:13]([O:15]CC)=[O:14])[C:6]([OH:18])=[N:5]2.O.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([C:13]([OH:15])=[O:14])[C:6]([OH:18])=[N:5]2
Reactant: CCOC(=O)c1nc2cc(F)c(F)cc2nc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2cc(F)c(F)cc2nc1O
Temperature: 50 °C

Procedure:
A mixture of ethyl 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylate (500 mg, 2.0 mmol) and lithium hydroxide monohydrate (330 mg, 7.9 mmol) in THF (10 mL) and water (5 mL) was heated at 50° C. under nitrogen for 1 h. The mixture was further cooled to 0° C., acidified to pH 2 with concentrated HCl and extracted with ethyl acetate (100 mL). The organic extract was washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure to provide 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylic acid as a yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.88 (dd, 1H), 7.29 (dd, 1H) ppm; ESI MS m/z 225 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])(C)(C)C.[B:14](OC)([O:17]C)[O:15]C.Cl>O1CCCC1.CCCCC>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:14]([OH:17])[OH:15]
Reactant: COB(OC)OC
Reactant: Cc1ccccc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromotoluene (1.0 g) in dry tetrahydrofuran (50 ml) was cooled to -70° C. under an atmosphere of argon. A solution of tert-butyl lithium in pentane (1.7M, 7.6 ml) was added dropwise to the mixture whilst maintaining the temperature below -60° C. The reaction mixture was stirred at -70° C. for 0.5 hours. Trimethyl borate (0.73 ml) was added and the mixture allowed to warm to ambient temperature. The mixture was poured onto a mixture of aqueous 2M hydrochloric acid and ice, and the mixture extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4) and evaporated to give 2-methylphenylboronic acid as a white solid (0.48 g) which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>O1CCCC1>[CH3:36][N:27]1[C:28]2[C:24](=[C:23]([CH2:22][O:21][CH2:20][C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3[nH]ccc23)(c2ccccc2)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cn1ccc2c(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl 4-phenyl-4-(((6-(trifluoromethyl)-1H-indol-4-yl)methoxy)methyl)piperidine-1-carboxylate (59 mg, 0.121 mmol) in tetrahydrofuran (5 ml) at 25° C. was treated with potassium tert-butoxide (13.6 mg, 0.121 mmol) and stirred for 5 minutes. Dimethyl sulfate (0.012 ml, 0.121 mmol) was added, the solution was stirred at 25° C. for 1 h, and then concentrated in vacuo. Column chromatography (ethyl acetate/hexanes gradient elution) afforded 45 mg (90%) as a colorless oil. Mass spec.: 503.17 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[CH:30][C:31]([F:37])=[C:32](B(O)O)[CH:33]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:30]2[CH:29]=[C:28]([C:26]#[N:27])[CH:33]=[CH:32][C:31]=2[F:37])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cc(C#N)ccc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (5-cyano-2-fluorophenyl)boronic acid (198 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 28.9 mg, 6%).