Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH:4]=[CH2:5])[CH3:3].C[N+]1([O-])CC[O:23]CC1.[OH2:27]>C(#N)C.[Os](=O)(=O)(=O)=O>[CH:17]1[C:18]2[N:6]([C:2]([CH3:1])([CH3:3])[CH:4]([OH:23])[CH2:5][OH:27])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CC(C)(C)n1c2ccccc2c2ccccc21
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Product: CC(C)(C(O)CO)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To a stirred solution of 9-(2-methylbut-3-en-2-yl)-9H-carbazole (0.400 g, 1.7 mmol), and 4-methylmorpholine N-oxide (0.398 g, 3.4 mmol) in acetonitrile (10 mL) and water (3 mL) was added 4% osmium tetroxide solution (0.540 mL, 0.1 mmol). The mixture was stirred at room temperature for 48 hrs. The reaction was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to give a yellow solid (0.43 g, 94%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 7.84 (d, 2H, J=8.4 Hz), 7.37 (t, 2H, J=7.5 Hz), 7.23 (t, 2H, J=7.5 Hz), 4.84 (m, 1H), 3.80-3.50 (m, 2H), 2.30 (br s, 1H), 2.11 (s, 3H), 2.05 (s, 3H), 1.82 (br s, 1H). ESI m/z: 269.8 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].FC1C=CC(F)=CC=1[N+]([O-])=O>C1(O)CCCCC1.CCOC(C)=O.CCOC(C)=O.CCCCCC>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cc(F)ccc1F
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: OC1CCCCC1
Product: CCOC(=O)N1CCC(Nc2ccc(F)cc2[N+](=O)[O-])CC1

Procedure:
A solution of ethyl 4-amino-1-piperidine carboxylate (9.0 g, 52 mmol.) and 2-chloro-5-fluoronitrobenzene (10.3 g, 58 mmol.) in cyclohexanol (30 mL) containing powdered sodium carbonate (6.1 g, 57 mmol.) was refluxed (>160° C.) for 30 hours or until no further reaction was indicated by tlc (30% EtOAc/hexane). (Alternatively, 2,5-difluoro-nitrobenzene can be used in place of the 2-chloro-5-fluoronitro-benzene). The deep reddish reaction mixture was cooled and diluted with EtOAc. This solution was washed with dil. aq. HCl (3×), water, and then the organic layer dried (anhydrous Na2SO4) and the solvent evaporated to give a red oil. This oil was flash chromatographed on a column of silica gel and the product eluted with a 10-25% EtOAc/hexane gradient. The appropriate fractions were combined, the solvents evaporated, and the residue triturated with 10% Et2O/hexane to give 1-ethoxycarbonyl-4-(4-fluoro-2-nitroanilino)-piperidine as a bright reddish-orange solid, mp: 115-116° C., which was used without further purification.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:24])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:10]([CH3:25])[C:9]2=[O:26])=CC=1.O>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:25][N:10]1[C:11]([CH3:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][C:9]1=[O:26]
Reactant: COc1ccc(CN2C(=O)N(C)C(C)(c3ccccc3)c3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)Nc2ccccc2C1(C)c1ccccc1

Procedure:
To a solution of 1-(4-Methoxy-benzyl)-3,4-dimethyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (1.00 g, 2.6 mmol) in trifluoroacetic acid (8 mL) and DCM (8 mL) is stirred at room temperature for 1 h. Then H2O is added and is extracted with DCM/H2O. The organic layer is concentrated and is purified by chromatography on silica gel to give product.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[CH:8][N:7]=[C:6]2[C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:28]=5)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)[CH2:2]1.CN(C)[CH:36]=[O:37].[CH:39](N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[OH:32][C:30]([CH3:33])([CH3:31])[CH2:29][N:27]1[CH:28]=[C:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:19]=[C:10]([C:6]5[N:5]([CH:3]6[CH2:4][N:1]([C:36](=[O:37])[CH3:39])[CH2:2]6)[CH:9]=[CH:8][N:7]=5)[S:11][C:12]=4[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH:25]=[N:26]1
Reactant: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4C4CNC4)nc2-3)cn1
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(=O)N1CC(n2ccnc2-c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 411 (0.110 g, 0.000238 mol) dissolved in N,N-Dimethylformamide (3.72 mL, 0.0480 mol) and treated sequentially with N,N-Diisopropylethylamine (0.248 mL, 0.00143 mol) Acetic acid (0.0270 mL, 0.000476 mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.108 g, 0.000285 mol). Stir at r.t. overnight. Add sat. sodium bicarbonate, extract with ethyl acetate. Dried combined organics over sodium sulfate and concentrated. The crude product was purified by rHPLC to give 416. MS: (ESI+)=505.2. 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.95-7.90 (m, 2H), 7.43 (dd, J=8.3, 1.8 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.17 (d, J=1.1 Hz, 1H), 6.24-6.13 (m, 1H), 4.78-4.66 (m, 2H), 4.51-4.39 (m, 2H), 4.36 (t, J=5.5 Hz, 2H), 4.04 (s, 2H), 3.39 (t, J=5.1 Hz, 2H), 1.84 (s, 3H), 1.10 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:25])[CH3:24]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3-Trifluoromethylphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=1)[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:34]4[CH:35]=[CH:22][CH:23]=[C:24]([CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:33]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(Cc2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(Cc2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(3-bromo-benzyl)-4-methyl-piperazine (77.0 mg, 0.286 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.036 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.24 (d, J=8.5 Hz, 2H), 8.09 (d, J=8.5 Hz, 2H), 7.66 (dd, J=7.4, 0.9 Hz, 1H), 7.58 (dd, J=7.8, 1.9 Hz, 1H), 7.46 (s, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.02 (t, J=7.2 Hz, 1H), 6.98 (d, J=7.5 Hz, 1H), 6.90 (s, 1H), 3.54 (s, 2H), 3.10 (s, 3H), 2.70-2.32 (m, 8H), 2.29 (s, 3H). MS=477 (MH)+.
Reaction SMILES: P.II.C([O:6][C:7](=[O:21])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=O)=O)=[CH:12][C:11]=1[Cl:20])C.O>C(O)(=O)C>[Cl:20][C:11]1[CH:12]=[C:13]([SH:16])[CH:14]=[CH:15][C:10]=1[O:9][CH2:8][C:7]([OH:21])=[O:6]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: II
Agent: P
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)COc1ccc(S)cc1Cl

Procedure:
To a refluxing solution of PH3 (17 g, 500 mmol) and I2 (2.4 g, 9.4 mmol) in glacial acetic acid (100 ml) was added slowly a solution of (4-chlorosulfonyl-2-chloro-phenoxy)-acetic acid ethyl ester (47.5 g, 151 mmol) in glacial acetic acid (1000 ml). The reaction mixture was refluxed for 24 h. Water (20 ml) was added carefully and the mixture was refluxed for further 1 h. After cooling, the reaction mixture was filtered and the filtrate diluted with water (500 ml). The mixture was extracted with dichloromethane (3×100 ml), and the organic phases were washed with water. After drying the dichloromethane phase was evaporated to give crude (2-chloro-4-mercapto-phenoxy)-acetic acid in 17 g yield.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2C=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1CN(C(OC(C)(C)C)=O)C1>>[NH:48]1[CH2:43][CH:44]([NH:49][C:26](=[O:28])[C:25]2[CH:29]=[C:30]([O:31][CH3:32])[C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[CH:23][C:24]=2[F:33])[CH2:47]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CC(N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 3-amino-N—Boc-azetidine. The Boc group was then removed by treatment with 1:1 trifluoroacetic acid and dichloromethane for 1 hour. At this time the solvent was removed and NaHCO3 (sat.) and EtOAc were added to the residue. The layers were separated, the organic layer was then dried over MgSO4, filtered, the solvent was removed and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.77 (m, 6H) 1.96 (br. s., 2H) 3.56 (dd, J=7.45, 4.42 Hz, 4H) 3.91 (s, 3H) 4.08 (t, J=14.02 Hz, 2H) 4.62-4.73 (m, 1H) 4.76-4.90 (m, 1H) 7.20 (d, J=6.82 Hz, 1H) 8.05 (s, 1H) 8.26 (d, J=13.39 Hz, 1H) 8.30 (s, 1H) 8.51 (d, J=3.54 Hz, 1H). [M+H] calculated for C24H28F3N7O3, 520. found 520.
Reaction SMILES: C([N:5]1[CH:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:15])[CH:11]=2)[C:6]1=[O:16])(C)(C)C.[NH2:17]N>C(O)(=O)C>[Cl:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]([OH:16])=[N:17][N:5]=[CH:13]2
Reactant: CC(C)(C)N1C(=O)c2ccc(Cl)cc2C1O
Reactant: NN
Solvent: CC(=O)O
Product: Oc1nncc2cc(Cl)ccc12
Yield: 98.6 %

Procedure:
A suspension of 2-tert-butyl-5-chloro-3-hydroxyisoindolin-1-one (5.26 g, 21.9 mmol) in glacial acetic acid (32 mL) was heated with stirring until the mixture became a clear solution. Anhydrous hydrazine (1.0 mL, 22 mmol) was added dropwise and the resultant solution was stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure. Water was added to the mixture, after which a solid material precipitated out of the solution. The solid was collected by filtration and rinsed thoroughly with water, followed by air-drying to afford 6-chlorophthalazin-1-ol (3.9 g, 98% yield) as an off-white powder (mp 271-273° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:18][CH2:17][CH2:16][CH:11]([C:12](OC)=O)[CH2:10]2)=[CH:6][CH:5]=1.[OH-:21].[Na+]>CO.O>[CH3:2][O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:18][CH2:17][CH2:16][C:11](=[CH2:12])[C:10]2=[O:21])=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C1CCCN(Cc2ccc(OC)cc2)C1=O
Yield: 71.4 %

Procedure:
A solution of methyl N-(p-methoxybenzyl)nipecotate hydrochloride (30.7 g) and 8.4 g of sodium hydroxide in 900 ml of methanol and 45 ml of water is stirred at room temperature for seventeen hours. The solution is evaporated to dryness in vacuo, the residue diluted with toluene, and this again evaporated to dryness in vacuo. To the residue is added 1 liter of acetic anhydride and 140 ml of triethylamine, and the resulting mixture is heated under reflux for four hours. The reaction mixture is evaporated to dryness in vacuo, the residue taken up in chloroform, washed with water, dried, and concentrated in vacuo. The residual oil is chromatographed on silica gel using 1:1 hexane-ethyl acetate as the eluant, and yields 16.9 g of 1-(p-methoxybenzyl)-3-methylene-2-piperidone as a chromatographically pure yellow oil. Alternatively, the oil can be distilled to give analytically pure 1-(p-methoxybenzyl)-3-methylene-2-piperidone, b.p. 145°-155°/0.05 mm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[N:13]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:12]=12.[CH2:26]([O:28][C:29](=[O:34])[C:30](Br)([CH3:32])[CH3:31])[CH3:27]>>[CH2:26]([O:28][C:29](=[O:34])[C:30]([O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:12]1=[C:11]2[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)([CH3:32])[CH3:31])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2c(c1)c(-c1ccc3ccccc3n1)c1n2CCCCC1
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc3ccccc3n1)c1n2CCCCC1

Procedure:
This compound was prepared from 11-(2-quinolyl)-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[N:3]=1
Reactant: c1c[nH]cn1
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(-n2ccnc2)n1
Temperature: 85 °C

Procedure:
A mixture of 2,6-dichloropyridine (5 g, 33.78 mmol), imidazole (2.3 g, 33.78 mmol) and potassium carbonate (4.66 g, 33.78 mmol) in DMF (50 ml) is heated to 85° C. over night. The cooled mixture is poured into ice-water and unreacted starting material is filtered off. The filtrate is acidified with diluted hydrochloric acid and is extracted once with ethyl acetate. The aqueous phase is rendered alkaline by addition of aqueous sodium hydroxide (10 M) and extracted with ethyl acetate. The organic extract is dried over sodium sulfate, concentrated under reduced pressure and eluted through silica gel with a mixture of ethyl acetate and methanol (9:1). Evaporation of solvent leaves 15a. Yield: 2.37 g (39%). Mp 71-73° C.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].FC(F)(F)S(O[CH2:17][C:18]([F:32])([F:31])[C:19]([F:30])([F:29])[CH2:20][O:21]S(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:29][C:19]1([F:30])[CH2:20][O:21][C:9]2[CH:2]=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=2[O:10][CH2:17][C:18]1([F:32])[F:31]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)OCC(F)(F)C(F)(F)CO2
Temperature: 50 °C

Procedure:
A mixture of 2 g of 3,5-dihydroxybenzaldehyde, 10 g of 2,2,3,3-tetrafluorobutane-1,4-diyl bis(trifluoromethanesulfonate) and 12 g of cesium carbonate in 100 mL of anhydrous acetonitrile was heated under nitrogen to 50° C. overnight. The mixture was allowed to cool, then filtered and concentrated under reduced pressure. The residue was partitioned between 250 mL of ethyl acetate and 100 mL of saturated sodium carbonate then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (0-35% ethyl acetate in hexanes) gave the product as crystalline solid. MS (m+1)=265.1; 1H NMR (400 MHz, CDCl3) 9.85 (s, 1H), 7.6 (m, 2H), 7.2 (d, 1H), 4.64 (t, 2H), 4.45 (t, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)=[O:2].[CH3:21][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)[CH3:21]
Reactant: O=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A suspension of 150 mg of 6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 10 ml of tetrahydrofuran is cooled to 5° C. 1.9 ml of a 3M solution of methylmagnesium chloride in tetrahydrofuran are added dropwise. The reaction mixture is stirred at 5° C. for 4 hours, then treated with 20 ml of a saturated ammonium chloride solution, stirred and then diluted with 30 ml of ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with a saturated sodium chloride solution, dried and concentrated to dryness under reduced pressure. After chromatographing on silica, elution being carried out with dichloromethane and then with mixtures of dichloromethane and ethyl acetate (85/15, then 60/40), the fractions comprising the expected product are combined and evaporated to dryness under reduced pressure to give 59 mg of 6-[(RS)-1-hydroxyethyl]-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][NH:22][CH2:23][CH2:24][OH:25].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:9][CH:10]([C:12](=[O:14])[N:22]([CH2:23][CH2:24][OH:25])[CH3:21])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CNCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CN(CCO)C(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 1-diphenylmethylazetidine-3-carboxylic acid (see Preparation 58) (1.8 g, 6.73 mmol), 2-methylaminoethanol (0.76 g, 1.5 mol. equiv.), 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (1.27 g, 1.1 mol. equiv.), 1-hydroxybenzotriazole hydrate (1.08 g, 1.05 mol. equiv.) and N-methylmorpholine (1.5 g, 2.2 mol. equiv.) in dry dichloromethane (50 ml) was stirred at room temperature for sixteen hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The layers were separated and the aqueous layer further extracted with ethyl acetate (30 ml). The combined organic layers were dried over anhydrous sodium sulphate. The solution was filtered, the solvent removed from the filtrate under reduced pressure and the residue chromatographed using silica gel eluting with methanol:dichloromethane (7:93, by volume) to give the title compound (1.76 g). TLC Rf 0.3 (silica, methanol:dichloromethane, 7:93, by volume). LRMS m/z=325(m+1)+. Found C, 71.99; H, 7.60; N, 8.47. C20H24N2O2.0.13 CH2Cl2 requires C, 72.14; H, 7.30; N, 8.36%.
Reaction SMILES: [CH3:1][C:2]1[S:7](=[O:9])(=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.O[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[S:7](=[O:9])(=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:19]=1
Reactant: CC1=C(c2ccc(O)cc2)Oc2ccccc2S1(=O)=O
Reactant: OCCCN1CCCC1
Product: CC1=C(c2ccc(OCCCN3CCCC3)cc2)Oc2ccccc2S1(=O)=O

Procedure:
The entitled compound was obtained according to the method of Example 3 but using the compound synthesized in the above (1) and 1-(3-hydroxypropyl)pyrrolidine as the starting material.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([NH:15][C@@H:16]([CH3:30])[CH2:17][N:18]2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[CH:13][CH:12]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>ClCCCl>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11]([Br:10])[CH:20]=2)[N:15]([C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[C@@H:16]([CH3:30])[CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CN(c2nc3ccccc3o2)c2cc(Br)ccc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H]1CN(c2nc3ccccc3o2)c2cc(Br)ccc2N1C(=O)C1CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
N,N-Diisopropylethylamine (0.041 mL, 0.232 mmol) was added to a solution of (S)-2-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)benzo[d]oxazole (0.016 g, 0.046 mmol) and cyclopropanecarbonyl chloride (0.021 mL, 0.232 mmol) in 1,2-dichloroethane (1.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was partitioned between water and dichloromethane. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-(4-(benzo[d]oxazol-2-yl)-6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(cyclopropyl)methanone (0.019 g, 99%) as a brown oil. MS (ESI, pos. ion) m/z 412, 414 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[I:14])=[O:4].[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[N:9]=[C:8]2[I:14])=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)c(I)nn2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of 3-iodo-1H-indazole-5-carboxylic acid methyl ester (1.0 g, 3.31 mmol) in THF (12 mL) at 0° C. was added KOt-Bu (520 mg, 4.63 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodomethane (0.29 mL, 4.63 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 2 h. The reaction was quenched with water and extracted with EtOAc (2×) then with CH2Cl2 (2×). The combined organics were dried over MgSO4 and concentrated to afford 950 mg of 3-iodo-1-methyl-1H-indazole-5-carboxylic acid methyl ester a pale yellow solid. NMR analysis revealed an 8:1 mixture of N1:N2 alkylated regioisomers. Major: 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.25 (s, 1H), 8.13 (dd, J=8.7, 1.5 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 4.13 (s, 3H), 3.98 (s, 3H).