Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][N:32]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:35]2[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cn1cc(B(O)O)cn1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2cnn(C)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 49.9 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (0.2 g, 0.42 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (0.105 g, 0.505 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.16 g, 1.51 mmol) was added and solution purged with argon for 15 min. Pd(PPh3)4 (0.048 g, 0.042 mmol) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was then diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by column chromatography to afford the title compound (0.100 g, 50%). LCMS: 478.20 (M+1)+; HPLC: 95.82% (@254 nm) (Rt; 4.322; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.12 (s, 1H), 8.10 (t, 1H), 7.81 (s, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 5.86 (s, 1H), 4.27 (d, 2H, J=4.8 Hz), 3.81-3.83 (m, 5H), 3.21-3.26 (m, 2H), 2.98-3.08 (m, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.63-1.66 (m, 2H), 1.48-1.52 (m, 2H), 0.86 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:24])OC3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]([NH2:45])(=[O:44])=[O:43]>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42]([NH:45][C:16]([NH:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2]([CH3:1])=[C:3]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]([C:25]([F:27])([F:26])[F:28])=[N:5]2)=[CH:12][CH:11]=1)=[O:24])(=[O:44])=[O:43]
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccc1F
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 2-fluoro-benzenesulfonamide: MS (ESI) m/z 547 [M+H]+, 545 [M−H]−, 1H-NMR (CDCl3) δ 7.86-7.81 (1H, m), 7.74-7.58 (1H, m), 7.48-7.24 (1H, m), 6.45 (1H, br.s) 3.54-3.49 (2H, m), 2.87 (2H, t, J=6.7 Hz), 2.23 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:33])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:34]([C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:33])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([O:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)#[N:35]
Reactant: CN(C)C=O
Reactant: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(Br)c4)oc3C)C2)c1C(=O)O
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(C#N)c4)oc3C)C2)c1C(=O)O
Temperature: 100 °C
Reaction time: 12 h

Procedure:
13 mg of 2-{3-[2-(3-bromophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-methylbenzoic acid and 25 mg of zinc cyanide were dissolved in 5 ml of dimethylformamide. The reaction mixture was degassed and charged with argon, and 20 mg of tetrakistriphenylphosphinepalladium were added. The mixture was stirred at 100° C. for 12 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, the solvents were removed under reduced pressure and the residue was purified by RP-HPLC. This gave 68 as an amorphous light-yellow solid. C27H28N2O5 (460.53), MS(ESI): 461.20 (M+H+).
Reaction SMILES: C[O-].[Na+].O1CCCC1.[F:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:22]2[N:23]([CH3:40])[C:24](=[O:39])[C:25]([CH3:38])=[C:26]([NH:27][C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=3)[C:21]=2[C:20](=[O:41])[N:19]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:18]1=[O:51]>CO>[F:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:22]1[N:23]([CH3:40])[C:24](=[O:39])[C:25]([CH3:38])=[C:26]2[C:21]=1[C:20](=[O:41])[N:19]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)[C:18](=[O:51])[N:27]2[C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4cccc(NC(C)=O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(NC(C)=O)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a solution (305 mg) of 28% sodium methoxide in methanol were added tetrahydrofuran (4.00 ml) and N-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide 87 (1.00 g). The wall was washed with tetrahydrofuran (4.00 ml). The mixture was stirred at room temperature for 1.5 hrs., 2N hydrochloric acid (900 μl) was added, and the mixture was concentrated under reduced pressure. To the residue was added isopropyl alcohol, methanol and water, and after refluxing, the mixture was allowed to cool to room temperature with stirring. The precipitated crystals were collected by filtration, washed with methanol, and dried to give N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 88 (974 mg, yield 97.2%) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1.Cl[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C(=O)(O)[O-].[Na+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1
Reactant: Clc1ccccn1
Reactant: Nc1ccc(Oc2nccnc2C2CCCOC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(Nc2ccc(Oc3nccnc3C3CCCOC3)cc2)nc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
4-(3-(Tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline (0.10 g, 0.38 mmol) and 2-chloropyridine (0.072 mL, 0.76 mmol) were mixed together neat in a microwave tube. The tube was sealed and stirred at 120° C. for 45 min before being warmed to 160° C. and stirred for 2 h. The reaction mixture was cooled to room temperature, diluted with sat. sodium bicarbonate, and extracted with EtOAc (2×). The combined organic layers were washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 349.1 (M+1). IC50 (uM) 0.021.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10](=O)[CH2:11][CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[CH2:10]([C:11]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)[CH3:9]
Reactant: Oc1ccccc1O
Reactant: CCC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCC1(C)Oc2ccccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.5 %

Procedure:
To a stirred solution of 20.0 g (0.180 mole) of catechol and 0.8 g (0.40 mole) of 2-butanone in 200 ml of methylene chloride was added 128.0 g (0.902 mole) of phosphorus pentoxide. The reaction mixture was stirred at room temperature for two days. The stirring was stopped, and the reaction solids were allowed to settle. The reaction mixture was decanted into a separatory funnel. The solid material was washed with methylene chloride, and the wash was decanted into the above separatory funnel. The combined organic phase was washed with aqueous, saturated sodium bicarbonate solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 17.3 g of 2-ethyl-2-methyl-1,3-benzodioxole.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.C(O[CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)(=O)C>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][CH:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:3]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)N1CCCC(N)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
A mixture of 3-amino-1-carbethoxypiperidine and 9-acetoxyxanthene in dry toluene is refluxed by the procedure of Example 1 to give N-(N-ethoxycarbonyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([C:18]([O-:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.[Na+].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:18]([C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH2:9][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[O:20])=[CH:25][CH:24]=1
Reactant: O=C([O-])c1cccc2c1CCN(Cc1ccncc1)C2
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2c1CCN(Cc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Sodium 2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (80 mg, 0.276 mmol) was dissolved in N,N-dimethylformamide (1 mL) then added 4-chloroaniline (42 mg, 0.331 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (133 mg, 0.414 mmol), and N,N-diisopropylethylamine (56 mg, 0.552 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The remaining orange oil was purified by silica gel chromatography (1% to 3% 7N ammonia in methanol/dichloromethane) to afford N-(4-chlorophenyl)-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (89 mg) as a light yellow solid. MS (ESI, pos. ion) m/z: 378.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:40][CH2:39]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)CC1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 2) was reacted with 4-piperidine-acetamide (Chembridge) to give the title compound. HR-MS (ES, m/z) calculated for C35H43Cl2N6O3 [(M+H)+] 665.2768, observed 665.2767.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]#[N:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[NH:14])[NH:16][OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=N)NO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
(R)-3-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (2.04 g, 10.4 mmol), hydroxylamine hydrochloride (0.79 g, 11.4 mmol) and NaHCO3 (0.97 g, 11.6 mmol) were added to MeOH (24 mL) and the solution was heated to reflux. After 4 h, the reaction was cooled to room temperature and filtered through a fritted funnel. The solution was concentrated in vacuo. The residue was purified by reverse phase HPLC to afford (R)-3-(N-hydroxycarbamimidoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.28 g, 5.58 mmol, 54%) as a yellow foam.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:9]=[C:8]2[C:24]1[N:33](S(C2C=CC(C)=CC=2)(=O)=O)[C:27]2=[N:28][CH:29]=[C:30]([F:32])[CH:31]=[C:26]2[CH:25]=1>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:9]=[C:8]2[C:24]1[NH:33][C:27]2=[N:28][CH:29]=[C:30]([F:32])[CH:31]=[C:26]2[CH:25]=1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCOCC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(-c3cc4cc(F)cnc4[nH]3)cn(CCN3CCOCC3)c2cc1OC
Yield: 60.8 %

Procedure:
A solution of 2.08 g of potassium hydroxide in 7 ml of water is added to a solution of 0.83 g of 2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 100 ml of methanol brought to reflux. The mixture is agitated at reflux for 3 hours 30 minutes. After returning to around 20° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 ml of water and extracted with three times 80 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: ethyl acetate/methanol (90/10 by volume)]. 0.37 g of 2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.[NH2:16][C:17]1[O:18][CH2:19][C@:20]2([N:37]=1)[C:33]1[CH:32]=[C:31]([OH:34])[C:30]([F:35])=[CH:29][C:28]=1[O:27][C:26]1[C:21]2=[CH:22][C:23](Br)=[CH:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:16][C:17]1[O:18][CH2:19][C@:20]2([N:37]=1)[C:33]1[CH:32]=[C:31]([OH:34])[C:30]([F:35])=[CH:29][C:28]=1[O:27][C:26]1[C:21]2=[CH:22][C:23]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)=[CH:24][CH:25]=1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1cc(F)c(O)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@]2(CO1)c1cc(C3=CCOCC3)ccc1Oc1cc(F)c(O)cc12
Temperature: 110 °C

Procedure:
A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (276 mg, 1.315 mmol), (S)-2-amino-7′-bromo-3′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (300 mg, 0.822 mmol), potassium phosphate (523 mg, 2.465 mmol) and Cl2Pdbis(di-tert-butyl(phenyl)phosphine) (15.28 mg, 0.025 mmol) in 3 ml of dioxane/water=2:1 was heated at 110° C. microwave for 30 min. The reaction mixture was purified by silica gel chromatography (DCM to DCM/MeOH=100:1 to 100:6) to give (R)-2-amino-7′-(3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:36][CH2:37][C:38]#[N:39])[CH:3]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:36][CH2:37][C:38]#[N:39])[CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4OCC#N)nccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the light brown crude oil from Step 2 was added DCM (3 ml) and TFA (1 ml) and the mixture stirred at room temperature for 30 min affording PMB deprotection. The mixture was dried under reduced pressure and purified using basic, then acidic conditions, respectively affording product (16 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ=12.91 (br. s., 1H), 8.69 (d, J=5.8 Hz, 1H), 8.56 (d, J=1.9 Hz, 1H), 8.14 (d, J=5.2 Hz, 1H), 7.86 (dd, J=1.9, 8.9 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.34 (dd, J=1.9, 8.1 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 5.16 (d, J=1.0 Hz, 2H). m/z (ESI) 457.0 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[N:9][OH:10])[NH2:8])([O-:3])=[O:2].[C:14](OC)(=O)[CH2:15][C:16]([CH3:18])=[O:17]>C1(C)C=CC=CC=1>[O:17]=[C:16]([CH3:18])[CH2:15][C:14]1[O:10][N:9]=[C:7]([C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:8]=1
Reactant: COC(=O)CC(C)=O
Reactant: NC(=NO)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(=O)Cc1nc(-c2cccc([N+](=O)[O-])c2)no1
Yield: 83.5 %

Procedure:
In a 250 ml flask, place 10 g (0.055 m) of 3-nitrobenzamidoxime (9a), 9.6 g (0.083 m) of methyl acetoacetate (10b; R1=methyl), and 100 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 16 hrs. Distill off toluene under a reduced pressure at 50-60° C. to thick oil. Add 60 ml of heptane to the oil with stirring, cool and stir at 0-5° C. for 30 min. Collect solid, wash with heptane, and dry in air to give 11.4 g (84%) of 5-(2-oxopropyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula II: R1=methyl and R2=3-nitrophenyl].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][CH3:23])[CH:30]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: COc1cccc(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+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 84.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.060 g (83%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methoxybiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1([Cl:25])[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:7]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:5][C:6]1([Cl:25])[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]1([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1)[C:6]1[CH:7]=[CH:15][C:1]([O:3][C:18](=[O:21])[CH3:17])=[CH:2][CH:8]=1
Reactant: CC(=O)Cl
Reactant: CC(=O)Oc1ccc([C@H]2[C@@H](c3ccccc3)C2(Cl)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C2(c3ccc(OC(C)=O)cc3)C(c3ccccc3)C2(Cl)Cl)cc1

Procedure:
Acetylation of Compound 36 (0.6 g, 0.0016 mol) was performed with pyridine (0.8 mL) and acetyl chloride (0.8 mL) as described in the preparation of Compound 10. The crude product was chromatographed (silica gel; CH2Cl2 /acetone, 98:2) to provide 0.02 g colorless amorphous solid, mp 74°-75° C. The fractions eluted with CH2Cl2 /acetone (95:5) had both the acetate and the phenolic products, which were subjected to acetylation. Additional purification provided a total 0.1 g of Compound 37 (13.7%). 1H NMR (CDCl3) δ 2.26 (s, 6H, OCOCH3), 3.55 (s, 1H, ArCH), 6.96-7.66 (m, 13H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)Cl>[Br:27][C:10]1[N:11]=[C:12]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[O:13][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(Sc2cnc(C3CCOCC3)o2)cc1
Solvent: ClCCl
Product: Clc1ccc(Sc2oc(C3CCOCC3)nc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (521 g, 17.61 mmol) in DCM (176 ml) was added NBS (3.45 g, 19.38 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica 330 g, 5 to 30% EtOAc in hexane), to give 4-bromo-5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2 H-pyran-4-yl)-1,3-oxazole (6.16 g). MS: M+H=376. H′NMR (400 MHz, CDCl3) δ: 7.28 (d, J=8.4 Hz, 2 H), 7.22 (d, J=8.4 Hz, 2 H), 4.01 (dt, J=11.7 Hz, 3.6 Hz, 2 H), 3.50 (td, J=2.7, 11.7 Hz, 2 H), 3.09-2.98 (m, 1 H), 2.02-1.86 (m, 4 H).