Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CC[O:4]CC1.[Li]CCCC.CCCCCC.Br[C:19]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22].[N+](C1C=CC=CC=1O)([O-])=O.Cl>C1COCC1>[OH:4][C:19]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: COc1cc(C=O)c(Br)c(OC)c1
Reactant: C1COCCN1
Agent: Cl
Agent: O=[N+]([O-])c1ccccc1O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(O)c(OC)c1
Temperature: -50 °C
Reaction time: 0.58 h
Yield: 54.9 %

Procedure:
Morpholine (2.05 g, 24 mmol) and THF (40 mL) were placed in a dry, three-necked, round bottomed flask equipped with a stirring bar, septum cap, dropping funnel, thermometer, and argon inlet. The flask was cooled in a dry ice-acetone bath to −50° C., and a solution of n-BuLi in hexane (1.6M, 15 mL, 24 mmol) was added all at once. After 10 min a solution of the 2-bromo-3,5-dimethoxybenzaldehyde 37 (4.9 g, 20 mmol) in THF (30 mL) was added dropwise via a syringe over a period of 4 min, and the mixture was cooled to ˜−75° C. over 20 min. n-BuLi in hexane (1.6M, 20 mL, 32 mmol) was then added dropwise over 45 min, keeping the temperature at −75° C. After complete addition of n-BuLi the solution was stritted for 35 min. A solution of nitrophenol (6.90 g, 46 mmol) in 10 mL THF was added from the dropping funnel, keeping the temperature at −75° C. The resulting dark mixture was stirred at −75° C. for 4 h and then allowed to warm to room temperature. It was acidified to pH 1 with 6N HCl and stirred for 15 min. After dilution with brine (100 mL), THF was removed in-vacuo. The aqueous solution was extracted with diethyl ether (4×40 mL). The combined organic layers were extracted with 2 N NaOH (3×40 mL). The combined NaOH extracts were washed with diethyl ether (3×20 mL) and then acidified to pH 1 with concentrated HCl. The resulting mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were washed with brine, dried (MgSO4) and adsorbed on silica gel. The product was purified by flash chromatography, eluting with EtOAc/hexane (1:2) to give 38 (2.0 g, 55%) as a yellow solid. m/z=183.06 (M+H). 1H NMR (500 MHz, CDCl3): δ: 10.71 (1H, s, OH), 9.91 (1H, s, CHO), 6.77 (1H, d, J4,6=2.8 Hz, H-6), 6.61 (1H, d, J4,6=2.8 Hz, H-4), 3.92 (3H, s, OMe), 3.84 (3H, s, OMe). 13C NMR CDEPT 135 (500 MHz, CDCl3): δ: 196.11 (CHO), 107.93 (C-6), 103.90 (C-4), 56.29 (OMe), 55.83 (OMe).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:49](=[O:57])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[OH:56])[C:5]([OH:48])=[C:6]([CH:47]=1)[C:7]([C:9]1[C:10]([OH:46])=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([O:14][CH2:15][C:16]1[CH2:17][S:18][C@@H:19]2[CH:30]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29](=[O:42])[N:20]2[C:21]=1[C:22]([O:24]C(C)(C)C)=[O:23])=[O:13])=[O:8].ClC1C=C(CC2C=CC=CC=2O)C(O)=C(C=1)CC1C(O)=C(C=CC=1)C(OCC1CS[C@@H]2C(NC(=O)COC3C=CC=CC=3)C(=O)N2C=1C(O)=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:49](=[O:57])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[OH:56])[C:5]([OH:48])=[C:6]([CH:47]=1)[C:7]([C:9]1[C:10]([OH:46])=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([O:14][CH2:15][C:16]1[CH2:17][S:18][C@@H:19]2[CH:30]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29](=[O:42])[N:20]2[C:21]=1[C:22]([OH:24])=[O:23])=[O:13])=[O:8]
Reactant: CC(C)(C)OC(=O)C1=C(COC(=O)c2cccc(C(=O)c3cc(Cl)cc(C(=O)c4ccccc4O)c3O)c2O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Agent: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3cccc(Cc4cc(Cl)cc(Cc5ccccc5O)c4O)c3O)CS[C@H]12
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3cccc(C(=O)c4cc(Cl)cc(C(=O)c5ccccc5O)c4O)c3O)CS[C@H]12
Yield: 94.2 %

Procedure:
Compound 20 (3.21 g, 4.23 mmol) was prepared from 18 (3.66 g, 4.49 mmol) in 94% yield by the method used for the preparation of 19. For 20: mp 180-182° C.; 1H NMR (DMSO-d6/D2O) d 3.69, 3.81 (AB, Jgem=19 Hz,2 H, CH2S), 4.61 (s, 2 H, OCH2CO), 4.93, 5.20 (AB, Jgem=14 Hz, 2 H, CH2O), 5.20 (d, J=5.0 Hz, 1 H, HC(6)), 5.77 (d, J=5.0 Hz, 1 H, HC(7)), 6.96-7.53 (m, 14 H, 4×ArH); IR (nujol): 3270-3400 (OH, NH, CO2H)), 1788 (β-lactam), 1725 (ester), 1680 (amide), 1620-1635 (C═O) cm−1. Anal. (C37H27N2O12SCl) C, H, N, S, Cl.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH:10]([CH3:15])[CH2:11][C:12](O)=[O:13])=O)([O-:4])=[O:3].O.[NH2:20][NH2:21]>C(O)C>[CH3:15][CH:10]1[C:8]([C:7]2[CH:16]=[CH:17][CH:18]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)=[N:21][NH:20][C:12](=[O:13])[CH2:11]1
Reactant: CC(CC(=O)O)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1cccc([N+](=O)[O-])c1

Procedure:
A 28 g. portion of 3-(m-nitrobenzyoly)butyronitrile [prepared as described in J. Org. Chem., Vol. 38, No. 23, 4044-4048 (1973)] is added to one liter of 6N hydrochloric acid and is stirred at reflux for one hour using a magnetic stirrer and a heating mantle. The reaction mixture is cooled and extracted with methylene chloride. The organic layer is separated and extracted with saturated sodium bicarbonate. The bicarbonate layer is added dropwise to a stirred cold hydrochloric acid solution and the resulting solid is kept cold in ice then is filtered and air dried to afford 27.24 g. of 3-m-nitrobenzoyl butyric acid as a white solid. The entire amount of the preceding compound is mixed with 12.8 ml of 99% hydrazine hydrate in 140 ml. of ethyl alcohol and is stirred at reflux for 3 hours. A solid beings to appear after about half an hour. The reaction mixture is cooled in an ice bath and the resulting solid is filtered and air dried to afford the compound 4,5-dihydro-5-methyl-6-(m-nitrophenyl)-3-(2H)-pyridazinone as white to light yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.O>C(#N)C>[Br:26][C:14]1[C:15]2[C:10](=[CH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[CH:17][CH:16]=2)[CH:11]=[CH:12][C:13]=1[OH:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Solvent: O
Solvent: CC#N
Product: Oc1ccc(-c2ccc3c(Br)c(O)ccc3c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 6-(4-hydroxyphenyl)-2-naphthol (4.02 g, 17.0 mmol) in acetonitrile (150 mL) at 0° C. was added NBS (3.03 g, 17.0 mmol). The reaction was stirred at 0° C. for 3 hr and then poured into water (200 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica column chromatography (20% ethyl acetate—hexanes) yielded 5.33 g (100%) of the title compound as a tan solid. The title compound was further purified by reverse phase HPLC to yield a white solid: mp 208-210° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.47 Hz), 7.28 (1H, d, J=8.80 Hz), 7.63 (2H, d, J=8.50 Hz), 7.85 (2H, d, J=8.84 Hz), 8.02-8.06 (2H, m), 9.60 (1H, s), 10.54 (1H, s); MS (ESI) m/z 313/315 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:14][CH:15]1[C:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17](=O)[NH:16]1)(=O)C.C(OCC)(=O)C>[OH-].[Na+].CC(C)=O>[CH2:19]([C:18]1([CH2:21][CH3:22])[C:15](=[O:14])[NH:16][CH:17]1[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:20]
Reactant: CCC1(CC)C(=O)NC1OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCC1(CC)C(=O)NC1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.7 %

Procedure:
A solution of 4-nitrophenol (2.37 gm, 17.0 mmol) in 2.5N sodium hydroxide (6.82 mL) was added to a solution of 2-acetoxy-3,3-diethyl-4-oxoazetidine (1.05 gm, 5.7 mmol) in acetone (5 mL). After stirring at room temperature for 2.5 hours, ethyl acetate (100 mL) was added and the solution successively washed with water (3×20 mL) and saturated salt solution (20 mL). The solution was dried over anhydrous sodium sulfate and the solvent removed by rotoevaporated. The product was purified by flash column chromatography on silica gel eluted with 25% ethyl acetate in hexanes and isolated as a beige solid (1.20 gm, 80% yield): 1H-NMR δ (CDCl3) 0.94 (6H, t, J=7 Hz), 1.62-1.92 (4H, m), 5.38 (1H, s), 6.90 (2H, d, J=9 Hz), 7.66 (1H, s), 8.10 (2H, d, J= 9 Hz).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=1)=[O:10].[C:20]([C:22]1[CH:39]=[CH:38][C:25]([O:26][CH2:27][CH:28]([NH:30][C:31](=[O:37])[C@H:32]([CH:34]([CH3:36])[CH3:35])[NH2:33])[CH3:29])=[CH:24][CH:23]=1)#[N:21].O>C(Cl)Cl>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH:28]([NH:30][C:31](=[O:37])[C@H:32]([CH:34]([CH3:35])[CH3:36])[NH:33][C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)=[O:10])[CH3:29])=[CH:38][CH:39]=1)#[N:21]
Reactant: Cc1ccc(OC(=O)Cl)cc1C
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1ccc(OC(=O)N[C@H](C(=O)NC(C)COc2ccc(C#N)cc2)C(C)C)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
0.6 g of N-methylmorpholine, and subsequently 1.2 g of 3,4-dimethylphenyl chloroformate were added to a suspension containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 50 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.7 g of the desired product in the form of a white crystal (yield: 74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cccc(F)c1
Product: CC(=O)NCCc1cccc(F)c1

Procedure:
In close analogy to the procedure described above, 2-(3-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=O>C(O)C>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=[C:2]1[CH2:3][CH2:4][CH2:5][C:6](=[CH:11][C:10]2[C:9]([Cl:8])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:17])[C:1]1=[O:7]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: O=C1CCCCC1
Solvent: CCO
Product: O=C1C(=Cc2c(Cl)cccc2Cl)CCCC1=Cc1c(Cl)cccc1Cl
Reaction time: 4 h

Procedure:
(76) Cyclohexanone (10 mmol), 60 ml of ethanol, and 2,6-dichlorobenzaldehyde (20 mmol) were used. The reaction stirred for 4 hours. A solid formed and was filtered. Recrystallization from ethanol yielded 3.24 g (78.6%) of bright-yellow flakes: mp 185.0-186.0° C. (lit. mp 183° C., Smith et al., supra). 1H NMR (250 MHz) δ 7.60 (s, 2 H), 7.37-7.18 (m, 6 H), 2.45 (t, 4 H), 1.73 (p, 2 H); 13C NMR (62.7 MHz) 188.2, 140.3, 134.6, 134.4, 132.4, 129.6, 128.1, 28.4, 22.1 ppm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:20][C@@H:19]2[CH2:21][OH:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[CH2:20][C@@H:19]2[CH:21]=[O:22])=[CH:16][CH:17]=1
Reactant: OC[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (17.50 mL, 2 M in DCM, 35.0 mmol) in DCM (150 mL) under nitrogen atmosphere and cooled to −78° C. was added dro wise DMSO (4.97 mL, 70.0 mmol), followed with the dropwise addition of a solution of the product from Example 8D, ((1S,2S)-2-(4-bromophenyl)cyclopropyl)methanol (5.3 g, 23.34 mmol) in DCM (100 mL). The mixture was stirred 30 minutes at −78° C. Then the mixture was treated with triethylamine (13.01 mL, 93 mmol), and then the reaction temperature was raised to ambient temperature. The mixture was partitioned between DCM (400 mL) and H2O (400 mL). The organic layer was separated, washed with water, dried and concentrated under reduced pressure to provide the title product. 1H NMR (300 MHz, CDCl3): δ 1.48 (m, 1H), 1.65 (dt, J=9 Hz, J=6 Hz, 1H), 2.15 (m, 1H), 2.57 (m, 1H), 6.98 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H), 9.46 (d, J=4.5 Hz, 1H). MS (DCI—NH3) m/z 226 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][N:13]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1>>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([C:14]([NH2:16])=[O:15])[CH:10]=2)=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][O:19][CH3:18])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: NC(=O)c1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cc(C(N)=O)n[nH]4)n3)cc2CC1

Procedure:
The title compound was prepared from 5-(2,5-dichloropyrimidin-4-ylamino)-2H-pyrazole-3-carboxylic acid amide (70 mg, 0.2 mmol) and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (57 mg, 0.256 mmol) in an analogous manner to Example 946 to afford a tan solid (66 mg, 60%). Mp: 208-10° C. LCMS (m/e) 457 (M+1); 1H-NMR (d6-dmso, 400 MHz) δ 10.08 (s, 1H), 9.73 (m, 1H), 9.49 (s, 1H), 8.63 (br s, 1H), 8.15 (s, 1H), 7.80 (br s, 1H), 7.52 (m, 3H), 7.16 (d, J=8 Hz, 1H), 3.70 (m, 6H), 3.40 (m, 2H), 3.36 (s, 3H), 3.27-2.90 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:31]([F:32])=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[C:4]([F:33])[CH:3]=1.[C:34](Cl)(=O)[O:35]C1C=CC([N+]([O-])=O)=CC=1.[NH2:47][CH2:48][C:49]([CH3:52])([OH:51])[CH3:50]>O1CCCC1>[F:32][C:31]1[CH:30]=[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:26])[F:27])[C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:4]([F:33])=[CH:3][C:2]=1[NH:1][C:34]([NH:47][CH2:48][C:49]([OH:51])([CH3:52])[CH3:50])=[O:35]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(O)CN
Reactant: Nc1cc(F)c(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: C1CCOC1
Product: CC(C)(O)CNC(=O)Nc1cc(F)c(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A solution of 2-(4-((4-(4-amino-2,5-difluorobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.311 mmol, 150 mg) and 4-nitrophenyl carbonochloridate (0.311 mmol, 62.7 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 30 minutes. 1-Amino-2-methylpropan-2-ol (0.622 mmol, 0.079 mL, 55.4 mg) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue purified by column chromatography (eluent: 2-10% methanol in dichloromethane) to afford the title compound (89.5 mg). MS (ESI) m/z 598.2 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([F:31])([F:30])C(OC)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]([F:14])([F:13])[F:15])=[CH:6][C:5]=1[O:16][CH:25]([F:31])[F:30]
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)cc1OC
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OC)cc(C(F)(F)F)cc1OC(F)F
Temperature: 65 °C

Procedure:
To a solution of 35 mg (0.140 mmol) 2-hydroxy-6-methoxy-4-trifluoromethyl-benzoic acid methyl ester in 350 ul N,N-dimethylformamide under nitrogen at room temperature, was added 29 mg (0.210 mmol) potassium carbonate, followed dropwise by 18.1 ul (0.168 mmol) methyl chlorodifluoroacetate. The reaction mixture was heated in a 65° C. oil bath for 22 hours. Water and ethyl acetate were added. Both phases were separated and the organic layer was washed 3 times with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude brown oil (49 mg) was purified with flash column chromatography on silica (10 g) eluting with a gradient formed from n-heptane and ethyl acetate (0%=>10% in 15 minutes) to provide 16 mg (y: 38.1%) of the title compound as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:28][NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=[C:2]([C:36]2[CH:35]=[CH:34][C:33]([S:30]([NH:29][CH3:28])(=[O:31])=[O:32])=[CH:38][CH:37]=2)[CH:3]=1)=[O:16]
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol), {4-[(methylamino)sulfonyl]phenyl}boronic acid (66.5 mg, 0.31 mmol) and bis(triphenylphosphine)palladium(II) chloride (8.4 mg, 0.01 mmol) were suspended in DME/water (4 mL, 3:1) and stirred for 10 min under nitrogen at room temperature. Sodium bicarbonate (52 mg, 0.62 mmol) was added and the heterogenous mixture was irradiated (microwave) at 150° C. for 30 min. After cooling to room temperature, water was added to the black mixture, and the contents were vacuum filtered. The crude product was dissolved in DCM/MeOH (1:1) and preabsorbed onto silica gel. The product was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient of 0 to 90:10:1). The light beige solid that was collected was suspended in EtOH, sonicated, and filtered. The solid was then air-dried for 15 min, and then in vacuum oven overnight. The final product was collected as 77 mg (70%). LCMS E-S (M+H)=523.2 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1 H) 8.78 (t, J=5.05 Hz, 1 H) 8.43 (m, J=8.59 Hz, 2 H) 7.93 (m, J=8.59 Hz, 2 H) 7.78 (s, 1 H) 7.58 (br. s., 1 H) 5.89 (s, 1 H) 5.29 (quin, J=6.63 Hz, 1 H) 4.40 (d, J=4.80 Hz, 2 H) 2.46 (d, J=1.26 Hz, 6 H) 2.25 (s, 3 H) 2.12 (s, 3 H) 1.52 (s, 3 H) 1.51 (s, 3 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[O:13][C:12]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([NH2:26])=[C:24]([CH3:25])[C:11]2=3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.CO.C(OC(C)C)(C)C>>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:26][C:23]2[C:22]([CH3:27])=[C:21]([CH3:28])[C:12]3[O:13][C:14]4([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=4)[C:11]=3[C:24]=2[CH3:25])=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Solvent: CC(C)OC(C)C
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Yield: 38 %

Procedure:
By using 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 38%. Melting point: 271-272° C. (Methanol-isopropyl ether).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO.O>[NH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 48.8 %

Procedure:
To a solution of 1.29 gm (20 mMol) potassium hydroxide in 10 mL methanol were added 1.32 gm (10 mMol) 5-amino-1H-indole followed by 2.46 mL (20 mMol) 1-methyl-4-piperidone. The reaction mixture was then heated to reflux for 18 hours. The reaction mixture was cooled to ambient, diluted with 20 ml water and the precipitate collected by filtration. The solid was recrystallized from ethyl acetate:methanol to give 1.11 gm (48.9%) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyr-idin-4-yl)-1H-indole as a tan solid (m.p.=200°-203° C.). The tan solid was subjected to flash chromatography, eluting with 100:20:0.5 dichloromethane:methanol:ammonium hydroxide, to give 0.99 gm 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a cream colored solid (m.p.=212°-215° C. (ethyl acetate:methanol)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[C:54]([NH:57]C1C=C(C=CC=1)C(O)=O)(=[O:56])[CH3:55].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:54]([NH:57][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6])(=[O:56])[CH3:55]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(NC(C)=O)c3)nn2)cc(OC)c1OC
Yield: 75 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (113 mg, 0.33 mmol), 3-(acetylamino)benzoic acid (110 mg, 0.61 mmol), diisopropylethylamine (0.40 mL, 2.3 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (252 mg, 0.66 mmol) in dimethylformamide (2 mL) gave 3-(acetylamino)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (116 mg, 75%) as a yellow solid. MS m/z 466 (M+1).