Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]1([CH3:20])[CH2:19][CH2:18]1)[C:9]([CH3:15])=[N:10]2)=[O:4].CN(C=O)C.[C:26]([O:30][C:31]([NH:33][C@H:34]([CH3:43])[C:35](=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>C([O-])(O)=O.[Na+].C1COCC1>[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH3:43])[C:35](=[O:42])[CH:36]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]1([CH3:20])[CH2:19][CH2:18]1)[C:9]([CH3:15])=[N:10]2)=[O:4])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:32])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCOC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC1(C)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC3(C)CC3)nc12)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 1000 mL round bottomed flask was added 2-bromo-1-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)ethanone (611) (14.6 g, 43.7 mmol), DMF (35 mL), THF (35 mL), ethyl (4R)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (13.7 g, 52.7 mmol) and K2CO3 (15.1 g, 109 mmol). The mixture was stirred at RT. After 4 h, the mixture was diluted with sat NaHCO3 and extracted with EtOAc (3×100 mL). The combined extracts were washed with water (2×100 mL) and brine (100 mL) and then dried (Na2SO4) and concentrated to afford ethyl (4S)-4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-2-oxoethyl)-3-oxopentanoate as a brown amorphous solid which was used without further purification. m/z (ESI, +ve) 513.2 (M+H)+. The brown amorphous solid was treated with EtOH (80 mL), AcOH (8.0 mL), and finally NH4OAc (10.1 g, 131 mmol). The mixture was stirred at RT for 12 h. The solution was partially concentrated and then was diluted with sat NaHCO3 and EtOAc. The phases were separated and the organic phase was washed with water, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (half of the material was purified on a Redisep Gold 330 g column, 0-50% EtOAc/hexanes and the other half on an Interchim 300 g column, 25 micron, 10 to 35% isocratic at 35% EtOAc/Hex) afforded ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-1H-pyrrole-3-carboxylate (6.96 g, 14.1 mmol, 32% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (br s., 1H), 7.87-7.96 (m, 2H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.47 (s, 1H), 7.33-7.40 (m, 1H), 7.06 (d, J=7.0 Hz, 1H), 5.32-5.45 (m, 1H), 4.17-4.28 (m, 2H), 2.47 (s, 3H), 1.57 (s, 3H), 1.32-1.44 (m, 12H), 1.28 (t, J=7.0 Hz, 3H), 0.91-1.05 (m, 2H), 0.80-0.91 (m, 2H). m/z (ESI, +ve) 494.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=O)[CH2:3][CH2:2]1.Cl.C1(N(C)C2C(Cl)=CC=CC=2Cl)CC1>O1CCCC1>[CH:1]1([CH2:4][NH:6][C:7]2[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:13])[CH2:2][CH2:3]1
Reactant: O=C(Nc1c(Cl)cccc1Cl)C1CC1
Agent: CN(c1c(Cl)cccc1Cl)C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1NCC1CC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
58.4 grams of N-cyclopropylcarbonyl-2,6-dichloroaniline was dissolved in 550 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere in a 2 liter 3-necked flask. The mixture was cooled in an ice bath to 4° C. To this mixture was added 389 ml of 0.9 M-diboronhexahydride in anhydrous tetrahydrofuran over a period of one hour and ten minutes while maintaining a temperature of less than 5° C. After addition was complete, the solution was allowed to warm to room temperature and stirred for one hour. The solution was then heated to reflux and reflux was maintained overnight. The solution was then cooled in an ice bath and 225 ml 6 N aqueous hydrogen chloride was added. This mixture was then evaporated in vacuo to remove the tetrahydrofuran. The resultant liquid and solid residue was diluted with 500 ml of water and cooled in an ice bath. 75 g of sodium hydroxide in 300 ml of water was then added. The mixture was then extracted with ether and the ether extract was washed twice with 500 ml of water, 250 ml of saturated saline solution and dried over sodium sulfate. The resultant mixture was then filtered and the filtrate was evaporated in vacuo. The resultant oil was dissolved in 100 ml of methanol and acidified with 250 ml of methanol/hydrogen chloride and then evaporated in vacuo at 35°-40° C. The resultant oil residue was dissolved in 250 ml of isopropanol and a crystalline precipitate formed. The reaction yielded 33.0 g of white solid N-cyclopropyl methyl-2,6-dichloroaniline having a melting point of 149°-158° C.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C(OC([N:12]1[C@H:16]([CH:17]([OH:27])[C:18]2[N+:19]3[C:20](=[CH:23][N:24]([CH3:26])[CH:25]=3)[S:21][CH:22]=2)[CH2:15][C@H:14]([S:28][C:29]2[C@H:30]([CH3:46])[C@@H:31]3[C@@H:41]([C@H:42]([OH:44])[CH3:43])[C:40](=[O:45])[N:32]3[C:33]=2[C:34]([O:36]CC=C)=[O:35])[CH2:13]1)=O)C=C.CNC1C=CC=CC=1.O>ClCCl.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]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:44][C@@H:42]([C@H:41]1[C:40](=[O:45])[N:32]2[C:33]([C:34]([OH:36])=[O:35])=[C:29]([S:28][C@H:14]3[CH2:15][C@@H:16]([CH:17]([OH:27])[C:18]4[N+:19]5[C:20](=[CH:23][N:24]([CH3:26])[CH:25]=5)[S:21][CH:22]=4)[NH:12][CH2:13]3)[C@H:30]([CH3:46])[C@H:31]12)[CH3:43]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cn(C)c[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CNc1ccccc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(O)c4csc5cn(C)c[n+]45)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (18.1 mg) is added to a solution of 55 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(6-methylimidazo[5,1-b]thiazolium-3-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate perchlorate (stereoisomer B) and 0.051 ml of N-methylaniline in 0.7 ml of dry dichloromethane, and the mixture is stirred in an argon atmosphere at room temperature for 45 min. Distilled water (3 ml) is added thereto, the mixture is washed three times with 3 ml of ethyl acetate, and the aqueous layer is filtered, followed by concentration under reduced pressure and freeze drying to give 31 mg of a light orange flocculent material. The light orange flocculent material is purified by column chromatography on Cosmosil 5C18-MS (water:methanol=10:1) to give 3.9 mg of the title compound as a colorless flocculent material.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:60][C@@H:58]([C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][CH:54]=2)[CH3:59])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H](NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.418 g, 1.10 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g, 1 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.156 g, 1.00 mmol) and DIPEA (0.524 mL, 3.00 mmol) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude material was treated with a 10% solution of TFA in DCM (5 mL) and stirred at room temperature. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-4-amino-N-(1-(4-chlorophenyl)ethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.211 g, 52.9%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:44]>C(Cl)Cl.CCOCC>[ClH:44].[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:22])[C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=4)[C:4]=23)[CH2:24]1
Reactant: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)cc1F
Yield: 63 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(3-fluoro-4-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.27 mmol) in DCM (3 mL) was treated with TFA (1 mL), followed by 1M HCl in ether according to the procedure described in Example 62, Step C, to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide hydrochloride (90 mg, 63% yield). 1H NMR (400 MHz, D2O) δ 8.20 (s, 1H), 7.67-7.64 (m, 1H), 7.62-7.59 (m, 1H), 7.35 (s, 1H), 7.18-7.14 (m, 1H), 3.84 (s, 3H), 3.46-3.40 (m, 1H), 3.28-3.18 (m, 2H), 3.12-3.09 (m, 2H), 1.79-1.74 (m, 1H), 1.68-1.61 (m, 1H), 1.46-1.30 (m, 2H); LCMS (APCI+) m/z 462, 464 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:14]2[C:10](=[N:11][C:12](=[O:15])[N:13]=2)[CH:9]=[CH:8][CH:7]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:20][CH2:19]1>>[OH:1][C@@H:2]([CH2:3][NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]([F:29])([F:27])[F:28])[CH2:20][CH2:19]1)[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: O=C1N=c2cccc(OC[C@@H]3CO3)c2=N1
Product: O=c1[nH]c2cccc(OC[C@@H](O)CNCC3CCN(CCC(F)(F)F)CC3)c2[nH]1
Yield: 31.6 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-benzimidazol-2-one (0.080 g, 0.38 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.250 g, 1.2 mmol) of according to the procedure used for Example 2 to give 0.050 g of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:18])[CH:10]=[CH:11]C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:9](=[O:18])[CH:10]=[CH:11]2
Reactant: O=C(C=Cc1ccccc1)Nc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=c1ccc2cccc(F)c2[nH]1
Temperature: 25 °C

Procedure:
N-(2-Fluorophenyl)cinnamamide (10.5 g, 44 mmol) was dissolved in chlorobenzene (60 mL) and aluminum trichloride (29 g, 218 mmol, 5 eq) was added. The reaction was heated to 125 C for 3 h and then cooled to rt over 45 minutes. The reaction was poured onto 300 g of ice with stirring, producing a tan solid. The solid was filtered and washed with 100 mL of water and 3×100 mL of hexanes and dried under high vacuum. The solid was extracted with 1 L of DCM and filtered to remove insoluble byproducts. The solvent was removed in vacuo to afford 8-fluoroquinolin-2(1H)-one. 1H NMR (400 MHz, CDCl3) δ ppm 10.95 (br s, 1H), 7.77 (dd, J=9.8, 1.6 Hz), 7.35 (d, J=7.8 Hz, 1H), 7.27 (ddd, J=10.2, 7.8, 1.2 Hz, 1H), 7.14 (td, J=8.0, 5.1 Hz, 1H), 6.76 (d, J=9.4 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][NH2:10])[CH:4]=1.N=[C:12]([CH3:16])[CH2:13][C:14]#[N:15].C(O)C>C(OCC)(=O)C>[CH3:16][C:12]1[CH:13]=[C:14]([NH2:15])[N:9]([C:5]2[CH:4]=[C:3]([S:2][CH3:1])[N:8]=[CH:7][N:6]=2)[N:10]=1
Reactant: CC(=N)CC#N
Reactant: CSc1cc(NN)ncn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1cc(-n2nc(C)cc2N)ncn1
Temperature: 85 °C

Procedure:
The mixture of (6-Methylsulfanyl-pyrimidin-4-yl)-hydrazine (1.0 g, 6.4 mmol), 3-Imino-butyronitrile (1.1 g, 12.8 mmol), and ethanol (30 mL) is heated to 85° C. for overnight. The reaction mixture is then cooled to room temperature, condensed, and treated with 75 mL ethyl acetate. The reaction mixture is partitioned between ethyl acetate and aqueous layer. The organic layer is dried over Na2SO4 and concentrated. The crude product is purified by ISCO chromatography eluting with ethyl acetate in hexanes from 10% to 80% to afford 5-Methyl-2-(6-methylsulfanyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamine: 1H NMR 400 MHz (d6-DMSO) δ 8.72 (s, 1H), 7.53 (s, 1H), 6.90 (s, 1H), 5.26 (s, 1H), 2.57 (s, 3H), 2.08 (s, 3H); MS m/z 222.07 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]2[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C.CCOCC>[CH3:35][O:34][C:32](=[O:33])[CH2:31][O:1][CH2:2][C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]2[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC(CO)(c2ccccc2)CC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)COCC1(c2ccccc2)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 130.8 %

Procedure:
To a stirred solution of 2-adamantyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (230 mg, 0.62 mmol) in dry DMF (5 mL) was added 60% NaH in oil (60 mg, 2.5 mmol). The mixture was stirred at rt for 0.5 h and methyl bromoacetate (0.24 mL, 2.5 mmol) was added. The mixture was stirred at 50° C. in an oil bath for 4 h. The mixture was diluted with ether (90 mL), washed with water (3×20 mL), dried over MgSO4 and concentrated to leave an oil (358 mg). This material was purified by column chromatography on silica gel, eluted with an EtOAc in hexanes gradient, followed by prep HPLC to afford the title compound (20 mg, 7%) as an oil. LC-MS Method 2 tR=11.79 min, m/z=442.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl(3-nitrophenyl)carbamate (17.1 g, 71.7 mmol) in ethanol (90 mL)/tetrahydrofuran (30 mL) was added 10% palladium-carbon (1.53 g), and the mixture was stirred at room temperature under a hydrogen atmosphere (3 atm) for 9 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether/hexane mixture to give the title compound (14.7 g, 98%) as a colorless solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]1([O:29][CH3:30])[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28])(C(C)(C)C)(C)C>C1COCC1>[OH:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]1([O:29][CH3:30])[C:19](=[O:28])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]1=[O:27]
Reactant: COC1(c2ccc(C(C)C)cc2O[Si](C)(C)C(C)(C)C)C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: COC1(c2ccc(C(C)C)cc2O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
2-(2-(tert-butyldimethylsilyloxy)-4-isopropylphenyl)-2-methoxy-1H-indene-1,3(2H)-dione (0.2 g, 0.47 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with quaternary ammonium fluoride (0.27 g, 1.04 mmol), and stirred at room temperature for 1 hr. The reaction mixture was concentrated, and extracted with ethylacetate, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (38 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].B(F)(F)F>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10]([C:19](=[O:21])[CH3:20])=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn3ccc(Cl)cc3c2C(C)=O)cc1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
To a solution of 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine (3.0 g, 11.6 mmol) in toluene (100 mL) at room temperature was added acetic anhydride (1.6 mL, 17.4 mmol). Boron trifluoride diethyletherate (1.8 mL, 13.9 mmol) was then added dropwise and the resulting solution was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of saturated aqueous sodium bicarbonate. The reaction was extracted with ethyl acetate, and the ethyl acetate phase washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by recrystallization from ethyl acetate-hexanes to give 1-[5-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (2.31 g, 66%). 1H NMR (CDCl3): δ 8.44 (d, 1H), 8.40 (d, 1H), 7.49 (d, 2H), 7.02 (d, 2H), 6.97 (dd, 1H), 3.85 (s, 3H), 2.15 (s, 3H); MS m/z 301 (M+1).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(S)CCCCCCCCCCC.[S].[OH-:38].[Na+]>O.CC(C)=O>[CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]([OH:10])(=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:38])=[O:9]
Reactant: O=C1C=CC(=O)O1
Reactant: [OH-]
Agent: C=CC=C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCCCCCCS
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)/C=C\C(=O)O
Reaction time: 6 h

Procedure:
A polymerization was carried out at 70° C. for 6 hrs. using 54.1 g. of butadiene, 98.1 g. of maleic anhydride, 1.7 g. of azobisisobutyronitrile and 36.0 g. of n-dodecylmercaptan in 750 cc. of acetone. There was obtained 61.0 g. of a white copolymer with an intrinsic viscosity of 0.08. Proportion of the end dodecylthio group in the copolymer was found by the elementary analysis for sulfur to be 5.4%. A reaction was carried out at 80° C. for 1 hr. using 16.1 g. of the copolymer, 6.0 g. of sodium hydroxide and 139 g. of water to give an aqueous solution of a butadiene-maleic acid copolymer sodium salt containing end dodecylthio groups. A composition identical in composition with the composition of Example 2 was prepared using the above-prepared aqueous solution, an aqueous calcium chloride solution at a concentration of 0.1 M/l, an aqueous solution of sodium lauryl sulfate at a concentration of 30% and water to which THPA was added in the same amount as that of the copolymer salt. Aqueous gel obtained from the composition was slower in rate of the gelation and lower in strength of the gel as compared with the aqueous gel of Example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:7][C:12](=[O:13])[NH:11][C:3]=12)=[O:6]
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cccc2c(=O)oc(=O)[nH]c12
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a mixture of 10.0 g (66.0 mmol) of 3-methylanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated in vacuo to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.66 g (99.5%) of the 3-methylisatoic anhydride as an off white solid. MS (Cl mode) m/z 160 (M-18, 100%), 178 (M+H, 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1Br.[F:11][C:12]([F:22])([F:21])[C:13]1[N:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([O:20][CH2:19][C:16]2[CH:17]=[N:18][C:13]([C:12]([F:22])([F:11])[F:21])=[CH:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COc1nccc(Br)c1Br
Reactant: OCc1ccc(C(F)(F)F)nc1
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(OCc2ccc(C(F)(F)F)nc2)ccn1
Yield: 72.4 %

Procedure:
4-BromoBromo-2-methoxypyridine (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromagraphy (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:21])[CH2:15]2)=[N:12][CH:13]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(C)C=CC=CC=1.C(O)C>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.C(OCC)(=O)C>[OH:29][CH:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:20]([C@H:16]2[CH2:17][CH2:18][CH2:19][N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:13][N:12]=3)[CH2:15]2)=[O:21])[CH2:24][CH2:25]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(NC1CCC(O)CC1)[C@H]1CCCN(c2ccc(Br)cn2)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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NC1CCC(O)CC1)[C@H]1CCCN(c2ccc(-c3ccccc3)cn2)C1

Procedure:
Sodium carbonate (21.2 mg, 0.000200 mol) in water (0.10 mL) was added to a mixture of (35)-1-(5-bromopyridin-2-yl)-N-(4-hydroxycyclohexyl)piperidine-3-carboxamide (38.2 mg, 0.000100 mol, prepared as example 154), phenylboronic acid (14.6 mg, 0.000120 mol) and tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 0.0000030 mol) in toluene (200.0 μL, 0.001878 mol) and ethanol (100.0 μL, 0.001713 mol). The resulting mixture was irradiated with microwaves at 150° C. for 20 min. Ethyl acetate (5 mL) was added and the mixture was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF and purified by prep.—HPLC to give the desired product. LCMS: m/z 380.2 (M+H)+.