Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](CC)(CC)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][O:14][CH3:15])=[CH:8][C:7]=1[CH3:16])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][O:14][CH3:15])=[CH:8][C:7]=1[CH3:16])#[CH:4]
Reactant: CC[Si](C#Cc1ccc(OCOC)cc1C)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1ccc(OCOC)cc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of triethyl((4-(methoxymethoxy)-2-methylphenyl)ethynyl)silane (1.0 equiv.) at 0° C. was slowly added tetrabutylammonium fluoride (1M solution in THF, 0.20 equiv.). At this point, the ice-bath was removed and the reaction mixture was allowed to stir at room temperature for 45 minutes. The reaction mixture was then passed through a pad of silica (packed with hexane) and eluted with 20% EtOAc in Hexanes to remove insoluble salts. The crude product was then purified by Combiflash using 0-10% EtOAc in Hexanes to give 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (6-8) as a slightly brown liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[N:5][N:4]=[N:3]1.O.NN>C(O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH2:11])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1nnnc1SCCCN
Yield: 50 %

Procedure:
1-Methyl-5-[3-(phthalimido)propylthio]-1,2,3,4-tetrazole (3.5 g) is dissolved in ethanol (50 ml). To the mixture is added hydrazine hydrate (85%, 2 g) and the mixture is refluxed for 1 hour. After cooling, the precipitate is filtered off and ethanol is distilled off. The residue is dissolved in ethyl acetate and dried over magnesium sulfate. Ethyl acetate is distilled off, and then the residue is purified by column chromatography (Alminium oxide 60, made by Merk & Co.), followed by eluting with chloroform to give 1-Methyl-5-(3-aminopropylthio)-1,2,3,4-tetrazole (1 g), colorless liquid, nD21.5 =1.5384.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([NH:36][C:37]1([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:36][C:37]1([C:43]([O:45][CH3:46])=[O:44])[CH2:42][CH2:41][N:40]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[N:9]=3)[N:7]=2)[CH2:39][CH2:38]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Yield: 67 %

Procedure:
Following the procedures of Example 144, and starting with 3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and methyl 4-(tert-butoxycarbonylamino)piperidine-4-carboxylate were reacted and purified via silica gel chromatography using a gradient of EtOAc in heptane to afford 241 mg (67%) of Methyl 4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylate. ESI MS m/z 614.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.ClCCl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1n[nH]c2ccncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Brc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccncc12
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
To a solution of 4.69 g of 3-bromo-1H-pyrazolo[4,3-c]pyridine in 72 mL of dimethylformamide was added 1.42 g of sodium hydride at room temperature and stirred for 15 minutes, and then added with 6.6 g of trityl chloride and stirred at this temperature for a day. The solution was diluted with dichloromethane, and the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The precipitated crystals were washed with ethyl acetate, the filtrate was evaporated, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:3), an the resultant product was combined with the above crystals, to afford 5.28 g of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8](F)=[C:7]([F:14])[C:6]=1[F:15])[CH3:2].N([O-])=[O:18].[Na+].Cl>CS(C)=O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([OH:18])=[C:7]([F:14])[C:6]=1[F:15])[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(F)c(F)c(O)c(F)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
25 parts by mass of pentafluorobenzoic acid ethyl ester and 21.6 parts by mass of NaNO2 were mixed in 200 parts by mass of DMSO, and the mixture was heated. After the mixture was stirred at 50° C. for 2 hours, it was cooled to room temperature, and 520 parts by mass of ice water was added thereto. Concentrated hydrochloric acid was added to the mixture to adjust pH to 2, and the mixture was then heated to 100° C. followed by stirring for 30 minutes. The mixture was cooled to room temperature followed by extraction with ether. Organic layers were washed with water and dried with anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was washed with hexane to obtain 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid ethyl ester. 200 parts by mass of the obtained 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid ethyl ester was dissolved in 500 parts by mass of DMF, and an equivalent amount of NaH was gradually added thereto followed by stirring for 1 hour. 20 parts by mass of tetrabutylammonium iodide was added thereto, 180 parts by mass of 2-chloroethyl vinyl ether was then added thereto, and the thus obtained mixture was stirred at 100° C. for 10 hours. After cooling to room temperature, the reaction solution was added to 4,600 parts by mass of ice water followed by extraction with ethyl acetate. Organic layers were washed with water and dried with anhydrous magnesium sulfate. The solvent was removed, and the residue was subjected to silica gel column chromatography to obtain the objective polymeric compound. The NMR of the thus obtained polymeric compound is shown in FIG. 2.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39]>>[CH3:36][O:37][C:38]([C:40]1[CH:45]=[C:44]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][C:28](=[O:33])[NH:29][S:30]5(=[O:32])=[O:31])=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)[CH:43]=[CH:42][CH:41]=1)=[O:39]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: COC(=O)c1cccc(B(O)O)c1
Product: COC(=O)c1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)c1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure G using 3-methoxycarbonylphenylboronic acid (108 mg, 0.6 mmol) to give 4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:41]>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=5)[C:36](=[O:41])[CH2:37]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C1CNCCN1c1ccccn1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(c4ccccn4)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 16 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1-(pyridin-2-yl)piperazin-2-one dihydrochloride salt (109 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 16 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 1.0 min (conditions 4), MH+=486).
Reaction SMILES: [F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:3]1.O.NN>C(O)C.[Ni]>[F:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(OCCCN2CCC(F)C2)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCCCN2CCC(F)C2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of crude 3-Fluoro-1-[3-(4-nitro-phenoxy)-propyl]-pyrrolidine (6.316 g, ˜24 mmol) was dissolved in absolute ethanol (180 mL) and to this solution was added hydrazine monohydrate (˜7.9 mL) followed by the addition of a small portion of Raney nickel (˜1 mL). The reaction mixture was heated to 50° C. with stirring for ˜2 h at which point all gas evolution had ceased. The reaction mixture was filtered through celite to remove the Raney nickel. The filtrate was concentrated in vacuo to give 4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamine as a brown oil which was subjected to flash silica gel chromatography (CHCl3 to CHCl3:MeOH, 1:40 gradient eluant). Pure 4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamine was isolated as a reddish oil (4.033 g, 79%).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].C(N(CC)CC)C>ClCCl>[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:3][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:11][CH:10]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a 0° solution of methyl amino{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate dihydrochloride (1.67 g; 4.55 mmol) in dichloromethane (10 mL) was added 4-but-2-ynyloxy-benzenesufonyl chloride followed by triethyl amine was dropped in. The mixture was stirred at room temperature overnight and then diluted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified using column chromatography on silica gel eluting with ethyl acetate to obtain 2.52 g of methyl ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate as an oil. Yield 92.6%. Electrospray Mass Spec 487.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:24][C@@H:25]1[CH2:29][CH2:28][O:27][CH2:26]1.Cl.CN(C)CCCN=C=NCC.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O.C(Cl)Cl>[CH3:42][O:43][C:44]1[CH:45]=[CH:46][C:47]([S:50]([NH:53][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:24][C@@H:25]5[CH2:29][CH2:28][O:27][CH2:26]5)[CH:5]=4)=[CH:10][CH:11]=[N:12]3)=[CH:23][CH:22]=2)(=[O:52])=[O:51])=[CH:48][CH:49]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(-c2ccnn2Cc2ccc(C(=O)O)cc2)cc1O[C@@H]1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(S(=O)(=O)NC(=O)c2ccc(Cn3nccc3-c3ccc(OC)c(O[C@@H]4CCOC4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Into a vial was added 4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzoic acid (50.0 mg, 0.127 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (30.2 mg, 0.158 mmol), 4-dimethylaminopyridine (19.3 mg, 0.158 mmol), 4-methoxybenzenesulphonamide (29.5 mg, 0.158 mmol) and 2 mL of methylene chloride. The reaction was stirred overnight at room temperature, poured into 10 mL of water and 10 mL of ethyl acetate and the pH of the aqueous layer was adjusted to pH˜6 by adding saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate, filtered and approximately 1 g of silica gel was added and the mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient elution going from 0% to 10% methanol in dichloromethane over 20 minutes to give N-[(4-methoxyphenyl)sulfonyl]-4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzamide (53 mg, 74%) as a yellow foam. LC/MS (EI) tR 5.22 (Method C), m/z 564.2 (M++1). 1H NMR (CDCl3 300 MHz) δ 1.8-2.0 (m, 2H); 2.6 (br s, 2H); 3.6 (m, 2H); 3.8 (m, 2H); 3.9 (s, 3H); 4.4 (br s, 1H); 5.2 (s, 2H); 6.3 (s, 1H); 6.4 (s, 1H); 6.9 (m, 3H); 7.2-7.6 (m, 3H); 7.7 (t, 2H); 7.8 (d, 2H); 7.9 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][Br:11]
Reactant: Cc1c(Cl)cc(Cl)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Clc1cc(Cl)c(CBr)c(Br)c1
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
Stir slowly, an intimate mixture of 220 g of 2-bromo-4,6-dichlorotoluene, 167 g of N-bromosuccinimide and 1 g of benzoyl peroxide in a flask (equipped with a condenser and stirrer) immersed in an 145° C. oil bath. After 10-20 min a vigorous eruption occurs and the mixture liquifies. Remove the oil bath and stir for an additional 5 min. Add 1.5 L of CCl4 slowly through the condenser. Cool the mixture and suction filter the resulting reaction mixture. Wash the filtrate with 5% aqueous sodium thiosulfate, dry over anhydrous K2CO3, filter and evaporate to a residue. Fractionally distill the residue to give 134 g of 2-bromo-4,6-dichlorobenzyl bromide, bp 94°-97° C. (0.2 tor).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.NO.F[P-](F)(F)(F)(F)F.[N:34]1([O:43][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH:34][OH:43])=[O:14])=[CH:11][N:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2cc(C(=O)O)c(-c3ccc(Br)cc3)n2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1ccc(-n2cc(C(=O)NO)c(-c3ccc(Br)cc3)n2)cc1
Yield: 3.2 %

Procedure:
A solution of 3-(4-bromophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid 65 (0.30 g, 0.804 mmol), hydroxylamine hydrochloride (0.112 g, 1.608 mmol), BOP (0.427 g, 0.965 mmol) and triethylamine (0.336 mLs, 2.412 mmol) in pyridine (10 mLs) was stirred at room temperature for 2 h. All solvents were then removed under reduced pressure, and the residue diluted with brine and aq. HCl until pH=1. Following extraction with EtOAc, the combined organic extracts were dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel using 50-100% EtOAc/hexanes as the eluent to afford title compound 66 (10 mgs, 3% yield) as a light orange solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:14]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](O)c1nnc2ccc(Cl)nn12
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](O)c1nnc2ccc(-c3ccccc3)nn12
Temperature: 85 °C

Procedure:
A suspension of (1S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanol (0.289 mmol, 1 eq), phenylboronic acid (0.650 mmol, 2.3 eq), Pd(PPh3)4 (45.9 mg, 0.0397 mmol, 14 mol %), and K2CO3 (132.0 mg, 0.9551 mmol, 3.3 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated conventionally at 85° C. for 1 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by pTLC [Silicycle, 1000 μM, 20×20 plate], which required two developments in a 3% MeOH in EtOAc solvent system. 1H NMR (400 MHz, CDCl3): δ=1.93 (d, J=6.6 Hz, 3H), 3.00 (br s, 1H), 5.64 (q, J=6.6 Hz, 1H), 7.53-7.61 (m, 3H), 7.66 (d, J=9.9 Hz, 1H), 7.95-8.01 (m, 2H), 8.25 (d, J=9.9 Hz, 1H). MS (ES+): m/z 241.08 (100) [MH+]. HPLC: tR=2.51 min (ZQ3, polar—5 min).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]1([CH3:43])[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[C@H:17]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[NH2:8][C:5]1[N:4]=[CH:3][C:2]([C:25]2[CH:24]=[CH:23][C:22]([N:18]3[C@@H:17]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:16]([CH3:15])([CH3:43])[O:20][C:19]3=[O:21])=[CH:27][CH:26]=2)=[CH:7][N:6]=1
Reactant: Nc1ncc(I)cn1
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)nc3)cc2)[C@H]1c1ccccc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
5-Iodopyrimidin-2-amine (84 mg, 0.381 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.), sodium carbonate (2M, 254 μL, 0.509 mmol), (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (100 mg, 0.254 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium (II) (20.76 mg, 0.025 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) were combined in dioxane (848 μL) and stirred at 130° C. for 2 hours. LC-MS indicated complete conversion to the desired product. The reaction mixture was passed through a syringe filter, and the material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-3-(4-(2-aminopyrimidin-5-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 2H), 7.53 (s, 4H), 7.34-7.41 (m, 2H), 7.22-7.33 (m, 3H), 6.70 (s, 2H), 5.47 (s, 1H), 1.64 (s, 3H), 0.91 (s, 3H). m/z (ESI) 361.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([NH:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)[CH:17]=[CH2:16]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 4-benzyloxyaniline (3.0 g), allyl bromide (1.27 mL), potassium carbonate (4.2 g) and dimethylformamide (15 mL) was heated at 80° C. for 3 hours. After cooling, the reaction solution was filtered and concentrated. The residue was purified by MPLC. The product with the molecular weight of 239.32 (C16H17NO); MS (ESI):240 ([M+H]+), was obtained in this way.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH3:20].O1CCCC1>O1CCCC1>[Cl:11][C:4]1[N:3]=[C:2]([N:19]([CH3:20])[CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (1.9 g, 10 mmole) and potassium carbonate (1.66 g, 12 mmole) in 30 ml of tetrahydrofuran was stirred at 0° C. for 5 min. A solution of dimethylamine/tetrahydrofuran (2 M, 6 ml, 12 mmole) was added dropwise to the reaction mixture over 40 min. After stirring for 5 min at 0° C., the mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered and the filtrate was collected and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with 87% hexane: 13% ethyl acetate to give
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:10]([NH2:12])[CH3:11].C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:10]([NH:12][C:42]([C:38]1[CH:37]=[C:36]2[C:41](=[CH:40][CH:39]=1)[N:33]([CH2:32][C:29]1[CH:28]=[CH:27][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:31][CH:30]=1)[C:34]([CH3:46])=[C:35]2[CH3:45])=[O:43])[CH3:11]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(F)c1F
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(F)c3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2,3-difluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 539 [M+H]+.