Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].O.[Co:11]=O>>[Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+:6].[Na+:6].[Na+:6].[Co:11]
Reactant: O=[Co]
Agent: [Na+]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: O
Product: [Co]

Procedure:
A paste is prepared from 149.5 g. of sodium silicate solution (38.8% by weight aqueous solution of 1 Na2O:3.25 SiO2) and 300 g. of cobalt oxide hydrate (61% cobalt) and extruded into 1/8 inch extrusions. The extrusions are dried at room temperature and then slowly dried further in a tube furnace. The dried material is reduced in hydrogen at 350° C. to provide a catalyst having a bulk density of 28 lbs./cu. ft. and a crushing strength of 2 pounds.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](OB(O)O)[CH:12]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OB(O)Oc1cccnc1
Reactant: N#Cc1cc(Br)ccc1I
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: Cc1ccccc1
Product: N#Cc1cc(Br)ccc1-c1cccnc1
Temperature: 100 °C

Procedure:
5-Bromo-2-iodobenzonitrile and 3-pyridylboric acid were dissolved in a mixture solution of aqueous 2 M sodium carbonate solution and toluene, then tetrakis(triphenylphosphine)palladium was added thereto, and the mixture was heated, stirred with heating in an argon atmosphere at 100° C. for 3 days to obtain 5-bromo-2-pyridin-3-ylbenzonitrile. EI: 258, 260.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([C:16]([OH:18])=O)=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.O.[NH3:26].[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([C:16](=[O:18])[NH2:26])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)OCc2ccccc2)o1
Reactant: N
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
170 mg of furan-2,5-dicarboxylic acid monobenzyl ester was dissolved in 5 mL of tetrahydrofuran, and added with 144 μl of triethylamine. After cooling to 0° C., 72.3 μl of ethyl chloroformate was added dropwise and stirred at this temperature for 30 minutes. 1 mL of concentrated ammonia water was added and stirred at room temperature for 10 minutes, and then aqueous ammonium chloride was added to stop the reaction. After extracting the aqueous phase with ethyl acetate, the organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 185 mg of the title compound as white crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([N:22]3[CH:26]=[C:25]([CH:27]=[O:28])[N:24]=[N:23]3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].Br[Mg][CH3:31].CCOCC.[NH4+].[Cl-]>C1COCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([N:22]3[CH:26]=[C:25]([CH:27]([OH:28])[CH3:31])[N:24]=[N:23]3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-n3cc(C=O)nn3)cc(-c3ccccn3)c2s1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-n3cc(C(C)O)nn3)cc(-c3ccccn3)c2s1
Temperature: 40 °C
Yield: 4 %

Procedure:
To a suspension of iv (40 mg, 0.1 mmol) in THF (0.7 mL) was added bromo(methyl)magnesium 3M in Et2O (0.250 mL, 0.1 mmol) and the mixture heated at 40° C. for 1 h. NH4Cl (sat. aq.) was added and the mixture extracted with DCM:IPA (5:1). The organic layers were washed with brine and then concentrated in vacuo to give a crude product that was purified by reverse phase SP4 (ACN gradient in H2O) affording Compound 9 (1.9 mg, 4%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>C(Cl)Cl>[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: COC[C@H]1CCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H]1CCCN1Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. (R)-2-(Methoxymethyl)pyrrolidine (380 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.37 (s, 1H), 4.11 (d, J=13 Hz, 1H), 3.90 (d, J=6 Hz, 2H), 3.41 (m, 2H), 3.34 (m, 3H), 2.89 (m, 1H), 2.71 (m, 1H), 2.38 (s, 3H), 2.19 (m, 1H), 1.93 (m, 2H), 1.54 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].I[CH3:14]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (15.2 g, 99 mmol) in N,N-Dimethylformamide (DMF) (100 mL) at 0 C was added 60% NaH (5.15 g, 129 mmol) portionwise. After H2 bubbling stopped, iodomethane (6.81 mL, 109 mmol) was added dropwise, and then the reaction mixture was allowed to warm to room temperature. After 3 hours, the reaction mixture was poured slowly onto water (˜800 mL; Caution: H2 evolution due to quenching excess NaH). The resulting solid was filtered and washed with water followed by hexanes to afford 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (12.2 g) as an off-white solid.
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[NH:15][C:16](=[O:24])[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22]Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:38]=[N+:39]=[N-:40].[Na+].[I-].[Na+]>CN(C=O)C>[C:32]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[NH:15][C:16](=[O:24])[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22][N:38]=[N+:39]=[N-:40])=[O:12])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1NC(COCCCl)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
195 mg (0.362 mmol) of 6-(2-chloroethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (3,3-diphenylpropyl)amide was dissolved in 10 ml of DMF. 35.3 mg (0.543 mmol) of sodium azide and 54.3 mg (0.362 mmol) of sodium iodide were added to the obtained solution, and they were stirred at 60° C. for 2 days. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1) to obtain the title compound.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][C:11]([CH3:43])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:32]=[C:31]3[C:26]([C:27]([C:34](=[O:42])[NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:28][C:29]([CH3:33])=[N:30]3)=[CH:25][CH:24]=2)=[CH:19][N:18]=1)[C:12](O)=[O:13].Br.[N:45]1[NH:46][N:47]=[N:48][C:49]=1[CH2:50][NH2:51].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[N:45]1[NH:46][N:47]=[N:48][C:49]=1[CH2:50][NH:51][C:12](=[O:13])[C:11]([CH3:10])([CH3:43])[CH2:15][O:16][C:17]1[N:18]=[CH:19][C:20]([C:23]2[CH:32]=[C:31]3[C:26]([C:27]([C:34]([NH:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:42])=[CH:28][C:29]([CH3:33])=[N:30]3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: NCc1nn[nH]n1
Reactant: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)O)nc3)cc2n1
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)NCc4nn[nH]n4)nc3)cc2n1
Reaction time: 8 h
Yield: 65 %

Procedure:
N-Ethyl-N,N-diisopropylamine (50.0 μL, 0.300 mmol) was added at room temperature to a solution of 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoic acid B-17 (45.5 mg, 0.10 mmol), (2H-tetrazol-5-yl)methanamine hydrobromide (27.7 mg, 0.154 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (64.0 mg, 0.123 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give 7-(6-(3-((2H-tetrazol-5-yl)methylamino)-2,2-dimethyl-3-oxopropoxy)pyridin-3-yl)-2-methyl-N-phenylquinoline-4-carboxamide B-24 (34.9 mg, Yield=65%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 6H), 2.77 (s, 3H), 3.71-3.74 (m, 2H), 4.75 (d, J=5.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 1H), 7.23-7.30 (m, 2H), 7.45 (t, J=6.5 Hz, 3H), 7.87 (d, J=8.0 Hz, 2H), 7.87 (d, J=8.5 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.47 (s, 1H), 8.45 (d, J=9.5 Hz, 1H), 8.59 (s, 1H); MS (ESI) [M+1]+ 537.
Reaction SMILES: C(OC([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.[CH2:42]([O:44][C:45](C1CCNCC1)=[O:46])[CH3:43]>>[CH2:42]([O:44][C:45]([CH:7]1[CH2:6][CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:16][CH:17]=2)[CH2:8]1)=[O:46])[CH3:43]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Product: CCOC(=O)C1CCCN(c2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)C1

Procedure:
(2S,4R)-1-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-3-carboxylic acid ethyl ester was prepared following the procedure for (2S,4R)-1-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-4-carboxylic acid ethyl ester, substituting piperidine-3-carboxylic acid ethyl ester for piperidine-4-carboxylic acid ethyl ester to yield the product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc3c(N4CCOCC4)nc(-c4cccc5[nH]ncc45)nc3s2)CC1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to 1-methylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 34.5 mg of 122. MS (Q1) 464.2 (M)+.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Br:6].C(O[CH:12]1[NH:15][C:14](=[O:16])[CH2:13]1)(=O)C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC=CC=1>[Br:1][CH2:2][CH:3]([O:7][CH:12]1[NH:15][C:14](=[O:16])[CH2:13]1)[CH2:4][CH2:5][Br:6]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: OC(CBr)CCBr
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CC(OC(CBr)CCBr)N1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 1,4-dibromo-2-butanol (5.8 ml), 4-Acetoxyazetidinone (6.46 g), Palladium acetate (450 mg), Triethylamine (7 ml) and dry Benzene (75 ml) was stirred at room temperature under nitrogen for 23 hrs. Resulting solid was filtered off and filtrate was washed with water, brine and then dried over Magnesium sulfate. The residual oil, after evaporation, was purified by column chromatography using Hexane and Ethyl acetate (2:1) and the title compound was obtained. Yield: 5.88 g (78%). NMR (CDCl3): 2.05-2.17 (2H, m), 2.87-3.27 (2H, m), 3.42-3.60 (4H, m), 3.90-4.02 (1H, m), 5.23-5.33 (1H, m), 6.53 (1H, br, s). IR (Neat), cm-1 : 3260, 1771.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:16][Si:15]([CH3:18])([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1ccc(Nc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Aniline (127.5 m mol)), (4-bromophenyl)trimethylsilane (102 m mol)), tris(dibenzylideneaceton)dipalladium(O) (1.53 m mol)), BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.06 m mol)), and sodium-tert-butoxide (132.6 m mol)) were dissolved in toluene (100 ml) in a 250 ml tri-neck-round bottom flask and then stirred in a bath of 100° C. for 24 hours. After the reaction was terminated, the toluene was removed from the solution. After extraction was performed on the solution using dichloromethane and water, the resulting solution was reduced in pressure and distilled. After a silica gel column chromatography, the solvent was reduced in pressure and distilled, thereby obtaining 4-(trimethylsilyl)-N-phenylbenzeneamine liquid having 0.3 g.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].C([Li])CCC.CCCCCC.C[O:23][B:24](OC)[O:25]C>C1COCC1>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]([F:10])=[C:2]([B:24]([OH:25])[OH:23])[CH:7]=1)[CH3:9]
Reactant: CCc1ccc(F)c(Br)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(F)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To 84B (550 mg, 2.3 mmol) in THF (10 mL) was added 1.6 M n-butyllithium in hexane (2.2 ml, 3.5 mmol) at −78° C. After stirring for 1 h, trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. The reaction mixture was warmed up to rt overnight. It was then quenched by 1.0 N HCl (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 255 mg white solid of 84C. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.15-1.27 (m, 3H) 2.61 (q, J=7.76 Hz, 2H) 6.94 (t, J=8.57 Hz, 1H) 7.17-7.27 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1>C(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: Fc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: CCO
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccc(Cl)cc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4,6-dichloro-2-(4-fluorophenyl)quinoline and isonipecotamide as starting materials. It was obtained as white needles, mp 250°-252° dec on recrystallization from ethanol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.[OH:23][C:24]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:23][C:24]2([C:27]([O:29][CH3:30])=[O:28])[CH:26]=[CH:25]2)=[O:21])=[CH:15][CH:14]=1
Reactant: COC(=O)C1(O)CC1
Reactant: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)C=C1
Reaction time: 14 h
Yield: 78.3 %

Procedure:
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 6.557 mmol) in DCM (50 mL), DMAP (1.4 g, 13.114 mmol) was added followed by methyl 1-hydroxycyclopropanecarboxylate (1.1 g, 9.836 mmol) under a nitrogen atmosphere at RT and the mixture was stirred for 14 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with a saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford crude methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropenecarboxylate (2.0 g,) as a solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[CH:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].CN(C)C=O.Cl[CH:39]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42][CH2:43][CH3:44])=[O:41].[F-].[K+]>C(OCC)(=O)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[CH:23]([C:24]([O:26][CH:39]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[O:25])[CH2:22][C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(Cl)OC(=O)C(C)(C)C
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1N=C(c2ccccc2)CC1C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OC(=O)C1CC(c2ccccc2)=NN1C(=O)CP(=O)(CCCCc1ccccc1)OCC)OC(=O)C(C)(C)C
Reaction time: 48 h

Procedure:
A solution of 2.0 g. of (+)-4,5-dihydro-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, from Example 1(c), in 30 ml. of dry dimethylformamide under argon at room temperature is treated with 1.2 g. of ethyl 2-chloro-2-pivaloyloxyacetate, from part (a), and 0.58 g. of anhydrous potassium fluoride. After stirring for 48 hours the mixture is diluted with ethyl acetate and washed with water (3×). The organic fraction is dried (MgSO4) and concentrated in vacuo to give crude product. Flash chromatography on silica gel and elution with acetone/hexane (2:1) gives homogeneous (+)-4,5-dihydro-1-[[ethoxy(4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, 1-(2,2-dimethyl-1-oxopropoxy)-2-ethoxy-2-oxoethyl ester as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:39]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([NH2:39])=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (365 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (158 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg), and 25% aqueous ammonia (2.7 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and crystallized from acetonitrile. The obtained crystals were recrystallized from ethyl acetate and diethyl ether to give the title compound (127 mg, yield 35%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClC(Cl)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]([NH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:20])[CH3:19]
Reactant: COC(=O)c1ncccc1N
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)CC(=O)Nc1cccnc1C(=O)OC
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-aminopicolinate (1.8 mL, 13.80 mmol) in dichloroethane (60 mL) was added ethyl 3-chloro-3-oxopropanoate (2.08 g, 13.80 mmol). The reaction was heated at reflux for 45 min. After this time the reaction was cooled to rt and partitioned between DCM (60 mL) and NaHCO3 (satd aq. solution, 30 mL). The separated aq. layer was extracted with DCM (40 mL) and the combined organic layer were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give methyl 3-(3-ethoxy-3-oxopropanamido)picolinate: LC-MS (ESI) m/z 267.1 [M+H]+.