Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](Br)([CH3:15])[CH:4]([C:17]#[N:18])[C:3]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.CB1OB(C)OB(C)O1>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>[NH2:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C:17]#[N:18])[C:5]([CH3:15])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[F:8]
Reactant: COC1=C(N)C(F)=C(c2ccccc2)C(C)(Br)C1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(N)c(F)c(-c2ccccc2)c(C)c1C#N
Temperature: 110 °C
Reaction time: 8 h

Procedure:
5-Amino-2-bromo-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-235) (2.02 g, 6.29 mmol), potassium carbonate (2.61 g, 18.87 mmol) and tetrakis(triphenylphosphine)palladium(0) (727 mg, 0.63 mmol) were dissolved in 10% water-containing 1,4-dioxane (50 ml), and at room temperature, trimethylboroxine (50 wt. % tetrahydrofuran solution, 1.90 ml, 7.55 mmol) was added. After stirring under nitrogen atmosphere at 110° C. for 8 hours and then cooling to room temperature, tetrakis(triphenylphosphine)palladium(0) (727 mg, 0.63 mmol) was added, followed by further stirring at 110° C. for 11 hours. After cooling to room temperature, the insoluble matter was separated by filtration, the filtrate was fractionated with ethyl acetate and saturated brine. The organic layer was separated, the aqueous layer was again extracted with ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].I[C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=[C:16]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=3)[C:24]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(NS(C)(=O)=O)cc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 2.6 %

Procedure:
A solution of 4-Methanesulfonylaminophenylboronic acid (24 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA40 (0.9 mg, 3% yield). ESI-MS (M+H)+ m/z calcd 347.1, found 347.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([CH:17]=[C:18]2[CH2:24][CH2:23][C:22](=[O:25])[O:21][C:19]2=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][N:1]([C:22]([CH2:23][CH2:24][C:18](=[CH:17][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[C:19]([OH:21])=[O:20])=[O:25])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=C1CCC(=Cc2cccc3ccccc23)C(=O)O1
Solvent: ClCCl
Product: O=C(O)C(=Cc1cccc2ccccc12)CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
2.85 ml (33 mmole) of morpholine were added to a solution of 7.5 g (30 mmole) of the 2-(1-naphthylmethylene)glutaric anhydride prepared as described above dissolved in 70 ml of methylene chloride, and the mixture was stirred at room temperature for 4 hours. It was then washed with a 5% w/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 10.0 g (30 mmole) of 4-morpholinocarbonyl-2-(1-naphthylmethylene)butyric acid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO[CH:15](OC)[CH2:16][CH:17](OC)OC.Cl>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:17]=[CH:16][CH:15]=[N:12]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COC(CC(OC)OC)OC
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2cccn2)cc1
Temperature: 0 °C
Yield: 79 %

Procedure:
To a solution of 4-(methylsulfonyl)phenylhydrazine (5.0 g, 26.8 mmol, 1.00 equiv) and 1,1,3,3-tetramethoxypropane (4.4 mL, 26.8, 1.0 equiv) in ethanol (37 mL) at rt was added concentrated HCl (2.8 mL). The resulting solution was heated at reflux for 1 hr, cooled to 0° C. and filtered to give 1-(4-methanesulfonyl-phenyl)-1H-pyrazole as a yellow solid (4.73 g, 79%). LCMS: (MH)+=223.1 (1.19 min).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][S:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCSCc1ccc(OCc2ccccc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCSCc1ccc(OCc2ccccc2F)cc1
Reaction time: 3 h

Procedure:
To a solution of Ethyl 3-((4-(2-fluorobenzyloxy)phenyl)-methylthio)propionate (Step C, 0.122 g, 0.35 mmol) in ethanol (5 ml) was added 1N NaOH (0.5 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified with 1M HCl and concentrated in vacuo to give white solid which was purified by flash chromatography on silica gel column (chloroform:methanol, 92.5:7.5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: C(OC([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C@:14]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:15]([S:17][C@@H:18]1[CH2:23][O:22][C@@H:21](/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=2[F:36])[O:20][CH2:19]1)[CH3:16])=[O:12])=O)C=C.C([SnH](CCCC)CCCC)CCC.CCCCCC>ClCCl.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>[OH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C@:14]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:15]([S:17][C@@H:18]1[CH2:23][O:22][C@@H:21](/[CH:24]=[CH:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][C:29]=2[F:36])[O:20][CH2:19]1)[CH3:16])=[O:12]
Reactant: C=CCOC(=O)OCCCC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)CCCO)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-Cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl 4-(allyloxycarbonyloxy)butyrate (352 mg, 4.94×10−4 mol) obtained from Example 11-(3) and bis(triphenylphosphine)dichloropalladium (2 mg) were dissolved in dichloromethane (3 ml). Tributyltin hydride (215 mg, 7.39×10−4 mol) was slowly added to the mixture at room temperature over a period of 5 minutes. After stirring at room temperature for 15 minutes further, hexane was added to the reaction mixture. The insoluble liberated oily material was separated by removing the supernatant liquid slowly. The insoluble residue was further washed twice with hexane. The oily residue was subjected to chromatography on a silica gel (15 g) column (eluent; ethyl acetate:hexane=3:1˜1:0) to afford the title compound (289 mg, 93% yield) as a colorless amorphous solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].Br[CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>O1CCCC1>[CH3:29][CH:22]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH2:20][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC(C)CCCC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCn1ccnc1-c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of 21.5 g. (0.14 mole) of 2-phenylimidazole in 60 ml. dry dimethylformamide and 300 ml. dry tetrahydrofuran under nitrogen atmosphere there is added at room temperature 9.0 g. (0.19 mole) of 50% sodium hydride/mineral oil suspension. The resulting mixture is stirred and heated to 50° C. for about 3 hours. After cooling to room temperature the resulting mixture is treated dropwise with a solution of 40.5 g. (0.18 mole) of (±)-1-bromo-3,7-dimethyloctane in dry tetrahydrofuran. The reaction mixture is stirred over night at room temperature and the resulting mixture is filtered and the residue washed with tetrahydrofuran. The combined filtrate is concentrated in vacuo to an oil, the oil is then dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oily product. Distillation gave (±)-1-(3,7-dimethyloctyl)-2-phenylimidazole; b.p. 150° to 157° C. at 0.2-0.16 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[C:25]([CH3:35])=[N:26][C:27]([N:30]5[CH:34]=[N:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC(OC(C)C)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[C:25]([CH3:35])=[N:26][C:27]([N:30]5[CH:34]=[N:33][CH:32]=[N:31]5)=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])[CH3:2]
Reactant: Cc1nc(-n2cncn2)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-n2cncn2)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A mixture of 4-[4-(2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 101; 50 mg, 0.105 mmol), trifluoroacetic acid (428 μL) and dichloromethane (2 mL) was stirred at room temperature for 30 min. The volatiles were evaporated under high vacuum and the residue was dissolved in dichloromethane (3 mL). Isopropyl chloroformate (1 M in toluene; 158 μL, 0.16 mmol) and triethylamine (95 μL, 0.68 mmol) were added and the mixture was stirred overnight at room temperature. 1 M aqueous sodium carbonate (6 mL) and dichloromethane (3 mL) were added, and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were evaporated and the residue was purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted three times with dichloromethane and the solvent was evaporated to give 4-[4-(2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (35 mg, 72%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.28 (d, 6H, J=6.0 Hz), 1.97-2.10 (m, 2H, J=10.9 Hz), 2.20-2.35 (m, 2H), 2.46 (s, 3H), 2.89-3.14 (m, 2H), 4.32-4.48 (m, 2H), 4.84-5.08 (m, 2H), 7.68 (d, 1H, J=8.8 Hz), 7.86 (d, 1H, J=8.8 Hz), 8.11 (s, 1H), 8.17 (s, 1H), 8.48 (s, 1H), 9.19 (s, 1H). Mass spectrum (ES) MH+=464. HRMS Calcd. for C22H26N9O3 (MH+): 464.2153. Found: 464.2151.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH:2]([F:12])[F:1])[N:9]=1
Reactant: OCc1cccc(OC(F)F)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (6-(difluoromethoxy)pyridin-2-yl)methanol (250 mg; 1.42 mmol) in anh. DCM (12 ml) was treated at rt with CBr4 (473 mg; 1.42 mmol), and with PPh3 (374 mg; 1.42 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 2-(bromomethyl)-6-(difluoromethoxy)pyridine as a yellow oil which was directly used for the next reaction. LC-MS (conditions D): tR=0.95 min.; [M+H]+: 237.82 g/mol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[C:16]([NH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:19])[CH:17]=[CH2:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:23]2[CH:22]=[C:21]([NH:20][C:16](=[O:19])[CH:17]=[CH2:18])[CH:26]=[CH:25][CH:24]=2)[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(Nc2ccccc2)c(Cl)n1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Nc2ccccc2)c1
Temperature: 90 °C

Procedure:
2,4-Dichloro-N-phenylpyrimidin-5-amine (80 mg, 0.333 mmol), (3-acrylamidophenyl)-boronic acid (70.0 mg, 0.367 mmol), triphenylphosphine (3.50 mg, 0.013 mmol) and palladium acetate (1.496 mg, 6.66 μmol) were dissolved in toluene (8 mL) and 1M sodium carbonate (70.6 mg, 0.666 mmol). The reaction mixture was heated for 24 h at 90° C., allowed to cool to room temperature, and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with water (10 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (20 mL), the combined organic layers were washed with brine (20 mL), and dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (20% ethyl acetate/hexane) to the title compound. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 7.66 (d, 1H, J=8.4 Hz), 7.49 (d, 1H, J=8.0 Hz), 7.38 (t, 1H, J=8.0 Hz), 7.30 (m, 2H), 7.09-7.03 (m, 3H), 6.39 (m, 1H), 6.20 (m, 1H), 6.09 (dd, 1H, J=10.4 and 17.2 Hz), 5.75 (d, 1H, J=10.4 Hz); ESI-MS: 351.1 [M+H]+.
Reaction SMILES: C1(=O)OC(=O)C2=CC=CC=C12.NC1N=CC(/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:35][N:23]([CH2:24][C:25]1[N:26]([CH3:34])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:22])[CH:20]=[CH2:19]
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Agent: O=C([O-])O
Agent: O=C1OC(=O)c2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Reaction time: 48 h
Yield: 32 %

Procedure:
Phthalic anhydride (0.81 g, 5.48 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.44 g, 1.37 mmole) and sodium bicarbonate (0.58 g, 6.85 mmole) in THF (70 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (10% MeOH/CHCl3) gave the title compound (0.10 g, 16%) as a light yellow solid: MS (ES) m/e 469 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[OH:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[OH:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: OC[C@@H]1CCCN1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCC[C@H]4CO)cc3c2)cc1

Procedure:
The product from Example 1C and 2-(S)-(hydroxymethyl)pyrrolidine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 347 (M+H)+;
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].Cl>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: c1csc(-c2cccs2)c1
Reaction time: 0.25 h

Procedure:
The Grignard reagent 2-thienylmagnesiumbromide (T-MgBr) was made from 2-bromothiophene (T-Br) in a standard fashion in a three-necked roundbottom flask with 9 gr (370 mmol) of magnesium and 45 gr (276 mmol) of T-Br in 120 ml diethylether. Initially, a small amount of ether and a few milliliters of T-Br were added to the magnesium and the reaction was initiated by crushing some of the magnesium with a glass rod. The reaction was maintained by adding the rest of the T-Br and the ether in small portions from a dropping funnel. The Grignard reagent was refluxed for an additional half hour. In a separate, three-necked roundbottom flask was placed 120 ml of ether, 37.5 gr (230 mmol) of T-Br and 180 mg (0.33 mmol) of Ni(dppp)Cl2. The Grignard reagent was then added slowly, under a steady outflow of argon. The mixture was refluxed and stirred for 3 hours and 15 minutes and poured on ice with dilute hydrochloric acid. The product was then extracted with ether. After drying the ether layer on anhydrous magnesium sulphate, the organic layer was filtrated and the ether evaporated. The residue was redissolved in warm methanol. Some water was added to the methanol, while still warm, until a yellow precipitate started to form. The mixture was then put overnight at 4° C. to form yellow crystals. After filtration and drying in vacuo the product was molten and poured in a dry storage vessel. Yield: yellow crystals of T2, 25.16 gr (152 mmol, 66%). M.p.: 31° C. (litt.: 33). Elemental analysis: found% (theory%) C 57.54 (57.79), H 3.61 (3.64), S 38.0 (38.6). 1H-NMR (300 MHz, CDCl3,): ∂=7.21 (2H, dd, H=5.0 and 1.2 Hz), ∂=7.01 (2H, dd, J=5.0 and 3.6 Hz), ∂=7.18 (2H, dd, J=1.2 and 3.6 Hz). M/z (Mass peak from mass spectrometry): 166 D (M.W.=166), small impurity at 248 D, probably 2,2':5',2"-terthiophene (M.W.=248).
Reaction SMILES: [CH2:1]([CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:12]Br>O>[Br:12][CH2:10][C:9](=[O:11])[CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: BrBr
Solvent: O
Product: CCOC(=O)C(CC)C(=O)CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-ethyl-3-oxobutanoate (5.17 g, 32.7 mmol) in water (10 mL) at 0° C. was added bromine (1.684 mL, 32.7 mmol) dropwise over 2 h. The resulting solution was stirred at rt for 16 h. The mixture was extracted with ethyl acetate (100 mL) and the organic phase was dried over sodium sulfate and concentrated to give ethyl 4-bromo-2-ethyl-3-oxobutanoate. 1HNMR (500 MHz, CDCl3), δ4.327-4.284 (m, 2H), 2.412 (s, 2H), 2.320-2.212 (q, 2H), 1.338-10309 (m, 3H), 1.042-1.013 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[CH:38][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:28]4=[O:37])[CH2:23][CH2:22]3)=[O:20])=[C:17]([O:40][CH3:41])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(OCC)(=O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[CH:38][C:18]([C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:28]4=[O:37])[CH2:25][CH2:26]3)=[O:20])=[C:17]([O:40][CH3:41])[CH:16]=2)[CH2:10][CH2:9]1
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Solvent: CCOC(C)=O
Product: COc1cc(OC2CCNCC2)ccc1C(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 250 mL of dry ethyl acetate under N2 was added 1-(1-(4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (1.5 gm, 2.65 mmol) from Example 189 and the solution was cooled to 0° C. in an ice-water bath. Anhydrous HCl gas was bubbled into the solution at 0° C. until for 30 min. The saturated solution was stirred for an additional 30 min at 0° C. then the ice bath was removed and N2 was bubbled through the mixture to remove excess HCl. Addition of hexane caused precipitation of the HCl salt. The solid was dried in vacuo to remove solvent and then was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with water (2×) and brine, and was dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:13]([OH:15])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:63][C@@H:64]([CH2:78][C:79]1[CH:84]=[C:83]([F:85])[CH:82]=[C:81]([F:86])[CH:80]=1)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=1.[ClH:87]>C(Cl)Cl.CO.C(OCC)C>[ClH:87].[ClH:87].[F:85][C:83]1[CH:84]=[C:79]([CH:80]=[C:81]([F:86])[CH:82]=1)[CH2:78][C@H:64]([NH:63][C:13](=[O:15])[C:12]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:10]([CH2:9][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH2:3][O:2][CH3:1])[CH:11]=1)[C@H:65]([OH:77])[CH2:66][NH:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][CH3:76])[CH:70]=1
Reactant: COC[C@@H]1CCCN1Cc1cc(C)cc(C(=O)O)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOCC
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(CN3CCC[C@H]3COC)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}-5-methylbenzoic acid (110 mg, 0.42 mmol) in methylene chloride (3 mL) is added HBTU (240 mg, 0.63 mmol), HOBt (85 mg, 0.63 mmol), and N,N -diisopropylethylamine (0.212 mL, 1.26 mmol), followed by (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of Example SP-272 (171 mg, 0.42 mmol). The reaction mixture is stirred for 12 h at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% methanol/chloroform) affords a clear oil, which is dissolved in methanol (2 mL). To this solution is added hydrochloric acid (5 mL, 4 N dioxane, 20 mmol), and the reaction mixture is stirred for 1 h at room temperature. The reaction mixture is then diluted with ethyl ether (10 mL)). The precipitate that is formed was collected by filtration to provide the title compound. ESI MS m/z 580.4 [M+H]+.