Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](B(O)O)=[CH:32]1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:33]2[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[S:31][CH:32]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: OB(O)c1csc2ccccc12
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2csc3ccccc23)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 1-benzothiophen-3-yl-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 555.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:14]1[CH2:15][C@@H:16]([CH3:19])[CH2:17][CH2:18][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][N:10]=1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc(Br)cc3)[nH]2)NC1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)CC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of (2S,5S)-2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine (400 mg, 1.25 mmol) and (S)-2-methoxycarbonylamino-3-methyl-butyric acid (219 mg, 1.25 mmol), HATU (475 mg, 1.25 mmol), and DIPEA (485 mg, 3.75 mmol) in DCM (20 mL) was stirred at RT overnight. The reaction mixture was concentrated and purified by thin layer chromatography (1:1 petroleum ether:EtOAc) to provide the title intermediate (550 mg, 92% yield). (m/z): [M+H]+ calcd for C22H28BrN4O3 476.13, 478.13. found 478.7.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.O>[CH3:10][C:4]1[S:3][C:2]2[NH:1][C:12](=[O:14])[NH:9][C:7](=[O:8])[C:6]=2[CH:5]=1
Reactant: Cc1cc(C(N)=O)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(=O)[nH]c(=O)[nH]c2s1
Temperature: 25 °C

Procedure:
To a stirred solution of Step 2 intermediate (16.5 g, 94.82 mmol) in dry THF (316 ml) was added triphosgene (14.07 g, 47.41 mmol) and the mixture was refluxed for overnight under nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water (200 ml) under stirring. The solid precipitated out was collected by filtration and dried to give 13.8 g of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 2.36 (s, 3H), 6.82 (s, 1H), 11.07 (br. s, 1H), 11.79 (br. s, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([CH3:19])=[N:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>CO.CC(=O)OCC.[Pd]>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][C:11]=2[CH3:19])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Cc1nc([N+](=O)[O-])ccc1N1CCN(C(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(N)ccc1N1CCN(C(C)C)CC1
Yield: 99.8 %

Procedure:
Stir 1-isopropyl-4-(2-methyl-6-nitro-pyridin-3-yl)-piperazine (2.52 g) and palladium over carbon 10% (600 mg) in methanol (38 mL) and EA (38 mL) under H2 (balloon) overnight. Filter over a celite pad and remove the solvent under vacuum. Purify by silica gel column chromatography eluting with DCM/methanol (0-10%) to afford 2.23 g of the title compound. MS (ES+): m/z=143 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]3[C:15]=2[NH:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC(=O)OCC.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.[Cu]I>[C:25]1([C:31]#[C:32][C:2]2[S:6][C:5]([C:7]3[N:8]=[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]4[C:15]=3[NH:16][C:17]([CH3:23])([CH3:24])[CH2:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2ccccn12
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2ccccn12
Temperature: 50 °C
Reaction time: 48 h
Yield: 16.2 %

Procedure:
324 mg (0.80 mmol) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine were dissolved together with 0.11 ml (0.96 mmol) of phenylacetylene, 14 mg (0.02 mmol) of bis(triphenylphosphine)-palladium(II) chloride and 7 mg (0.04 mmol) of copper(I) iodide in DMF (6 ml) After addition of 1.1 ml (8.0 mmol) of triethylamine, the mixture was stirred at 50° C. for 2 d. The reaction solution was then diluted with EA and combined with a sat. aq. sodium carbonate solution. The phases were separated and the aqueous phase extracted with EA. The combined organic phases were washed 2× with a sat. aq. sodium carbonate solution and 2× with a sat. aq. common salt solution and dried over magnesium sulfate. After filtration and removal of the solvents under a vacuum, column chromatography (EA/DIPE/DCM 3:3:4) was carried out with the group, after which 54 mg (0.13 mmol, 16% of theoretical) of [2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine were obtained.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].[CH3:12]NCCC[Si](OC)(OC)OC.C[Si](OC(=O)C)(OC(=O)C)OC(=O)C.C[Si](OCC)(OCC)OCC.C[Si](OC)(OC)OC>>[SH:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CNCCC[Si](OC)(OC)OC
Reactant: CO[Si](CCCS)(OC)OC
Agent: CC(=O)O[Si](C)(OC(C)=O)OC(C)=O
Agent: CCO[Si](C)(OCC)OCC
Agent: CO[Si](C)(OC)OC
Product: CO[Si](C)(CCCS)OC

Procedure:
Mercaptopropyltrimethoxysilane; N-methylaminopropyltrimethoxysilane; Methyltriacetoxysilane; Methyltriethoxysilane; Methyl trimethoxysilane;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:13]([F:28])[CH:12]=3)=[CH:6][N:5]2[CH:29]=1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.O.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:30]1([C:33]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[C:13]([F:28])[CH:12]=4)=[CH:6][N:5]3[CH:29]=2)=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a solution of benzyl {4-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-fluorophenyl}carbamate (12.1 g, 30.9 mmol) in N,N-dimethylacetamide (84.7 mL) was added cyclopropanecarbonyl chloride (3.36 mL, 37.0 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (9.7 g, 68%) as a thin-brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15]([N:19]=[C:20]=[O:21])[CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:20](=[O:21])[NH:19][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=O)Oc1ccc2oc3ccccc3c2c1
Yield: 54.4 %

Procedure:
A solution of 2-hydroxydibenzofuran (1.47 g, 7.98 mmol), butyl isocyanate (1.26 mL, 11.2 mmol) and triethylamine (0.89 mL, 6.39 mmol) in 50 mL of methylene chloride was stirred under N2 at room temperature for 1 hour. The solvent was removed under reduced pressure to give a solid. Recrystallization from diethyl etherhexane gave 1.23 g (54%) of the title compound as a white crystalline solid, mp 124°-126° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]([CH3:26])[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[O:19])[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH2:12][CH2:13][CH:14]([N:17]([CH3:26])[C:18]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[O:19])[CH2:15][CH2:16]3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: CN(C(=O)c1ccncc1)C1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)c1ccncc1)C1CCN(c2ncnc3[nH]cc(Br)c23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-{1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}-N-methyl-4-pyridinecarboxamide D26 (41 mg) was dissolved with Tetrahydrofuran (THF) (1 mL) and Methanol (0.500 mL). Cesium carbonate (72.2 mg, 0.221 mmol) was added. The mixture was stirred at room temperature for 30 min. The mixture was partitioned between ethyl acetate (15 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (15 mL). The combined organic phase was filtered by a phase separator and the solvent was removed in vacuo. The crude material was purified by MDAP. Evaporated the solvent and put in the vacuum oven to give the product E39 in 0.0168 g as a white powder. LCMS [M+H]+414.94/416.94@1.86 min (5 min run)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]1[C:16](=O)[C:17](=[O:22])[C:18]=1[O:19]CC)[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]1[C:18](=[O:19])[C:17](=[O:22])[C:16]=1[NH:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccc2[nH]c(=O)oc12
Solvent: CCO
Product: CCOc1c(Nc2cccc3[nH]c(=O)oc23)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
A mixture of 0.247 g of 7-amino-3H-benzooxazol-2-one (1.6 mmol, 1 eq) and 0.36 ml of 3,4-diethoxycyclobut-3-ene-1,2-dione (2.5 mmol, 1.5 eq) in 9 ml of ethanol was stirred at ambient temperature for 2 days (formation of a precipitate). Ethanol was added in order to promote the fall of the precipitate, which was filtered off, washed with diethyl ether and dried under vacuum at 45° C. 0.35 g of product was obtained in the form of a light khaki solid. Yield=78%.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(S(F)(F)[F:20])CC)C.C([O-])(O)=O.[Na+]>ClC(Cl)C.O>[C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([F:20])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a well stirred and cooled (−30° C.) solution of Step 1 intermediate (1.5 g, 8.01 mmol) in dichloroethane (50 ml) was added diethylaminosulphur trifluoride (1.94 mg, 12.01 mmol) under nitrogen and the reaction mixture was maintained at this temperature for 1 h. The reaction mixture was gradually allowed to warm to room temperature and stirring was continued for another 14 h. The reaction mixture was poured onto a mixture of ice and solid NaHCO3 and stirred till no effervescence was seen. The mixture was diluted with water and extracted with dichloromethane (3×100 ml). The combined organic extracts were washed with water, brine and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to give 840 mg of the desired compound as yellow oil; IR (neat) 3500, 2978, 1698, 1407 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.44 (s, 9H), 1.89-2.28 (m, 2H), 3.44-3.77 (m, 4H), 5.11-5.31 (m, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[CH2:8]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]([C@H:21]2[C:25]([F:27])([F:26])[C@H:24]([OH:28])[C@@H:23]([CH2:29][OH:30])[O:22]2)[C:17](=[O:31])[N:16]=1)=[O:13])[CH:9]=[CH2:10].C(N(CC)C(C)C)(C)C>CC#N>[CH2:8]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][N:18]([C@H:21]2[C:25]([F:26])([F:27])[C@H:24]([O:28][C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3])[C@@H:23]([CH2:29][OH:30])[O:22]2)[C:17](=[O:31])[N:16]=1)=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: C=CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OC(=O)OCC=C)C2(F)F)c(=O)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
Allyl chloroformate (0.23 mL, 2.2 mmol) was added to a solution of 1 (694 mg, 2 mmol), N,N-diisopropylethylamine (0.7 mL, 4 mmol) in 20 mL MeCN at 0° C. The reaction mixture was stirred at 0° C. for 4 h and concentrated in vacuo. The crude residue was purified by flash column chromatography (2:1→4:1 EtOAc/Hexane) to give 2 (white solid, 65% yield): 1H NMR (400 MHz, DMSO-d6) δ11.05 (s, 1H), 8.19-8.22 (d, 1H), 7.16-7.18 (d, 1H), 6.32-6.37 (t, 1H), 5.93-6.05 (m, 2H), 5.43 (s, 1H), 5.27-5.39 (m, 5H), 4.74-4.75 (d, 2H), 4.67-4.69 (d, 2H), 4.31-4.33 (m, 1H), 3.82-3.84 (m, 1H), 3.73-3.76 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:21](=[O:22])[C:11]3=[CH:10]2)=[N:6][CH:7]=1.[CH3:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.CS(C)=O.[Cu]I>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[CH:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([N:34]4[CH:35]=[C:31]([CH3:30])[N:32]=[CH:33]4)=[CH:7][N:6]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: O=c1c2cn(Cc3ccc(Br)cn3)c3ccccc3c-2nn1-c1ccccc1F
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2ccc(Cn3cc4c(=O)n(-c5ccccc5F)nc-4c4ccccc43)nc2)cn1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
5-[(5-Bromopyridin-2-yl)methyl]-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one [(Example 257, Step 1), 0.13 g, 030 mmol], 4-methyl-1H-imidazole (99 mg, 1.2 mmol, 4 equiv), copper(I) iodide (23 mg, 0.12 mmol, 0.4 equiv), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (34 mg, 0.24 mmol, 0.8 equiv) and potassium phosphate (0.19 g, 0.90 mmol, 3 equiv) were combined in water (0.2 mL) and dimethylsulfoxide (1 mL). The mixture was sparged under an atmosphere of nitrogen, the vessel was sealed and placed into a preheated oil bath at 100° C. for 9 hours. The mixture was cooled to ambient temperature, poured into water (25 mL) and extracted with chloroform (2×25 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 96:4; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.70 (1H, d, J=2.7 Hz), 8.55 (1H, s), 8.42 (1H, d, J=7.2 Hz), 7.76 (1H, s), 7.67-7.63 (2H, m), 7.56-7.47 (3H, m), 7.39-7.31 (2H, m), 7.29-7.23 (2H, m), 7.00 (1H, s), 5.59 (2H, s), 2.30 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 451.1653 [(M+H)+; calculated for C26H20FN6O: 451.1677].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)[CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCC2)c1)c1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCC2)c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 6.8 %

Procedure:
To the product from Example 202 (1.27 g, 0.002 mole) in H2O (15 mL) and CH3CN (15 mL) was added LiOH (345 mg, 0.0082 mole). The reaction mixture was stirred at room temperature for 1.5 hours. The pH was lowered to 2.7 with TFA and the product was isolated by RPHPLC to yield the title compound (80 mg after lyophilization) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:30]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:30]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (700 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (560 mg, yield: 85%). This was recrystallized from acetone-hexane. Melting point: 92–93° C.
Reaction SMILES: O[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.C(N(S(F)(F)[F:24])CC)C>C(Cl)Cl>[F:24][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CO)C2
Solvent: ClCCl
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CF)C2
Temperature: -78 °C
Yield: 32.3 %

Procedure:
2-Hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (500 mg) was suspended in anhydrous methylene chloride (20 ml). To the suspension, diethylaminosulfur trifluoride (DAST) (372 mg) was added while stirring and cooling at -78° C. Subsequently, the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, methylene chloride was further added thereto, and washed with aqueous sodium bicarbonate solution, and aqueous NaCl solution in this order. After drying, the solvent was distilled off to obtain 487 mg of a crude product. The crude product was purified by silica gel column chromatography (eluent=chloroform:methanol=400:1-20:1), and then by separative thin layer chromatography (developer=chloroform:methanol=10:1) to obtain a purified product, which was subjected to recrystallization using a solvent mixture of chloroform and n-hexane to obtain 163 mg of colorless needles (32%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][N:13]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]4[C:34]([O:35][CH3:36])=[CH:33][C:32]([O:37][CH3:38])=[CH:31][C:30]=4[O:39][CH3:40])[CH:26]=[C:25]([C:41]([O:43]CC)=[O:42])[N:24]=3)[CH2:18][CH2:17][N:16]([CH2:46][C:47]3[N:52]=[C:51]([C:53]([O:55]CC)=[O:54])[CH:50]=[C:49]([C:58]4[C:63]([O:64][CH3:65])=[CH:62][C:61]([O:66][CH3:67])=[CH:60][C:59]=4[O:68][CH3:69])[CH:48]=3)[CH2:15][CH2:14]2)[CH:9]=[C:8]([C:70]2[C:75]([O:76][CH3:77])=[CH:74][C:73]([O:78][CH3:79])=[CH:72][C:71]=2[O:80][CH3:81])[CH:7]=1)=[O:5])C.[Cl-].[Tb+3:83].[Cl-].[Cl-]>>[Tb+3:83].[C:41]([C:25]1[N:24]=[C:23]([CH2:22][N:19]2[CH2:18][CH2:17][N:16]([CH2:46][C:47]3[CH:48]=[C:49]([C:58]4[C:63]([O:64][CH3:65])=[CH:62][C:61]([O:66][CH3:67])=[CH:60][C:59]=4[O:68][CH3:69])[CH:50]=[C:51]([C:53]([OH:55])=[O:54])[N:52]=3)[CH2:15][CH2:14][N:13]([CH2:12][C:10]3[N:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]([C:70]4[C:71]([O:80][CH3:81])=[CH:72][C:73]([O:78][CH3:79])=[CH:74][C:75]=4[O:76][CH3:77])[CH:9]=3)[CH2:21][CH2:20]2)[CH:28]=[C:27]([C:29]2[C:30]([O:39][CH3:40])=[CH:31][C:32]([O:37][CH3:38])=[CH:33][C:34]=2[O:35][CH3:36])[CH:26]=1)([OH:43])=[O:42]
Reactant: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CN2CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CC2)n1
Agent: [Cl-]
Agent: [Tb+3]
Product: COc1cc(OC)c(-c2cc(CN3CCN(Cc4cc(-c5c(OC)cc(OC)cc5OC)cc(C(=O)O)n4)CCN(Cc4cc(-c5c(OC)cc(OC)cc5OC)cc(C(=O)O)n4)CC3)nc(C(=O)O)c2)c(OC)c1

Procedure:
Deprotection of compound 21 followed by treatment with terbium chloride as described in Example 20 yielded the title compound.
Reaction SMILES: [Cl:1][CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[NH4+:15]>CO>[NH2:15][C:7]([CH2:8][CH3:9])=[C:2]([Cl:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCC(N)=C(Cl)C(=O)OC
Reaction time: 4 h
Yield: 94.7 %

Procedure:
A solution of 576.1 g (3.5 mol) of methyl 2-chloro-3-oxovalerate and 674.5 g (8.75 mol) of ammonium acetate in 1.2 l of methanol is heated at 65° C. with stirring for a period of 4 h. After cooling, the solvent is removed in vacuo, the residue is taken up in 2.5 l of diisopropyl ether, and the solid is removed. The solid is dissolved in a little water and subsequently extracted with ethyl acetate. The organic fractions are combined, dried over MgSO4 and evaporated in vacuo. Yield: 94.7% [GC]