Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][C@@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][CH2:11][C:12]([NH:39][CH2:40][C@@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:14]
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Reactant: O=C(O)CCc1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1nc2ccccc2[nH]1)NC[C@@H](O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To a solution of 3-(1H-benzo[d]imidazol-2-yl)propanoic acid (300 mg, 1.579 mmol) in DCM (10 mL) was added HATU (722 mg, 1.895 mmol) and TEA (478 mg, 4.737 mmol). After stirring for 30 min at room temperature, (R)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (488 mg, 2.368 mmol) was added and the resulting mixture then stirred at room temperature for 16 h. Once TLC analysis showed the reaction to be complete, the solvent was evaporated at reduced pressure and the residue purified by preparative HPLC to give the title compound (184.6 mg, 30.9%) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ=7.56-7.46 (m, 2H), 7.22-7.17 (m, 2H), 7.13-7.07 (m, 3H), 7.02-6.97 (m, 1H), 3.94 (t, J=5.8 Hz, 1H), 3.61 (d, J=3.3 Hz, 2H), 3.40-3.35 (m, 1H), 3.25-3.18 (m, 3H), 2.89-2.84 (m, 2H), 2.79 (t, J=7.4 Hz, 2H), 2.74-2.69 (m, 2H), 2.47 (d, J=6.5 Hz, 2H). LCMS (m/z): 379.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[N:13]=[C:12]([CH2:14][O:15][CH3:16])[S:11][C:8]2=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>C(O)C>[CH3:16][O:15][CH2:14][C:12]1[S:11][C:8]2[C:7]([N:13]=1)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=2
Reactant: COCc1nc2cc(C(=O)OC)cnc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc2cc(C(=O)O)cnc2s1

Procedure:
A mixture of 1.1 g (4.62 mmol) of methyl-2-methoxymethylthiazolo[5,4-b]pyridine-6-carboxylate and 9.2 mL of 2N sodium hydroxide solution were stirred into 50 mL of ethanol for one hour at room temperature. Then 9.2 mL of 2N hydrochloric acid were added, the alcohol was distilled off, and it was diluted with 20 mL of water. The aqueous phase was acidified with concentrated hydrochloric acid whilst cooling with ice, the beige precipitate formed was filtered off, then washed with water and dried. Yield: 1.03 g (100% of theory); Rf value: 0.10 (silica gel; ethyl acetate/petroleum ether=3:7).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N+:16]([O-])=O.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])[CH:6]=[CH:7][CH:2]=1
Reactant: CC(=O)NC(C)(C)Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)Cc1cccc(N)c1
Reaction time: 6 h
Yield: 74.9 %

Procedure:
A solution of 3.5 g (11 mmol) of N-[2-(4-bromo-3-nitrophenyl)-1,1-dimethyl-ethyl]acetamide in 60 ml of ethanol was treated with 3 ml (22 mmol) of triethylamine and 500 mg of 10% palladium on charcoal. The mixture was hydrogenated at atmospheric pressure for 6 hours, filtered and evaporated. The residue was partitioned between 60 ml of ethyl acetate and 60 ml of saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 1.7 g (75%) of N-[2-(3-aminophenyl)-1,1-dimethyl-ethyl]-acetamide as an orange gum. [Mass spectrum (ESI) MH+ =207].
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[O:11][C:12]([CH2:15][CH3:16])=[N:13][N:14]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:15]([C:12]1[O:11][C:10]([CH2:9][CH2:8][NH2:7])=[N:14][N:13]=1)[CH3:16]
Reactant: CCc1nnc(CCNC(=O)OC(C)(C)C)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nnc(CCN)o1

Procedure:
2.95 g (12.23 mmol) tert-butyl[2-(5-ethyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamate and 10 ml trifluoroacetic acid are stirred in 100 ml dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is made basic and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Cl:16][C:17]1[C:18]([OH:24])=[CH:19][C:20](=[O:23])[NH:21][CH:22]=1>N1C=CC=CC=1>[Cl:16][C:17]1[C:18]([O:24][C:6](=[O:7])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:19][C:20](=[O:23])[NH:21][CH:22]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: COc1cc(C(=O)Oc2cc(=O)[nH]cc2Cl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34 %

Procedure:
A 3.80 g quantity of 3,4,5-trimethoxybenzoyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 100 ml of pyridine, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate and water, thereby producing 1.60 g of the title compound in a yield of 34%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:9]=1[N:8](CC1C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=1)[C:7]([CH2:47][CH3:48])=[N:6]2.[Cl:49][C:50]1[C:57]2[N:53]([N:54]=[C:55]([CH2:58][CH3:59])[N:56]=2)[N:52]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[C:73]3[N:77]([C:78]([C:91]4[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=4)([C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)[C:79]4[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=4)[N:76]=[N:75][N:74]=3)=[CH:63][CH:62]=2)[CH:51]=1>>[Cl:49][C:50]1[C:57]2[N:53]([N:54]=[C:55]([CH2:58][CH3:59])[N:56]=2)[N:52]([CH2:60][C:61]2[CH:62]=[CH:63][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[C:73]3[N:77]([C:78]([C:79]4[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=4)([C:91]4[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=4)[C:85]4[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=4)[N:76]=[N:75][N:74]=3)=[CH:65][CH:66]=2)[CH:51]=1.[Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:9]=1[NH:8][C:7]([CH2:47][CH3:48])=[N:6]2
Reactant: CCc1nn2ncc(Cl)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCc1nc2c(Cl)cn(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Product: CCc1nn2ncc(Cl)c2[nH]1

Procedure:
In the same manner as described in Example 66, 1.60 g of 7-chloro-2-ethyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 73a) and 1.18 g of 7-chloro-2-ethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 73b) were obtained from 1.10 g of 7-chloro-2-ethyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O-:23].[Na+]>CO.C(OC(=O)C)C>[CH3:22][O:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(N(C)c2nc(OC)nc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.167 mmol) in 2 ml methanol was added sodium methoxide (500 μl, 25% by wt. in methanol). The solution was stirred at 80° C. for 1 h, and it was diluted with 50 ml ethylacetate. The solution was washed with water, dried and concentrated. The product was purified using small silica column and isolated as off white solid (22 mg, 54%). 1H NMR (CDCl3): 7.89 (d, J=8.4 Hz, 1H), 7.53 (ddd, J=8.7, 5.4 and 2.4 Hz, 1H), 7.19-7.14 (m, 2H), 6.99-6.93 (m, 2H), 6.90-6.85 (m, 2H), 4.14 (s, 3H), 3.86 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[SH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:34]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (2.00 g), potassium carbonate (1.23 g) and DMF (11 mL) was added dropwise 2-ethylhexyl 3-sulfanylpropanoate (2.02 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow liquid (3.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[CH:15]=[C:11]2[O:12][C:13]=1[CH3:14].C1C(=O)N([Br:26])C(=O)C1>CN(C=O)C>[Br:26][C:15]1[C:16]([CH3:18])=[N:17][N:10]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:13]([CH3:14])[O:12][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2oc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Solvent: CN(C)C=O
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (Intermediate HE) (0.755 g, 2.69 mmol) in DMF (10 ml) is added NBS (0.502 g, 2.82 mmol). The reaction is stirred at RT for 30 mins and then partitioned between Na2CO3 and EtOAc. The mixture is extracted with EtOAc (×2) and the combined organic phases are dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. This resulting solid is recrystallised from hot EtOAc/iso-hexane to yield the title compound. MS: m/z 360.99 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:43]([CH:45]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:46][Mg]Br)[CH3:44]>O.C(OCC)C>[CH2:43]([CH:45]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:46][C:2]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:6])[CH3:1])[CH3:44]
Reactant: CCCCC(CC)C[Mg]Br
Reactant: CC1(c2ccccc2)OCCO1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCC(CC)CC(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
2-Methyl-2-phenyl-1,3-dioxolane (0.25 g, 1.5 mmol), sodium dodecyl sulfate (0.1 g, 0.35 mmol) and a stir bar were added to the inside of a PDMS thimble. p-Toluene sulfonic acid monohydrate (72.4 mg, 0.38 mmol) dissolved in 2 mL water was added to the inside of the PDMS thimble followed by 1 mL of hexanes. The reaction was stirred at 25° C. for 4 hours. Hexanes (2.5 mL) was added to the outside of the PDMS thimble followed by 12 mL of 1 M 2-ethylhexyl-magnesiumbromide (2.6 g, 12 mmol). The reaction was stirred for an additional 12 hours after which 5 mL water was added. The PDMS thimble was swelled with 20 mL hexanes and 2×20 mL diethyl ether. The organics were combined and dried over MgSO4. The product was purified by column chromatography, eluting with 100% hexanes to yield a colorless oil (0.28 g, 80% yield). 1H NMR (CDCl3): δ 0.68-0.86 (m, 6H), 1.08-1.29 (m, 9H), 1.57 (s, 3H), 1.63 (s, 1H), 1.70-1.75 (m, 2H), 7.19-7.46 (m, 5H). 13C NMR (CDCl3): δ 10.43, 10.49, 14.00, 14.05, 22.86, 22.95, 26.95, 27.12, 28.48, 28.61, 30.45, 30.72, 33.82, 34.04, 34.62, 34.68, 47.99, 48.01, 75.07, 75.09, 124.82. 124.84, 126.27, 126.31, 127.88, 148.32, 148.38. HRMS: Calculated for C16H26O: 234.1984.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.O.[NH2:37][NH2:38].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[C:3]3[C:4](=[O:22])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:38][N:37]=2)=[CH:26][CH:27]=1
Reactant: NN
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(C(F)(F)F)cc3)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethylphenyl)-3-(4-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one (985 mg, 2.0 mmol) produced in Synthesis Example 16 in DMF (10 mL) was added hydrazine monohydrate (purity of 80%, 388 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(4-trifluoromethylbenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (342 mg, yield 35%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.[CH3:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][NH2+:21]1.C1(S([O-])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H]1CCC[NH2+]1
Reactant: O=C1CCC(c2ccc(OCCCCl)cc2)=NN1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1
Agent: [I-]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
In a 500 mL round bottom flask, 6-[4-(3-chloro-propoxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (5.2 g, 19.5 mmol), benzenesulfonate (R)-2-methyl-pyrrolidinium (9.5 g, 39.0 mmol), potassium carbonate (10.8 g, 78.0 mmol), and potassium iodide (200 mg, 1.2 mmol) in acetonitrile (300 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, then washed with water three times. The organics were extracted three times with 3% citric acid solution. The combined aqueous layers were basified with sat. NaHCO3 sol. and extracted with methylene chloride, then dried over MgSO4. Ethereal HCl was added and the solvents reduced under vacuum. Crystallization from MeOH/Et2O produced 3.17 g (46%). Mp 221-223° C. MS m/z 316 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)=[O:9])=[C:6]([NH:19][C@H:20]([C:22]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26](=[O:34])[C:25]3=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]3[N:23]=2)[CH3:21])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=[O:9])=[C:6]([NH:19][C@H:20]([C:22]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26](=[O:34])[C:25]3=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]3[N:23]=2)[CH3:21])[N:5]=[CH:4][N:3]=1
Reactant: COc1cccc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3cccc(O)c3)n(-c3ccccc3)c(=O)c12
Yield: 23 %

Procedure:
(S)-4-Amino-N-(3-methoxyphenyl)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxamide (27 mg, 0.05 mmol) was treated with boron tribromide (1M in dichloromethane, 160 μl, 0.16 mmol) in dichloromethane according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 6 mg (23% yield) as a white solid. Purity 100%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:44])(=[O:43])[N:20]=1.[OH-].[Na+:46]>O>[CH3:17][C@@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH:36]=[CH:35][CH:34]=4)(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:44])(=[O:43])[N:20]=2)[C:4]1=[O:18].[Na+:46]
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cccc5ccccc45)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cccc5ccccc45)ccc3N2)=C([O-])c2ccccc21
Yield: 67.1 %

Procedure:
A mixture of Example 105A (30.0 mg, 0.048 mmol) and 0.998 M sodium hydroxide (0.048 mL, 0.048 mmol) in water (3 mL) was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (21 mg, 68% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.40 (m, 1H) 0.65 (d, J=6.62 Hz, 3H) 0.67 (m, 3H) 0.75 (m, 1H) 1.26 (m, 1H) 1.34 (s, 3H) 1.69 (m, 1H) 2.10 (m, 1H) 7.12 (m, 2H) 7.23 (s, 1H) 7.29 (m, 1H) 7.44 (m, 2H) 7.64 (m, 2H) 7.74 (m, 1H) 8.00 (d, J=7.72 Hz, 1H) 8.07 (d, J=7.72 Hz, 1H) 8.16 (d, J=7.35 Hz, 1H) 8.20 (m, 1H) 8.76 (s, 1H) 10.82 (s, 1H) 15.39 (s, 1H). MS (ESI+) m/z 652.0 (M+H)+, 630.0 (M+H−Na)+, 647 (M−Na+NH4)+, (ESI−) m/z 628.0 (M−H−Na)−.
Reaction SMILES: [F:1][C:2]([F:26])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][C:11]=2[CH:25]=1)[C:3]([F:6])([F:5])[F:4].CCO.[OH-].[Na+]>C1COCC1>[F:26][C:2]([F:1])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([F:17])([F:18])[F:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][C:11]=2[CH:25]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CCOC(=O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(C(F)(F)C(F)(F)F)ccc2OC1C(F)(F)F
Reaction time: 16 h

Procedure:
To a stirred solution of the ethyl ester (Step 1) (0.090 g, 0.231 mmol) in THF:EtOH:H20(7:2:1) (4 mL) was added aqueous NaOH solution (0.11 mL, 2.5 M). After stirring 16 hours, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H2O, and washed with diethyl ether. The resulting aqueous phase was acidified with concentrated HCl, extracted with diethyl ether, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. The oil was purified by flash chromatography (silica, hexanes-ethyl acetate, 3:1 with 5% acetic acid). This procedure yielded the title acid (0.020 g, 24%) as a white powder: mp 162.3–164.7° C. 1H NMR (acetone-d6/300 MHz) 8.05 (s, 1H), 7.90 (s, 1H), 7.74 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=8.7 Hz), 5.97 (q, 1H, J=6.8 Hz). FABLRMS m/z 361 (M−H). ESHRMS m/z 361.0111 (M−H, Calc'd 361.0094).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=1>CO.[Pd]>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:16]([F:18])([F:17])[F:19])[CH:8]=1
Reactant: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CCCN1c1ccc(N)c(C(F)(F)F)c1
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a solution of (S)-2-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (12.0 g, 43.68 mmol) in methanol (75 mL) was added 10% Pd/C (1.2 g). The reaction was stirred under H2 atmosphere for 16 h. The mixture was filtered through a pad of Celite and concentrated. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes) provided (S)-4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)aniline as a brown oil (10.5 g, 98% yield). LC/MS m/z 245.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(Cc2ccccc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Cc2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-benzyl-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 32, Part D) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Br[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1[CH3:24]>>[CH3:24][C:15]1[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[C:18]([CH3:20])=[CH:19][C:14]=1[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Product: Cc1cc([N+](=O)[O-])c(C)cc1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
Prepared from tert-butyl 3-iodoazetidine-1-carboxylate and 1-bromo-2,5-dimethyl-4-nitrobenzene by following the general protocol as described in Billotte, S. Synlett 1998, 379.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[C:21]([CH3:27])[CH:20]=3)[CH:12]=2)=C([CH:9]=1)C#N.[OH-].[Na+].[C:30]([O:33]CC)(=[O:32])[CH3:31]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[N:23]([CH:24]([CH3:25])[CH3:26])[N:22]=[C:21]([CH3:27])[CH:20]=3)[CH:12]=2)=[C:31]([CH:9]=1)[C:30]([OH:33])=[O:32]
Reactant: CCOC(C)=O
Reactant: Cc1cc(Nc2cc(Nc3ccc(Cl)cc3C#N)c(Cl)cn2)n(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccc(Cl)cc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Yield: 90 %

Procedure:
A solution of 5-chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (850 mg, 2.118 mmol) in sodium hydroxide −1 M (20 mL, 20.00 mmol) and 1,4-dioxane (20 mL) was refluxed overnight. Ethyl acetate was added and the layers were separated. The organic layer was washed with 1 M NaOH (40 ml). Combined aqueous layers were washed with ethyl acetate. The organic layers were combined, evaporated, dissolved in MeOH and evaporated again. 5-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (800 mg, 1.903 mmol, 90% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (d, J=6.57 Hz, 6 H) 2.12 (s, 3 H) 4.40 (quin, J=6.51 Hz, 1 H) 5.97 (s, 1 H) 6.79 (s, 1 H) 7.56-7.62 (m, 1 H) 7.62-7.69 (m, 1 H) 7.94 (d, J=2.27 Hz, 1 H) 8.04 (s, 1 H) 8.58 (s, 1 H) 9.94 (br. s., 1 H) 13.97 (br. s., 1 H); HPLC Rt=2.65 min, MS (ESI): 420.2, 421.1 [M+H]+.