Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2ccc(N)cc21
Reaction time: 0.25 h

Procedure:
To a stirring solution of 1-Boc-6-nitroindole (250 mg, 0.95 mmol) in THF (5 mL) and MeOH (10 mL) at 0° C., was added Ni(OAc)2.4H2O (473 mg, 1.9 mmol). After complete dissolution, NaBH4 (143 mg, 3.8 mmol) was added slowly. Upon addition of the NaBH4, the reaction mixture turned black and vigorous gas evolution was observed. After 15 min, the solvents were removed in vacuo and the residue was dissolved in a stirring mixture of ethyl acetate (100 mL), conc NH4OH (10 mL) and water (20 mL). The layers were separated and the organic phase was washed again with 33% conc NH40OH in water and then washed twice with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[OH:1][C:2]1([C:9]2[S:13][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][CH:7]([CH2:20][OH:21])[CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl[CH2:23][C:24]([N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[O:25].[OH-].[Na+].O>CS(C)=O>[CH2:1]([N:5]1[CH2:10][CH:9]([CH2:11][O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:8][CH:7]([CH2:20][O:21][CH2:23][C:24]([N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[O:25])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: CCCCN1CC(CO)OC(COCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN1CC(COCC(=O)N(CCC)CCC)OC(COCc2ccccc2)C1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of 16.2 g of 4-butyl-6-[(phenylmethoxy)methyl]-2-morpholinemethanol (0.055 mole) and 9.81 g of 2-chloro-N,N-dipropylacetamide (0.055 mole) are dissolved in 200 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly, 1.0 g of sodium hydroxide (0.04 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4×300 ml portions of water. The CHCl3 layer is separated, dried over anhydrous Na2SO4, and the CHCl3 removed in vacuo yielding 22.4 g (94%) of the title compound as a yellow oil. The resulting oil is purified on a neutral Alumina III column (500 g), 40% chloroform/hexane yielding 12.9 g (54%) of product as a pale yellow oil. The 12.9 g of product are dried in vacuo (80° @0.2 mm) to give the desired product.
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5])=[N-].[Cl:11][C:12]1[C:13](=[O:22])[C:14](=[O:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=1[Cl:18]>C1C=CC=CC=1>[Cl:11][C:12]1[C:13]2[O:22][CH:3]([C:4]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)=[O:5])[O:21][C:14]=2[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=1[Cl:18]
Reactant: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Reactant: [N-]=[N+]=CC(=O)c1cccs1
Solvent: c1ccccc1
Product: O=C(c1cccs1)C1Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2O1
Yield: 43.7 %

Procedure:
2-diazo-1-(thiophen-2-yl)ethanone (2.3 g, 0.0151 mol) and 3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione (3.36 g, 0.0136 mol) were then combined in dry benzene (25 mL) and refluxed vigorously for 6 hours. The solvent was then evaporated to dryness, and the crude material was subjected to column chromatography using 100-200 mesh silica gel and 15% ethyl acetate-hexane solvent system. Evaporation of the solvent yielded (4,5,6,7-tetrachlorobenzo[d][1,3]dioxol-2-yl)(thiophen-2-yl)methanone as an orange solid (2.2 g, 43.4%).
Reaction SMILES: CC([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=C.OO.[OH:19]S(O)(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[OH:19][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: C=C(C)c1ccc(OC(C)C(=O)OC)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ccc(O)cc1
Temperature: 10 °C
Reaction time: 0.03 h
Yield: 94 %

Procedure:
An 86.0 g-portion of methyl 2-(4-(1-methylethenyl)phenoxy)propanoate was dissolved in 360 ml glacial acetic acid. An equimolar portion of 30% aqueous H2O2 was added. The solution was cooled to 10° C. and 7.6 mol % of 98% H2SO4 was added. The solution was allowed to slowly warm to 35° C. over 11 minutes at which point the ice bath was put back on. The temperature peaked at 84° C. two minutes later. The reaction mixture was allowed to cool slowly to 36° C. over 25 minutes. A 26 g-portion of 20% aqueous Na2SO3 was added, followed by 900 ml water. The mixture was extracted with four 200 ml-portions of CH2Cl2. The combined organic layers were washed with two 200 ml-portions and one 400 ml-portion of 5% aqueous NaHCO3. The organic layer was dried with Na 2 SO4. Removal of solvent gave 74.8 of 94% pure methyl 2-(4-hydroxyphenoxy)propanoate, corresponding to a 92% yield. Distillation under reduced pressure gave 59.3 g of methyl 2-(4-hydroxyphenoxy)propanoate (b.p. 154°-155° C./4 torr) corresponding to a 77% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][CH:26]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc(Br)c1
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1OC
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 500 mg (1.90 mmol) 4-chloro-7-ethoxy-6-methoxy-3-quinolinecarbonitrile, 20 ml ethanol, and 250 μl (2.28 mmol) 3-bromoaniline was heated to reflux under N2. At 3 hours, added 103 μl (0.95 mmol) and 10 ml ethanol and refluxed overnight. Removed heat and made basic with saturated sodium bicarbonate. Stripped solvent, slurried residue with hexane, collected solids, and dried. Washed with water and dried in vacuo, giving 554 mg of tan solid: mass spectrum (electrospray m/e): M+H=398, 399.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([NH:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CN(C)CCCN
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1NCCCN(C)C
Yield: 55.8 %

Procedure:
Following the procedure used to prepare Example 27, 150 mg (0.34 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile is reacted with 209 mg (2.05 mmol) of N, N-dimethyl-1,3-propanediamine in 1 mL of 1-methyl-2-pyrrolidinone at 105° C. for 16 hours to yield 99 mg of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-{[3-(dimethylamino)propyl]amino}-6-methoxyquinoline-3-carbonitrile as a tan solid, mp 198-200° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1

Procedure:
A solution of 5-hydroxyindole 1-3 (5.50 g, 41.3 mmol, 1 equiv), tert-butyldimethylsilyl chloride (7.47 g, 49.6 mmol, 1.20 equiv), and imidazole (7.03 g, 103 mmol, 2.50 equiv) in N,N-dimethylformamide (20 mL) was stirred at 23° C. for 20 h. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water (3×), then dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (40% dichloromethane in hexanes, then 60% dichloromethane in hexanes) to give 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole as a colorless oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.00 (br s, 1H), 7.22 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=2.8 Hz), 7.06 (d, 1H, J=2.3 Hz), 6.76 (dd, 1H, J=8.6, 2.3 Hz), 6.44 (m, 1H), 1.00 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1I.[N:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[N:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[C:15]1[CH:16]=[N:11][CH:12]=[N:13][CH:14]=1
Reactant: N#Cc1nccc(I)c1F
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1nccc(-c2cncnc2)c1F
Temperature: 85 °C
Yield: 68.3 %

Procedure:
A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (1.25 g, 5.04 mmol), pyrimidin-5-ylboronic acid (1.249 g, 10.08 mmol), and cesium carbonate (3.45 g, 10.58 mmol) in dioxane (Ratio: 2.0, Volume: 10.18 ml) and water (Ratio: 1.000, Volume: 5.09 ml) was degassed with N2 for 5 min, then PdCl2(dppf)-CH2Cl2Adduct (0.218 g, 0.267 mmol) was added. The solution was heated at 85° C. for 17 hr, and then allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was purified by MPLC (80 g column, 60 mL/min, 30-100% EtOAc in hexanes) to give the title compound (695 mg, 3.44 mmol, 68.2% yield) as a pink solid. ESI MS (M+H)+=201.1.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20]N(C5C=CC=CC=5)C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]=[C:40]=[O:41].Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:39]([C:33]5[C:32]([Cl:31])=[CH:37][CH:36]=[CH:35][C:34]=5[Cl:38])[C:40]4=[O:41])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Agent: Cl
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1c(Cl)cccc1Cl

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 2,6-dichlorophenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 237°-241° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].CN(C)C=O.[C:9]([N:11]=[C:12](SC)[NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)#[N:10]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:12]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:19]=2)=[N:11][C:9]([NH2:10])=[N:3]1
Reactant: CNN
Reactant: CSC(=NC#N)NCCCOc1cccc(CN2CCCC2)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCC2)c1

Procedure:
Methyl hydrazine (6.9 g) and dry dimethylformamide (10.95 g) were heated at reflux in toluene for 1 hr. N'-Cyano-N-[3-[3-(1-pyrrolidinylmethyl)phenoxy]propyl]carbamimidothioic acid, methyl ester (10 g) was then adde and the mixture heated at reflux for 5 hr. Evaporation of the solvent gave the title compound as a yellow oil which was converted to the fumarate salt in ethanol. The title compound was regenerated as the free base with aqueous sodium carbonate, and extracted into ethyl acetate. Evaporation of the solvent and trituration of the residue with light petroleum (b.p. 60°-80°) gave the title compound as a white solid (3.4 g) m.p. 95°-95.5°. TLC silica; methanol:0.88 ammonia (80:1) single spot Rf 0.5.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[CH3:19][O:20][C:21](Cl)=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([O:11][C:21]([O:20][CH3:19])=[O:22])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:22]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)OC12CC3CC(C1)CC(OC(=O)OC)(C3)C2
Temperature: 25 °C
Yield: 90 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and 24 mmole of pyridine were dissolved in 10 mL of DMF. To the mixture, 22 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1,3-bis (methoxycarbonyloxy)adamantane (yield 90%) was formed.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:20]([CH3:22])[CH3:21])=[CH:6][C:5]=1[O:23][CH3:24])([O-:3])=[O:2].CO[CH2:27][Cl:28]>ClCCl>[CH:17]([C:16]1[CH:15]=[C:14]([CH:13]=[C:12]([CH:20]([CH3:22])[CH3:21])[C:11]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:23][CH3:24])[CH:6]=1)[CH2:27][Cl:28])([CH3:19])[CH3:18]
Reactant: COc1cc(Oc2c(C(C)C)cccc2C(C)C)ccc1[N+](=O)[O-]
Reactant: COCCl
Solvent: ClCCl
Product: COc1cc(Oc2c(C(C)C)cc(CCl)cc2C(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Stannous chloride (0.46 mL) was carefully added under nitrogen gas to a ice-cooled mixture of 2-nitro-5-(2,6-diisopropylphenoxy)anisole (3.8 g), chloromethyl methyl ether (1.8 mL) and dichloromethane (5 mL). After 16 hours, the reaction mixture was concentrated and purified on column (silica gel, ethyl acetate/petroliumether, 97:3), to give 1.4 g of 3,5-diisopropyl-4-(3-methoxy-4-nitrophenoxy)benzylchloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:9]([F:11])[CH3:10])[CH:3]=1.C([Li])CCC.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C.Cl>C(OCC)C.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:3][C:4]=1[CH:9]([F:11])[CH3:10]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(F)c1cc(Br)ccc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(F)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
4-Bromo-1-chloro-2-(1-fluoroethyl)benzene (2.55 g, 10.74 mmol) was dissolved in dry diethyl ether (50 mL) and cooled to −75° C. n-Butyllithium (4.72 mL, 11.81 mmol) was added dropwise keeping the temperature below −70° C. The reaction mixture was then stirred for 15 min, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.197 g, 11.81 mmol) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then diluted with water and diethyl ether. The aqueous phase was acidified with 12N HCl and the product was then extracted with diethyl ether. The organic phase was dried and concentrated under vacuum to yield the title compound (1.55 g, 5.45 mmol, 50.7% yield) as a white solid: 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.65 (m, 1H), 7.36 (m, 1H), 5.96 (dq, 1H), 1.64 (dd, 3H), 1.34 (s, 12H).
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([NH:17][C:18]([C:20]1[S:21][C:22]([C:27](=[O:39])[NH:28][CH2:29][C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[CH:23][C:24]=1[C:25]#[N:26])=[O:19])[CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]([OH:15])[CH:9]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[C:25]([C:24]1[CH:23]=[C:22]([C:27](=[O:39])[NH:28][CH2:29][C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)[S:21][C:20]=1[C:18]([NH:17][C@@H:4]([CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([OH:14])[CH:13]=1)[C:3]([OH:40])=[O:2])=[O:19])#[N:26]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(O)cc(O)c1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cc(O)cc(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-2-({3-Cyano-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-3-(3,5-dihydroxy-benzoylamino)-propionic acid methyl ester (124.1 mg, 0.22 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (65 mg, 1.54 mmol) in water (12 mL). The mixture was then stirred at room temperature 1.5 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to afford to pure product, 78.6 mg (65%). MS m/e 549.0 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:4]([O:26][CH3:27])[CH:5]=1
Reactant: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CN
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)cc1CNC(=O)C(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-79, 0.200 g), pivaloyl chloride (0.2 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.015 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.15 (s, 9H), 3.91 (s, 3H), 4.22 (m, 2H), 7.26 (s, 1H), 7.42 (s, 1H), 7.87 (m, 2H), 7.99 (m, 1H), 8.15 (m, 2H), 12.57 (s, 1H); MS (m/z): 483.38 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:18]([N:21]1[C:30]2[N:29]=[C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:41](O)=[O:42])=[C:36]4[C:40]=3[O:39][CH2:38][CH2:37]4)[N:27]=[CH:26][C:25]=2[N:24]([CH3:44])[C:23](=[O:45])[C@@H:22]1[CH2:46][CH3:47])([CH3:20])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:41]([C:35]4[CH:34]=[CH:33][C:32]([NH:31][C:28]5[N:27]=[CH:26][C:25]6[N:24]([CH3:44])[C:23](=[O:45])[C@H:22]([CH2:46][CH3:47])[N:21]([CH:18]([CH3:19])[CH3:20])[C:30]=6[N:29]=5)=[C:40]5[O:39][CH2:38][CH2:37][C:36]=45)=[O:42])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (577 mg, 2.43 mmol), the crude compound 7-[[(7S)-8-isopropyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 43e (1 g, 2.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (780 mg, 2.43 mmol) and diisopropylethylamine (690 mg, 5.35 mmol) were dissolved in 60 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting mixture was added with 50 mL of aqueous ammonia and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7S)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 43 (1.12 g, yield: 74.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:26][CH2:22][CH:23]([CH3:25])[CH3:24])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CC(C)CN
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(NCC(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 75.6 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and isobutylamine (0.15 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), which was warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give a light yellow oil (0.44 g, 76%): GCMS m/z 377.00 (M+). 1H NMR (CDCl3/400 MHz) 7.57 (s, 1H), 7.09 (s, 1H), 6.30 (s, 1H), 5.63 (q, 1H, J=7.0 Hz), 4.27 (m, 2H), 3.00 (m, 2H), 1.95 (m, 1H), 1.31 (m, 3H), 1.00 (m, 6H).