Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43]([CH:51]=O)[CH:42]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:43]1[CH:42]=[N:41][C:50]2[C:45]([CH:44]=1)=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: O=Cc1cnc2ccccc2c1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
1,1,3,3-Tetramethylguanidine (94 μL, 0.75 mmol) was added to a solution of rac.-N-[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 133; 244 mg, 0.5 mmol) in tetrahydrofuran (7 mL) at −20° C. After 30 min, quinoline-3-carboxaldehyde (82.5 mg, 0.525 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (30 mL) was added. The solution was washed with saturated sodium bicarbonate solution (15 mL) and the aqueous layer was extracted with ethyl acetate (10 mL). Each organic layer was washed with brine. The combined organic layers were dried (MgSO4), filtered, evaporated and chromatographed over silica gel (20-50% ethyl acetate/hexanes) to (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (221 mg, 86% yield) as an orange-yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:11].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:11])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)CN2CCN(Cc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium carbonate (18.84 g) and water (41.4 ml) was added to a stirring suspension at 0° to 5° C. of 2-bromo-1-(3,4-dimethoxyphenyl)-1-ethanone (32.03 g, described in Example 4) and 1-benzylpiperazine (24 ml) in acetonitrile (90 ml). The suspension was stirred at room temperature for 2.5 hr and evaporated. The residue was dissolved in a mixture of water and chloroform, and the chloroform layer was dried and evaporated. Chromatographic purification on silica gel (700 g) using ethyl acetate-hexane (60:1 to 100:1) gave 32 g of 2-(4-benzyl-1-piperazinyl)-1-(3,4-dimethoxyphenyl)-1-ethanone, nmr(CDCl3) δ2.65, 3.57, 3.74, 3.89, 3.91, 6.81, 7.37 and 7.53.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([Br:26])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cccnc2N)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate (5.64 g, 22.90 mmol) in acetonitrile (229 mL) was added NBS (4.16 g, 23.36 mmol) in two portions at 0° C. The reaction mixture was stirred at 0° C. for 20 min. After quenched with sat Na2S2O3 and NaHCO3, and stir for 30 min. The reaction mixture was extracted with EtOAc 3 times, the organic washed by sat NaHCO3, water and brine. Dried and concentrated. The crude material was triturated with ether to provide 7.05 g of methyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate in 95% yield. LCMS (m/z): 327.1 (MH+), 0.66 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)c(Cl)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1ccc(OC2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]benzonitrile (D29) (5.0 g) was dissolved in methanol (150 ml) and 4N HCl in dioxane (100 ml) was added. The reaction stirred at rt overnight. The reaction mixture was then evaporated to give the title compound (D30) as a white solid (4.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([Si](C)(C)[O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][OH:16])=[CH:25][CH:24]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Cl)ccc1Oc1ccc(OCCO)cc1
Yield: 75.5 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluorobenzaldehyde (1.2 g, 7.6 mmol) (Aldrich) was reacted with 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol (2.1 g, 7.8 mmol) prepared in Example 60b and K2CO3 in N,N-dimethylacetamide at 170° C. for 0.5 h to give 5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-benzaldehyde as a colorless oil (Yield 1.68 g, 75%).
Reaction SMILES: Cl[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[O:7][CH2:8][CH2:9][OH:10].C[O-].[Na+].[C:21](OCC)(=[O:23])C>CO>[N+:12]([C:5]1[CH:4]=[C:3]([N+:15]([O-:17])=[O:16])[C:2]([O:23][CH3:21])=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(OCCO)cc1Cl
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To 20.0 g (0.076 moles) of 2-(5'-chloro-2',4'-dinitrophenoxy) ethanol in 200 ml methanol is added 10.8 g (0.20 moles) sodium methoxide, with stirring. The mixture is heated to reflux. TLC (ethyl acetate) after 6 hours shows the reaction is complete. The hot mixture is poured into 1 liter ice. The pale yellow precipitate is collected by vacuum filtration, washed with water and dried in a vacuum oven at 50° C. Yield is 16.3 g (82.9%), m.p. 137°-140°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1
Reactant: COc1ccnc(C)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C)ncc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
To a stirred solution of 4-methoxy-2-methylpyridine (25 g, 0.148 mol) in conc. H2SO4 (17 mL, S. D. Fine, India), a mixture of H2SO4 (17 mL, S.D. Fine, India) and 65% HNO3 (22 mL, Rankem, India) was added in a drop-wise fashion at 0° C. over 30 min. The resulting solution was heated at 65° C. for 12 h. After completion, the reaction mixture was poured in to ice water and neutralized (PH˜8) with 40% NaOH solution to give a yellow precipitate. The precipitate was further stirred and filtered, dried to give a mixture of 3-nitro (major product) and the desired 5-nitro isomers. The product was isolated by column chromatography, silica gel (230-400), eluting with 15% EtOAc in petroleum ether to give the title compound as yellow needles. 1H NMR (400 MHz, DMSO-d6) δ: 8.86 (s, 1H), 7.33 (s, 1H), 3.99 (s, 3H), 2.52 (s, 3H). MS (ESI, positive ion) m/z: 169.0 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][OH:10]>C(OCC)(=O)C.C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCC#Cc1ccccn1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCCc1ccccn1

Procedure:
A solution of 3-(2-pyridyl)-2-propyn-1-ol (540 mg, 4.06 mmol) in ethyl acetate (15 ml) and ethanol (3 ml) was hydrogenated over 10% palladium on carbon at room temperature for 13 h. The mixture was filtered through celite and the filtrate on evaporation gave an oil, which was flash chromatographed on silica using 3% methanol/dichloromethane. Fractions with Rf of about 0.09 on evaporation gave the title alcohol as a yellow oil.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=4[F:25])[N:18]([CH3:27])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)cc(F)c34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide (30 mg, 0.06 mmol) in CH2Cl2 (1.5 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 4 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h then concentrated. The residue was purified by silica gel chromatography with 0% to 5% MeOH/EtOAc to afford 18 mg (82%) of 2-(4,6-difluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid isopropylamide as a light yellow powder. MS (M+Na)+=393; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.83 (s, 1H), 8.99 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=7.9 Hz, 1H), 7.59 (dd, J=9.1, 1.9 Hz, 1H), 7.12-7.23 (m, 1H), 4.16-4.27 (m, 1H), 4.14 (s, 3H), 1.22 (d, J=6.4 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O:14][C:15]([C:17]#[C:18][CH2:19][OH:20])=O)C>C(O)C>[OH:20][CH2:19][C:18]1[N:7]2[C:2]([CH2:3][O:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=32)=[N:1][C:15](=[O:14])[CH:17]=1
Reactant: CCOC(=O)C#CCO
Reactant: NC1=Nc2ccccc2OC1
Solvent: CCO
Product: O=c1cc(CO)n2c(n1)COc1ccccc1-2
Yield: 72.5 %

Procedure:
A solution of the compound of formula II, 3-amino-2H-1,4-benzoxazine (10.7 g, 72.1 mmol, described in Example 3) and hydroxymethylacetylenecarboxylate ethyl ester (9.7 g, 75.7 mmol) in ethanol (100 ml) was allowed to stand at room temperature (20° to 24° C.) for 6 days. The resulting precipitate was collected giving 12.03 g of the title compound as tan crystals with mp 235°-237° L C., the mp remaining unchanged or recrystallization from ethanol. The title compound had IR(nujol)3130, 1640 cm-1 ; NMR(Trifluoroacetic acid)δ5.2 (s,2H); 5.3(s,2H); 7.6(m,5H); Anal. Calc'd: C, 62.60%; H, 4.38%; N, 12.17%; Found: C, 62.32%; H, 4.24%; N, 12.17%.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1>>[CH:1]1([C:4]([O:6][C:10]([CH:7]2[CH2:9][CH2:8]2)=[O:11])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: O=C(Cl)C1CC1
Product: O=C(OC(=O)C1CC1)C1CC1

Procedure:
This was prepared from cyclopropanecarboxylic acid (Aldrich) and cyclopropanecarboxylic acid chloride (Aldrich) by the method given (Example IV) for the preparation of the cyclobutyl analogue and purified by vacuum distillation; bp 95°-100° C. at 6 torr (lit.: Castro and Dormoy, Bull. Soc. Chem. Fr. 8, 3034 (1971) bp 102°-104° C. at 8 torr); IR anhydride C=O stretch absorptions at 5.53 and 5.74μ.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[C:5]2[OH:16].S(=O)(=O)(O)O.[C:22](OCC)(=O)C.CCCCCC>CO>[CH3:22][O:13][C:12]([C:7]1[C:6]([CH3:15])=[C:5]([OH:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: Cc1c(C(=O)O)cc2ccc(F)cc2c1O
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Temperature: 25 °C
Yield: 54 %

Procedure:
To a 0° C. solution of crude 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid (28 g, approx. 118 mmol) in MeOH (240 mL) was added concentrated sulfuric acid (18.9 mL, 382 mmol) dropwise. The reaction mixture was then warmed to room temperature and refluxed overnight. After this time, the methanol was distilled off under reduced pressure, and the crude mixture was diluted with ethyl acetate. This solution was washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Silica gel column chromatography (6% ethyl acetate-hexane) afforded 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (14.8 g, 54%) as light yellow solid. MS cald. for C13H12FO3 [(M+H)+] 235, obsd. 235.2.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]=2)[CH2:5][C@@H:4]([C:20](O)=[O:21])[NH:3]1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:46][C@H:47]([C:54]([N:56]1[CH2:63][CH2:62][CH2:61][C@H:57]1[C:58]([NH2:60])=[O:59])=[O:55])[CH2:48][C:49]1[N:53]=[CH:52][NH:51][CH:50]=1>C(N(CC)CC)C.CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:10]=2)[CH2:5][C@@H:4]([C:20]([NH:46][C@H:47]([C:54]([N:56]2[CH2:63][CH2:62][CH2:61][C@H:57]2[C:58]([NH2:60])=[O:59])=[O:55])[CH2:48][C:49]2[N:53]=[CH:52][NH:51][CH:50]=2)=[O:21])[NH:3]1
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N[C@H](C(=O)O)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O)C2
Reaction time: 1.5 h
Yield: 33.3 %

Procedure:
A mixture of (3S)-1-oxo-7-tert.-butyloxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (680 mg), N-hydroxysuccinimide (280 mg), DCC (500 mg) and DMF (7 ml) is stirred for 1.5 hours. L-Histidyl-L-prolinamide.2HBr (990 mg) and triethylamine (1 ml) are added to the mixture. The mixture is stirred for 2 days. Insoluble materials are filtered off, and the filtrate is distilled under reduced pressure to remove DMF. The residue is dissolved in 20% citric acid, and washed with chloroform. The washed solution is adjusted to pH 9, and the solution is passed through a column (2.6×20 cm) packed with CHP-20P resin. The column is washed with water (one liter) and 30% methanol (1.5 liter) successively, and then the product is eluted with 50% methanol. The fraction positive to Pauly reagent are collected, and the collected solution is lyophilized, whereby Nα -[(3S)-1-oxo-7-tert.-butyloxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-L-histidyl-L-prolinamide (400 mg) is obtained. Yield: 33.3%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide (Stage 20.1) and 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester to afford an off-white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=449.0 [M+H]+, m/z=493.0 [M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.79 (m, 1H) 1.80-1.92 (m, 1H) 2.72 (d, J=10.88 Hz, 1H) 3.03-3.18 (m, 2H) 3.19-3.30 (m, 1H) 4.19 (br. s, 1H) 4.77-4.92 (m, 1H) 6.22-6.42 (m, 1H) 6.76-6.93 (m, 1H) 7.31 (d, J=8.56 Hz, 2H) 7.45-7.81 (m, 1H) 7.83-7.95 (m, 4H) 10.12 (s, 1H) 12.71-13.12 (m, 1H).
Reaction SMILES: I[C:2]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC.[Cl-].[Li+].O>CN(C)C=O>[CH3:23][C:21]1[C:20]([CH3:24])=[CH:19][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:22]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3I)c2cc1OC
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3-c3ccccn3)c2cc1OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxyquinoline (compound 164) (95 mg), tri-n-butyl(2-pyridyl)tin (0.25 ml), and tetrakistriphenylphosphine palladium (64 mg) were dissolved in N,N-dimethylformamide (7 ml), lithium chloride (102 mg) was added to the reaction system, and the mixture was stirred at 100° C. for one hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (3 mg, yield 4%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:51]([F:54])([F:53])[F:52])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([N:16]([CH2:18][C@@H:19]4[C@H:23]5[O:24]C(C)(C)[O:26][C@H:22]5[C@H:21]([N:29]5[C:33]6[N:34]=[CH:35][N:36]=[C:37]([NH:38]CC7C=CC(OC)=CC=7OC)[C:32]=6[CH:31]=[CH:30]5)[CH2:20]4)[CH3:17])[CH2:13]3)[NH:7][C:6]=2[CH:50]=1>FC(F)(F)C(O)=O.O>[NH2:38][C:37]1[C:32]2[CH:31]=[CH:30][N:29]([C@@H:21]3[CH2:20][C@H:19]([CH2:18][N:16]([CH:14]4[CH2:13][CH:12]([CH2:11][CH2:10][C:8]5[NH:7][C:6]6[CH:50]=[C:2]([Cl:1])[C:3]([C:51]([F:53])([F:52])[F:54])=[CH:4][C:5]=6[N:9]=5)[CH2:15]4)[CH3:17])[C@@H:23]([OH:24])[C@H:22]3[OH:26])[C:33]=2[N:34]=[CH:35][N:36]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (60 mg, 0.078 mmol) was dissolved in a mixture of trifluoroacetic acid (3.6 mL) and water (0.4 mL) which had been precooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, and then warmed to room temperature. After 3 h at room temperature, HPLC indicated the reaction was complete. The now very pink reaction mixture was concentrated. The residue was taken up in 10 mL MeOH and concentrated. This procedure was repeated twice and the residue placed on high vac for 1 h. The material was taken up in 7 mL MeOH and was treated with 120 mg K2CO3 and ten drops of water. The mixture was allowed to stir for 1 hr. The mixture was filtered through a fine frit, the solids were washed with 10 mL MeOH and the filtrate was concentrated to yield a nearly colorless solid. The crude material was purified by flash chromatography (30 g silica gel; 10-15% 7N NH3 in CH3OH/CH2Cl2) to yield Compound 7 (31 mg, 69%) as a colorless glass/stiff foam: MS (ESI+) for C27H31ClF3N7O2 m/z 578.3 (M+H)+; MS (ESI−) for C27H31ClF3N7O2 m/z 576.4 (M−H)−; HPLC purity >95% (ret. time, 2.57 min); 1H NMR (400 MHz, d4-MeOD) δH 8.06 (s, 1 H), 7.89 (d, J=2.07 Hz, 1 H), 7.69 (d, J=2.28 Hz, 1 H), 7.21 (dd, J=3.42, 1.76 Hz, 1 H), 6.59 (d, J=3.52 Hz, 1 H), 4.33 (t, J=6.84 Hz, 1 H), 3.89 (q, J=5.25 Hz, 1 H), 3.03 (m, 0.5 H), 2.89 (m, 2 H), 2.70 (m, 0.5 H), 2.49 (m, 1 H), 2.40 (m, 2 H), 2.27 (br. s., 2 H), 2.16 (d, J=7.26 Hz, 4 H), 2.06 (m, 2 H), 1.91 (m, 2 H), 1.62 (m, 1 H), 1.52 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][S:8][N:9]=2.[C:11]([Cu])#[N:12]>CN(C=O)C.Cl.O>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2=[N:9][S:8][N:7]=[C:6]2[CH:10]=1)#[N:12]
Reactant: N#C[Cu]
Reactant: Brc1ccc2nsnc2c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2nsnc2c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
5-Bromobenzo[1,2,5]thiadiazole from Step 1 was dissolved in anhydrous DMF (160 mL) under nitrogen. Then, CuCN (7.27 g, 81 mmol) was added and the mixture was heated to 150° C. overnight. After cooling down, a solution of FeCl3 (19.7 g) in concentrated HCl (7 mL) and water (40 mL) was added dropwise and the mixture was stirred at 70° C. for 30 minutes. After extraction with DCM (200 ml×2), the combined organic phases were extracted with HCl (6M, 100 mL×3), water (100 mL), and brine (100 mL), and dried over MgSO4. Concentration gave a brown solid which was purified by column chromatography with DCM as the eluent. Finally, a white solid was obtained (2.95 g, 65% yield for two steps). 1H NMR (CDCl3 500 MHz): δ: 8.48 (d, 1H, J=1.5 Hz), 8.16 (d, 1H, J=9.0 Hz), 7.75 (dd, 1H, J=9.0, 1.5 Hz).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][NH:10][CH3:11])[N:8]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH:29]([CH3:31])[CH3:30])[NH:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O.C(N(CC)CC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH:29]([CH3:30])[CH3:31])[NH:16][C:17]([N:10]([CH3:11])[CH2:9][C:7]1[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=1)=[O:19]
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Reactant: CNCc1csc(C(C)C)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Yield: 72.1 %

Procedure:
A solution of 15.7 g (92 mmol) of 2-isopropyl-4-(((N-methyl)amino)methyl)thiazole in 200 ml of THF was combined with a solution of 20.5 g (69 mmol) of N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester. The resulting solution was treated with 1.6 g of 4-dimethylaminopyridine and 12.9 ml (92 mmol) of triethylamine, heated at reflux for 2 h, allowed to cool, and concentrated in vacuo. The residue was taken up in CH2Cl2, washed extensively with 5% aqueous K2CO3, dried over Na2SO4, and concentrated in vacuo. The resulting product mixture was purified by silica gel chromatography using chloroform as an eluent to provide 16.3 g (54%) of the desired compound. 1H NMR (DMSO-d6) δ0.88 (d, J=7 Hz, 3H), 0.92 (d, J=7 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 2.05 (octet, J=7 Hz, 1H), 2.86 (s, 3H), 3.25 (heptet, J=7 Hz, 1H), 3.61 (s, 3H), 3.96 (dd, J=8, 7 Hz, 1H), 4.44 (AA', 2H), 6.58 (d, J=8 Hz, 1H), 7.24 (s, 1H). Mass spectrum: (M+H)+ =328.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17][CH2:18]O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)nc1Cl
Yield: 85.2 %

Procedure:
Esterification of 2,6-dichloronicotinic acid (25.5 g, 0.1328 mmol) in EtOH (200 proof, 200 mL) catalyzed with 96% H2SO4 (1.7 g) at refluxing temperature for 40 h under N2 gave the desired ethyl 2,6-dichloronicotinate as grey solid (24.89 g, 0.1131 mmol, yield 85.2%) after a normal work-up.