Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:17][C:18]1[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[ClH:2].[F:17][C:18]1[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH:20][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cc(O)c(F)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(O)c(F)cc3F)c2cc1OC
Yield: 75.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline hydrochloride (300 mg, 1.15 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 2,4-difluoro-5-hydroxyaniline (184 mg, 0.90 mmol) in isopropanol (10 ml) were heated at reflux for 2 hours. The reaction mixture was then allowed to cool, the precipitated product collected by filtration, washed with isopropanol and dried to give 4-(2,4-difluoro-5-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (250 mg, 65%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[CH:19]=[C:20]([C:22]#[N:23])[O:21][C:17]=3[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C=O)C.O>[N:23]1[NH:26][N:27]=[N:28][C:22]=1[C:20]1[O:21][C:17]2[CH:16]=[C:15]([CH2:14][NH:13][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[C:2]([Br:1])[CH:3]=3)[CH:25]=[CH:24][C:18]=2[CH:19]=1
Reactant: N#Cc1cc2ccc(CNc3ccc(OC(F)(F)F)c(Br)c3)cc2o1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(NCc2ccc3cc(-c4nn[nH]n4)oc3c2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-carbonitrile (651 mg, 1.58 mmol), sodium azide (0.12 g, 1.90 mmol) and ammonium chloride (0.10 g, 1.90 mmol) were dissolved in DMF (15.84 ml). The mixture was stirred at RT for 18 hr. After 18 hr the r×n was not complete and the reaction was heated to 50° C. for 2 hr. The reaction was cooled to RT and diluted with water (pH˜1). The crude material was extracted from the diluted aqueous pH=1 layer three times with a 10% MeOH/90% EtOAc mixture. The combined organic layers were washed 5× with pH=1 water to remove DMF and sodium azide, they were then washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified on basic HPLC (ammonium hydroxide modifier) 15-40% MeCN/Water to give N-((2-(2H-tetrazol-5-yl)benzofuran-6-yl)methyl)-3-bromo-4-(trifluoromethoxy)aniline (413 mg). LCMS retention time=1.35 minutes (LC method 1); MS (m+1)=454.2. 1H NMR (400 MHz, DMSO-d6) δ 4.39 (d, J=5.8 Hz, 2H), 6.66 (dd, J=9.0, 2.8 Hz, 1H), 6.83 (t, J=5.9 Hz, 1H), 6.93 (d, J=2.7 Hz, 1H), 7.08 (d, J=0.9 Hz, 1H), 7.17 (dd, J=9.2, 1.1 Hz, 1H), 7.25 (dd, J=8.0, 1.3 Hz, 1H), 7.54-7.64 (m, 2H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:14]([O:13][C:11]([NH:10][C@H:9]1[C@H:5]([OH:4])[CH2:6][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8]1)=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
t-Butyl (3R,4R)-3-acetoxy-4-benzyloxycarbonylaminopyrrolidine-1-carboxylate (27 g) was dissolved in methanol (350 mL), followed by addition of potassium carbonate (16 g) with ice cooling, and the mixture was stirred overnight at room temperature. Water was added, and then the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1-2:1) to obtain t-butyl (3R,4R)-3-benzyloxycarbonylamino-4-hydroxypyrrolidine-1-carboxylate (22 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:22][OH:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH:22]=[O:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: O=CC1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Tetra-n-propylammonium perruthenate (70 mg, 0.2 mmol) was added in one portion to a stirred mixture of 4-[3-(benzyloxy)-5-fluorophenyl]-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-pyran (1.28 g, 4.0 mmol), N-methylmorpholine N-oxide (0.70 g, 6.0 mmol) and powdered 3 Å molecular sieves (2.0 g) at room temperature under nitrogen atmosphere. After 20 min tetra-n-propylammonium perruthenate (30 mg, 0.085 mmol) and N-methylmorpholine N-oxide (0.30 g, 2.6 mmol) were added and stirring continued for 30 min. The mixture was chromatographed (silica-gel, 110 g: 25% ethyl acetate in n-hexane) to give the titled compound as a colorless liquid (1.08 g, 86%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27]CCCCC.CI>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: CCCCCC
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2csc3ccccc23)C1
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(C2=CCN(CCc3csc4ccccc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (358 mg, 1 mmol) (obtained from example 29, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Light green semi-solid. Yield: 98 mg (26%); 373 (M+H); 1HNMR (400 MHz, CDCl3): 8.08˜7.82 (m, 3H); 7.40˜6.90 (m, 7H); 6.21˜6.19 (s, 1H); 3.80 (s, 3H); 3.48˜2.60 (m, 10H).
Reaction SMILES: CS(C1C=CC([N:11]2C(=O)C=CC(C([O-])=O)=N2)=CC=1)(=O)=O.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([O:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[C:30]([C:49]([O:51]C)=O)=[N:29]2)=[CH:24][C:23]=1[F:53]>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([O:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:38][CH2:37]3)[C:30]([C:49](=[O:51])[NH2:11])=[N:29]2)=[CH:24][C:23]=1[F:53]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)[O-])ccc2=O)cc1
Reactant: COC(=O)c1nn(-c2ccc(Br)c(F)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Br)c(F)c3)nc2C(N)=O)CC1
Yield: 100 %

Procedure:
tert-Butyl 4-(1-(4-bromo-3-fluorophenyl)-3-carbamoyl-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was prepared in 100% yield according to procedures described in Example 31 (Step A) substituting methyl 441-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate for methyl 1-(4-bromo-3-fluorophenyl)-4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-6-oxo-1,6-dihydropyridazine-3-carboxylate (Example 43). MS (ESI) 511 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH2:4][N:3]1[C@@H:8]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:20][C:21]1[N:26]=[C:25]([CH2:27]O)[CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH3:19][C@@H:16]([CH2:17][CH3:18])[C@H:8]([N:3]1[CH2:4][C:5](=[O:7])[N:6]([CH2:27][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:20])[N:26]=2)[C:2]1=[O:1])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: Cc1cccc(CO)n1
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)NC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.6 %

Procedure:
A solution containing the product from Example 36C (0.107 g, 0.396 mmol) in dichloromethane (2 mL) at 0° C. was treated with 6-methyl-2-pyridinemethanol (0.053 g, 0.435 mmol), triphenylphosphine (0.135 g, 0.515 mmol), followed by diethyl azodicarboxylate (0.080 mL, 0.515 mmol), stirred at 25° C. for 16 hours. Water (2 mL) was added and the reaction was stirred for 2 hours at 25° C. The reaction mixture was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate/dichloromethane to give the title compound (0.154 g, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[N:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[CH2:10]2)=[O:4].C(N(CC)CC)C.CCCP(=O)=O.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C1C=CN=CC=1)C.ClCCCl>[F:37][C:38]([F:46])([F:47])[C:39]1[CH:40]=[C:41]([NH:42][C:18]([C:17]2[CH:16]=[C:15]([N:9]3[CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=4[CH2:7][CH2:8]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:43]=[CH:44][CH:45]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)O)c1)C2
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
To a mixture of 3-[5-(methoxycarbonyl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]benzoic acid (63 mg, 0.20 mmol), triethylamine (0.084 mL, 0.60 mmol), and catalytic DMAP in 3.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.143 mL, 0.24 mmol). After 5 min at rt, 3-(trifluoromethyl)aniline (0.037 mL, 0.30 mmol) was added and the reaction stirred at rt for 18 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, dilute aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc to give the title compound as a yellow solid (50 mg, 55%). 1H NMR (Acetone-d6) δ: 9.75 (br. s., 1H), 8.89 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 8.09 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.37-7.47 (m, 3H), 7.28-7.34 (m, 1H), 4.61 (s, 2H), 3.92 (s, 3H), 3.67-3.73 (m, 2H), 3.37 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](=[S:6])[NH2:5].Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:3]([C:4]1[S:6][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:5]=1)[CH:2]([CH3:7])[CH3:1]
Reactant: CC(C)CC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(CC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methylbutanethioamide (example 72, step b) (5.6 g) in ethanol (100 mL) was added ethyl 3-bromo-2-oxopropanoate (6.7 mL). The resulting mixture was stirred overnight at RT, then heated at reflux for 5 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (250 mL) and saturated sodium hydrogen carbonate solution (100 mL). The layers were separated and the organic phase was washed with brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 20:1 to 10:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 5.2 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH:14]=2)[N:9]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:8]1=[O:29].[CH:35]([O-])=[O:36].[NH4+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH:14]=2)[N:9]([CH:23]2[CH2:28][CH2:27][N:26]([CH:35]=[O:36])[CH2:25][CH2:24]2)[C:8]1=[O:29]
Reactant: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCNCC3)c2=O)cc1OC
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 47.2 %

Procedure:
A mixture of 0.070 g of N-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(piperidin-4-yl)-1,2,3,4-tetrahydroquinazolin-6-yl]methyl}acetamide obtained in stage 5.7 and 0.028 g of ammonium formate in 2 ml of ACN is irradiated under a microwave field at 140° C. for 1 h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an MeOH/DCM mixture, (0.5/99.5, v/v) as far as (7/93, v/v), to give 0.035 g of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:7])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
0.35 g (0.8 mmol) of 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoic acid was refluxed together with 0.15 g (0.9 mmol) of N,N'-carbonyldiimidazole in 15 ml of absolute tetrahydrofuran for 2 hours. Then, 1.03 ml (10 mmols) of benzyl alcohol were added, and the mixture was refluxed for 3.5 hours. The reaction mixture was then evaporated in vacuo, and the residue was purified by column chromatography on silica gel (chloroform/acetone=9/1).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH3:4].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:44][CH2:45][C:46]1[C:47]([OH:54])=[N:48][C:49]([CH3:53])=[CH:50][C:51]=1[CH3:52]>ClCCl>[OH:54][C:47]1[C:46]([CH2:45][NH:44][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([CH:3]([CH:2]([CH3:1])[CH3:14])[CH3:4])=[CH:13][CH:12]=2)=[C:51]([CH3:52])[CH:50]=[C:49]([CH3:53])[N:48]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)C(C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C(C)C)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of 4-(3-methylbutan-2-yl)benzoic acid (0.10 g, 0.50 mmol), 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g, 0.7 mmol) and 1-hydroxybenzotriazole (0.10 g, 0.70 mmol) in dichloromethane (20 mL) was added triethylamine (0.2 g, 2.0 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and followed by 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.08 g, 0.5 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water, dried by anhydrous sodium sulfate, then the solvent removed in vacuo to give the crude product, which was purified by Prep-TLC (dichloromethane:methanol=20:1) to give the pure product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(3-methylbutan-2-yl)benzamide (0.08 g, 44%) as a white solid. LR MS (M+H+): calcd for 326.2. found 326. HPLC Purity (214 nm) 99.6%. 1H NMR (CH3OH-d4, 300 MHz): δ 7.71 (d, J=8.1 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 6.10 (s, 1H), 4.49 (s, 2H), 2.49-2.44 (m, 1H), 2.37 (s, 3H), 2.24 (s, 3H), 1.82-1.75 (m, 1H), 3.14-3.06 (m, 1H), 1.24 (d, J=7.2 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.76 (d, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:37]([Si:39]([CH3:42])([CH3:41])[CH3:40])#[CH:38]>C1(C)C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:9]([C:38]#[C:37][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Br)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(C#C[Si](C)(C)C)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C

Procedure:
A mixture of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (200 mg, 0.36 mmol), ethynyltrimethyl silane (184 mg, 1.87 mmol), Pd(PPh)3Cl2 (26 mg, 0.036 mmol), CuI (17 mg, 0.087 mmol) and TEA (0.26 mL, 1.87 mmol) in toluene (5 mL) was sealed in a microwave vile and purged with N2 three times. The resulting mixture was heated at 80° C. for 2 hr before diluted with EA (20 mL) and water (20 mL). The layers were separated. The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 0 to 100% EA in PE) to afford (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-6-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (110). The product was then dissolved in MeOH (5 mL) and KF was added to the solution. The resulting mixture was stirred at r.t. for 30 min and then concentrated in vacuo. The residue was diluted with DCM (10 mL) and water (10 mL). The layers were separated. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford (R)-tert-butyl 3-(4-amino-6-ethynyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (111) (70 mg, 39% yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 496.1.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[C:8](=[O:13])[C:9](=[O:12])[C:10]=1[CH3:11].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].O>CN(C=O)C>[O:12]([C:9]1[C:8](=[O:13])[C:7](=[O:6])[C:10]=1[CH3:11])[Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: Cc1c(O)c(=O)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(O[Si](C)(C)C(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole (11 mmol) is added to a solution of compound 93 (5 mmol) and tert-butyldimethylchlorosilane (5.5 mmol) in 5 mL of DMF cooled by an ice bath. The mixture is allowed to warm to room temperature. After 16 hours, the mixture is poured into water (50 mL) and extracted with ether (3×50 mL), the organic phases are washed with brine (50 mL) and dried over anhydrous MgSO4, and the solvent is evaporated in vacuo. The residue is purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]2[CH:16]=1)=[O:5])C.[OH-].[Na+]>O1CCOCC1.O>[C:14]([C:12]1[CH:11]=[CH:10][N:9]2[CH:16]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]2[CH:13]=1)#[N:15]
Reactant: CCOC(=O)c1cn2ccc(C#N)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccn2cc(C(=O)O)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-cyano-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (501 mg, 2.33 mmol) in 5:1 dioxane/water (30 mL) add sodium hydroxide (130 mg, 3.26 mmol) and stir at 50° C. overnight. Concentrate to a solid and acidify with 4 M HCl in dioxane. Concentrate again to afford the desired product 7-cyano-imidazo[1,2-a]pyridine-2-carboxylic acid and use without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](Cl)=[O:33])=[CH:27][CH:26]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(CC(=O)N2CCCC[C@@H]2COc2cccc3c2C(N)=NS(=O)(=O)N3)cc1
Yield: 14 %

Procedure:
Prepared as in Example 8 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-(4-methoxyphenyl)acetyl chloride in 14% yield. 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.15-1.29 (m, 1H), 1.44-1.65 (m, 4H), 1.70-1.78 (m, 1H), 3.01 (m, 1H), 3.66 (s, 2H), 3.70 (s, 3H), 3.90 (br s, 1H), 4.19 (br s, 1H), 4.43 (t, J=12 Hz, 1H), 5.03 (br s, 1H), 5.64 (d, J=8 Hz, 1H), 6.80 (t, J=8 Hz, 3H), 7.13 (d, J=8 Hz, 2H), 7.41 (t, J=8 Hz, 1H), 7.81 (br s, 2H), 10.63 (s, 1H). M+H=459.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23]([CH2:25][CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)=[N:22][N:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([CH2:26][CH2:25][C:23]3[O:24][C:20]([CH3:19])=[N:21][N:22]=3)=[CH:28][CH:29]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cnccc1-c1ccc(F)cc1
Reactant: Cc1nnc(CCc2ccc(N)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(CCc2ccc(NC(=O)/C=C/c3cnccc3-c3ccc(F)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 21 h
Yield: 73.2 %

Procedure:
A mixture of (2E)-3-[4-(4-fluorophenyl)pyridin-3-yl]prop-2-enoic acid (730 mg), 4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]aniline (640 mg), 1-hydroxy-1H-1,2,3-benzotriazole monohydrate (505 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (733 mg) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 21 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and the obtained solid was recrystallized from water-containing ethanol to give the title compound (941 mg).