Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([Cl:5])(=O)=O.[CH:6]1([NH:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH:6]1([NH:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][Cl:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCCCN(CCO)Cc1ccccc1)NC1CCCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCN(CCCl)Cc1ccccc1)NC1CCCCCC1
Temperature: 20 °C
Yield: 100.5 %

Procedure:
Methanesulfonyl chloride (0.78 g, 0.52 ml, 6.6 mmole) is added dropwise with stirring to a cooled solution of N-cycloheptyl-5-[benzyl(2-hydroxyethyl)amino]pentanamide (2.14 g, 6 mmole) in dichloromethane (20 ml) in the presence of triethylamine (0.69 g, 0.94 ml, 6.6 mmole). Agitation is maintained for 18 hours at 20° C. The reaction mixture is filtered with iced water (25 ml) then dried over magnesium sulfate. Filtration and evaporation of the solvent under reduced pressure give 2.2 g (98%) of the desired compound in the form of an oil.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][S:9][C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][S:9][C:10]2[C:15]([O:16][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCCc1c(CSc2ncccc2O)ccc(C(C)=O)c1O
Product: CCCc1c(CSc2ncccc2OCC(=O)OCC)ccc(C(C)=O)c1O
Yield: 70.8 %

Procedure:
Using as starting materials 0.10 g of 2-[(4-acetyl-3- hydroxy-2-propylbenzyl)thio]-3-hydroxypyridine obtained in Example 17 and 0.07 g of ethyl bromoacetate, 0.09 g of ethyl [[2-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]pyridin-3-yl]- oxy]acetate was obtained in a manner similar to Example 15.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([O:25][C:26]([NH:28][CH:29]1[CH:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][CH:29]1[CH:33]([CH3:34])[CH2:32][N:31]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1CNCC1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1NC(=O)OC(C)(C)C
Yield: 39.1 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-t-butoxycarbonylamino-4-methylpyrrolidine (0.53 g) and DBU (0.27 g) was refluxed for an hour. After cooling in a refrigerator, the resulting precipitate was collected by filtration and washed with acetonitrile and ether successively to give the title compound (0.32 g) as pale yellow powder, mp 230°-231° C.
Reaction SMILES: O.[NH:2]1[C:6]([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][CH:16]3[CH:11]([CH2:12][CH:13]([C:19]([OH:21])=[O:20])[NH:14][CH2:15]3)[CH2:10]2)=[N:5][N:4]=[N:3]1.S(Cl)(Cl)=O>C(C(CC)CO)C>[CH2:8]([CH:9]([CH2:10][CH3:11])[CH2:18][O:20][C:19]([CH:13]1[CH2:12][CH:11]2[CH:16]([CH2:17][CH2:18][CH:9]([CH2:8][CH2:7][C:6]3[NH:2][N:3]=[N:4][N:5]=3)[CH2:10]2)[CH2:15][NH:14]1)=[O:21])[CH3:7]
Reactant: O=C(O)C1CC2CC(CCc3nnn[nH]3)CCC2CN1
Agent: CCC(CC)CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCC(CC)COC(=O)C1CC2CC(CCc3nnn[nH]3)CCC2CN1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 2.5 g (8.4 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid monohydrate (prepared as described in J. Med. Chem., 39 (11), pp. 2232-2244, (1996) or U.S. Pat. No. 5,670,516 (issued Sep. 23, 1997)) in 20 ml of 2-ethyl-1-butanol, 6.8 ml (92.8 mmol) of thionyl chloride is added. The solution is stirred at 120° C. for 3 hr. The mixture is concentrated in vacuo and the residue washed with ethyl ether. The residue is purified by SPE (Oasis HLB) to afford the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16]([NH2:17])=[C:15]3[CH:18]=[CH:19][O:20][C:14]3=[N:13][CH2:12]2)=[CH:7][CH:6]=1)(=O)C>[OH-].[K+].CCO.O>[NH2:17][C:16]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([NH2:4])=[CH:10][CH:9]=2)[CH2:12][N:13]=[C:14]2[O:20][CH:19]=[CH:18][C:15]=12
Reactant: CC(=O)Nc1ccc(N2CN=c3occc3=C2N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Temperature: 60 °C
Yield: 57.7 %

Procedure:
Compound 3-(4-acetamidophenyl)-4-aminofuro[2,3-d]pyrimidine 8 (242 mg) was dissolved in 2 M potassium hydroxide in the mixture of EtOH (16 mL) and water (4 mL). The mixture was heated (60° C.) for 24 h then concentrated in vacuo. Residual oil was triturated with cold water (6 mL) to give precipitation, which was filtrated, washed with water, and dried under the reduced pressure. The compound 9 (118 mg) as pale orange colored was obtained. MS(ES) m/e 227M+H].
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[N:56]1[C:65]2[C:60](=[CH:61][CH:62]=[C:63]([NH2:66])[CH:64]=2)[CH:59]=[CH:58][CH:57]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([C:17]3[C:12]([NH:66][C:63]4[CH:64]=[C:65]5[C:60]([CH:59]=[CH:58][CH:57]=[N:56]5)=[CH:61][CH:62]=4)=[N:13][CH:14]=[C:15]([C@H:44]([N:46]4[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:53])=[O:54])[CH2:48][CH2:47]4)[CH3:45])[CH:16]=3)[N:19]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: Nc1ccc2cccnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4cccnc4c3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0 M in THF) (Aldrich, St. Louis, Mo.; 0.863 mL, 0.863 mmol) was added to a mixture of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 146, Step 6; 156.7 mg, 0.246 mmol) and quinolin-7-amine (Ark Pharm, Libertyville, Ill.; 71.1 mg, 0.493 mmol) in THF (2.5 mL) at 0° C., and the resulting dark brown solution was stirred at 0° C. for 2 h. Excess sodium bis(trimethylsilyl)amide was then quenched with saturated aqueous NH4Cl (2 mL), and the reaction mixture was partitioned between EtOAc (50 mL) and saturated aqueous NH4Cl (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were sequentially washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 6% MeOH/CH2Cl2) furnished (R)-N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)quinolin-7-amine (189 mg, 0.249 mmol, 101% yield) as a yellow-orange foam, which was used directly in Step 2. m/z (ESI, +ve) 760.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=1.NC(N)=[O:27].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:19]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N+:11]=1[O-:27]
Reactant: NC(N)=O
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC(C)C)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-isobutoxynicotinate (758 mg) in acetonitrile (9.4 mL) were added urea-hydrogen peroxide adduct (555 mg) and trifluoroacetic anhydride (793 μL) at 0° C., and the mixture was gradually warmed to room temperature and stirred overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (631 mg) as a pale-yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C>C(OCC)(=O)C>[N+:18]([C:12]1[CH:13]=[C:14]([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:17][C:11]=1[F:10])([O-:20])=[O:19]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Reaction time: 2 h
Yield: 81.1 %

Procedure:
Benzoyl chloride (12 mL, 103 mmol) was added dropwise to 4-fluoro-3-nitroaniline (15.64 g, 100 mmol) and triethylamine (17 mL, 122 mmol) in ethyl acetate (400 mL) at room temperature. The reaction mixture was stirred for 2 hours and then allowed to stand overnight. The reaction mixture was washed with 10% aqueous citric acid solution (200 mL) saturated aqueous sodium bicarbonate solution (200 mL), and brine (100 mL); dried (magnesium sulfate), filtered, and concentrated to about 100 mL at which point a solid began to precipitate. The mixture was cooled to zero degrees and the straw-colored solid collected by filtration to afford the product (21.1 g) in two crops.
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH2:10][OH:11]>ClCCCl.[O-2].[O-2].[Mn+4]>[N:1]1[N:9]2[C:4]([CH2:5][O:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[CH:10]=[O:11]
Reactant: OCc1cc2n(n1)CCOC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Product: O=Cc1cc2n(n1)CCOC2
Temperature: 60 °C
Yield: 76.1 %

Procedure:
To a solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethanol (1.08 g, 7.0 mmol) in 1,2-dichloroethane (30 ml) was added 5.4 g of activated manganese dioxide at room temperature with stirring. The mixture was heated to 60° C. for 1 hr and then stirred at room temperature for 16 hr. The final mixture was filtered through a column of silica gel topped with celite. The filter pad was eluted with methylene chloride, followed by ethyl acetate. The ethyl acetate eluent was evaporated and the residue triturated with to give 0.81 g of a white solid; mp 91° C.; MS (ESI) m/z 153.2 (M+H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(F)cc3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(F)cc1

Procedure:
The 2-trifluoroacetamido-3-(4-fluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (18.6 g, 43.7 mmol) was converted to product in a manner substantially analogous to Example 56 to yield 11.2 g. (77.2%). EA, MS(FD).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C.[ClH:22]>CO>[ClH:22].[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCCO
Agent: Cl
Solvent: CO
Product: NCCCCCCCCCCCCO

Procedure:
To a suspension of 5.0 g of tert-butyl N-(12-hydroxydodecyl)carbamate in 25 ml of methanol was added 3 ml of hydrochloric acid and the mixture was heated under reflux for one hour. The reaction solution was distilled off under reduced pressure, ethyl acetate was added to the residue, the crystal thus precipitated out was recovered by filtration and dried under reduced pressure to afford 3.23 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(Br)c1
Reaction time: 0.33 h
Yield: 10.2 %

Procedure:
To a solution of 3-bromo-4-hydroxy-5-methoxybenzaldehyde (12.1 g, 0.52 mol) in dichloromethane (200 ml) was added 1.0 M boron tribromide in dichloromethane (2.2 eq, 115 ml) at 0°. The reaction was stirred at 0° for 20 min, then at ambient temperature for 2.5 h. The reaction was then cooled to 0°, and quenched by the slow addition of methanol. The solvents were removed under reduced pressure and the trimethyl borate was removed by azeotropation with added methanol. Drying in vacuo yielded the desired product (11.51 g, 100%).
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:13]([NH2:15])=[O:14])#[N:3].O>CO>[NH2:3][C:2]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:10][CH3:11])[CH:9]=2)[N:12]=[C:13]([OH:14])[N:15]=1
Reactant: CCc1ccc(NC(N)=O)c(C#N)c1
Agent: [Na]
Solvent: CO
Solvent: O
Product: CCc1ccc2nc(O)nc(N)c2c1
Yield: 93.5 %

Procedure:
To a solution of sodium metal (0.365 g) in dried methanol (300 ml) was added (2-cyano-4-ethylphenyl)urea (10 g) and the reaction mixture was heated under reflux for 5 hours and a half. The resultant mixture was concentrated under reduced pressure to give a residue, to which was added water. The resultant crystals were separated by filtration, washed with water and dried under reduced pressure to give crystalline 4-amino-6-ethyl-2-hydroxyquinazoline (9.35 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:52])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:49][CH2:50][CH3:51])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[C:38]([CH2:39][CH3:40])=[CH:37][C:36]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)=[C:35]([OH:48])[CH:34]=3)=[CH:23][CH:24]=2)[O:19]1)=[O:17])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][O:11][C:12](=[O:52])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:49][CH2:50][CH3:51])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[C:38]([CH2:39][CH3:40])=[CH:37][C:36]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)=[C:35]([OH:48])[CH:34]=3)=[CH:23][CH:24]=2)[O:19]1)=[O:17]
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCNC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCN)CC2
Reaction time: 2 h
Yield: 110.1 %

Procedure:
2-((tert-butoxy)carbonylamino)ethyl-3-((7-(3-(6-ethyl-4-(4-fluorophenyl)-3-hydroxyphenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propanoate (55.4 mg, 0.07 mmol) was added to dichloromethane (4 mL), followed by anisole (30 mg, 0.28 mmol) and trifluoroacetic acid (4 mL). The solution was stirred for 2 hours, concentrated under reduced pressure, and purified on a short silica column (chloroform/methanol) to afford 48 mg of product. NMR (CDCl3): 0.90, t (3H); 1.14, t (3H), 1.50, m (2H); 1.62, m (2H); 1.87, m (2H); 2.27, m(3H); 2.54, q (2H); 2.58, m (4H); 3.42, b (2H); 4.14, m (6H); 4.44, b (1H); 6.47, d (1H); 6.57, s (1H); 6.80, m (2H); 6.95, s (1H); 7.10, dd (2H); 7.40, dd (2H); 8.81, b (3H). Mass Spec (EI): m/z=623.4 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)[CH:10]=4)[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: Cn1ccnc1COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccnc1COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35_90 mins) to afford N-(1H-indazol-5-yl)-2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-quinazolin-4-amine. (5.4 mg, 0.012 mmol).
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][C:12]2([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:6]1)[CH3:4].C(N(C(C)C)CC)(C)C.CN(C)C=O.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]>ClCCl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([N:15]2[CH2:14][CH2:13][C:12]([CH2:11][CH:7]3[CH2:8][CH2:9][CH2:10][N:5]([CH2:3][CH3:4])[CH2:6]3)([OH:18])[CH2:17][CH2:16]2)=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: CCN1CCCC(CC2(O)CCNCC2)C1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1CCCC(CC2(O)CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Yield: 99.3 %

Procedure:
To a mixture of 4-[(1-ethylpiperidin-3-yl)methyl]piperidin-4-ol dihydrochloride (80 mg) in dichloromethane (10 mL) was added di-iso-propylethylamine (0.12 mL), dimethylformamide (1 mL) and 3,4-dichlorophenylisocyanate (55 mg). After 10 minutes the mixture was evaporated and the residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in dichloromethane to give the title compound as a white solid (110 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[CH:6]=[C:5]([O:16][CH3:17])[C:4]=1B(O)O.[CH2:21]([O:23][C:24](=[O:45])[C@H:25]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[NH:26][C:27](=[O:36])[C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])[CH3:22].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:23][C:24](=[O:45])[C@H:25]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][N:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)=[CH:6][C:5]=2[O:16][CH3:17])=[CH:40][CH:39]=1)[NH:26][C:27](=[O:36])[C:28]1[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=1[Cl:34])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CN2CCSCC2)cc(OC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CN3CCSCC3)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 15.2 %

Procedure:
A mixture of 2,6-dimethoxy-4-(thiomorpholinomethyl)-benzeneboronic acid (1.1 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (0.71 g), Pd(PPh3)4 (1.0 g) and K2CO3 (1.00 g) in DME/H2O (10 mL/0.5 mL) was heated at 80° C. for 6 h under N2. The mixture was worked up and purified according to the procedure described in Example 8-3) to yield 0.15 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-(thiomorpholinomethyl)phenyl]-L-phenylalanine ethyl ester. mp. 86-89° C. ESMS: m/z 616 (MH+). HCl salt: mp. 204-205° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[NH:6][C:7]([CH2:16][CH3:17])=[CH:8][C:9](=[O:15])[C:10]=1[C:11]([O:13]C)=[O:12])[CH3:4]>CO>[CH2:3]([C:5]1[NH:6][C:7]([CH2:16][CH3:17])=[CH:8][C:9](=[O:15])[C:10]=1[C:11]([OH:13])=[O:12])[CH3:4]
Reactant: CCc1cc(=O)c(C(=O)OC)c(CC)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(=O)c(C(=O)O)c(CC)[nH]1

Procedure:
2M Sodium hydroxide (30 ml) was added to a solution of methyl 2,6-diethyl-1,4-dihydro-4-oxopyridine-3-carboxylate (obtained as described in European Patent Application No. 453210) in methanol (60 ml) and the solution was heated under reflux for 48 hours. Volatile material was removed by evaporation and the residue was dissolved in water (50 ml). The solution was washed with ethyl acetate and acidified to pH 4 with 1M citric acid solution. The resultant precipitate was collected by filtration to give 2,6-diethyl-1,4-dihydro-4-oxopyridine-3-carboxylic acid (E) (2.1 g), m.p. 238°-240° C. (decomposition); NMR (CDCl3): 1.3(t, 6H), 2.7(q, 2H), 3.3(q, 2H), 6.45(s, 1H), 12.1(br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[NH:5][CH:6]=1.[Cl-].ClC=[N+](C)C.[O:29]1CCC[CH2:30]1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:8])=[O:9])[NH:5][C:6]=1[CH:30]=[O:29]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)c2[nH]cc(C)c2-c2ccccc2)cc1
Agent: C[N+](C)=CCl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)c2[nH]c(C=O)c(C)c2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
4-Methyl-2-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrole (374 mg) and (chloromethylene)dimethylammonium chloride (872 mg) were stirred at 60° C. for 16 hr in a mixed solvent of tetrahydrofuran (10 mL) and acetonitrile (5 mL). The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a pale-yellow solid (yield 187 mg, 46%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:14][CH2:15][C:16](OC)(OC)OC>>[Cl:14][CH2:15][C:16]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: COC(CCl)(OC)OC
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Product: ClCc1nnc(-c2ccc3c(c2)CCO3)o1
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
A mixture of 2,3-dihydro-1-benzofuran-5-carbohydrazide (2.02 g, 11.3 mmol) and 2-chloro-1,1,1-trimethoxyethane (7.92 ml, 56.7 mmol) was tightly sealed in a vial, and microwave was irradiated thereon at 160° C. for 5 min. The reaction mixture was recrystallized from hexane to give the title compound (2.01 g, yield 75%) as colorless crystals.