Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:5]#[N:6].[OH-:22].[K+]>>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:5]([NH2:6])=[O:22]
Reactant: [OH-]
Reactant: CON=C(C#N)c1ccccc1COc1cccc(Cl)c1
Agent: [K+]
Product: CON=C(C(N)=O)c1ccccc1COc1cccc(Cl)c1
Temperature: 80 °C
Yield: 58 %

Procedure:
7.0 g (23 mmol) of 2-methoxyimino-2-[2-(m-chlorophenoxymethyl)-phenyl]acetonitrile were added to a mixture of 50 ml of glycol and 10 ml of a 25% by weight aqueous solution of potassium hydroxide, and the reaction mixture was then heated at 80° C. for 2 hours. The solid was then separated off, washed with methyl tert-butyl ether and dried. Yield: 58%;
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(NC(=O)c5cccc(C(C)(C)C#N)c5)c4)cc3s2)CC1
Reaction time: 14 h
Yield: 28.6 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (452 mg, 1.05 mmol) produced in Example A12(iv) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (273 mg, 1.18 mmol), N,N-dimethylpyridine-4-amine (89.1 mg, 729 μmol), triethylamine (10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (492 mg, 2.57 mmol) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (483 mg, 2.52 mmol) and N,N-dimethylpyridine-4-amine (292 mg, 2.39 mmol) and the mixture was further stirred for 4 hr. To the reaction mixture was added methanol (10 mL), and the mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (50 mL×2) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→20/80) and triturated with ethyl acetate and diisopropyl ether to give the title compound (171 mg, 29%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CN(C)C=O.N1C(Cl)=NC(Cl)=NC=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([NH:12][C@H:3]([C:2]#[N:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@@H](C#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound obtained from Example 11 was added dimethylformamide (1019.5 g) followed by addition of cyanuric chloride (112.0 g) dropwise for 1.5 hours at temperature below 25° C. The reaction solution was stirred for one hour at room temperature, and then 0.1 N aqueous sodium hydroxide solution (1850.0 g) and toluene (1860 ml) were added thereto to separate the layers. The organic layer thus obtained was washed once again with water (700 ml) and then distilled under reduced pressure to obtain 318.3 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2S[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])[CH3:2].C(=O)([O-])O.[Na+].ClC1C=CC=C(C(OO)=O)C=1.[S:47]([O-:51])(O)(=O)=[O:48].[Na+]>ClCCl>[CH2:1]([C:3]1[C:11]2[S:47](=[O:51])(=[O:48])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])[C:4]=1[CH3:30])[CH3:2]
Reactant: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Reactant: O=S(=O)([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a mixture of N-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (225 mg, 0.512 mmol) obtained in Example 164 and sodium hydrogen carbonate (250 mg, 0.590 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (283 mg, 1.65 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 2 hours. To the reaction solution was added an aqueous sodium hydrogensulfate solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 74 mg (yield: 28%) of the title compound. Amorphous powder.
Reaction SMILES: COC1C=C(C(C2C=CC=C(N)C=2)=CC#N)C=CC=1OC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=2)=[CH:33][C:34]#[N:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>[Pd].C(OCC)(=O)C>[NH2:42][C:39]1[CH:40]=[CH:41][C:36]([C:32]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:33][C:34]#[N:35])=[CH:37][CH:38]=1
Reactant: COc1ccc(C(=CC#N)c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd]
Agent: COc1ccc(C(=CC#N)c2cccc(N)c2)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC#N)c2ccc(N)cc2)cc1OC

Procedure:
3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to 3-(3,4-dimethoxyphenyl)-3-(3-aminophenyl)acrylonitrile using 3-(3,4-dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile (1.24 g, 4 mmol) and 0.15 g of 10% palladium on carbon catalyst in 100 mL of ethyl acetate. The crude mixture was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) to afford 0.19 g (17%) of a mixture of the E and Z isomers as a yellow solid: mp 150-152° C.; 1H NMR (CDCl3) δ7.38-6.56 (m, 14 H); 5.51 (s, 1 H), 5.44 (s, 1 H), 3.97 (br s, 4 H), 3.93 (s, 3 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.82 (s, 3 H); 13C NMR (CDCl3) δ162.8, 162.6, 150.8, 150.3, 148.8, 148.7, 148.5, 148.4, 132.4, 131.4, 130.1, 129.5, 129.9, 128.6, 126.7, 123.0, 122.1, 114.4, 114.3, 112.8, 111.6, 110.7, 90.3, 89.9, 56.0, 55.9; Anal. Calcd for C17H16N2O3. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.79; H, 5.83; N, 9.59.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.CCCCCC.[C:21]1([CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([CH2:27][CH2:28][C:29]([N:5]2[C@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]2=[O:9])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)C1COC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[C@@H]1COC(=O)N1C(=O)CCc1ccccc1
Temperature: 78 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a stirred solution of 4-(2-propyl)-oxazolidine-2-one in anhydrous tetrahydrofuran (250 ml) under a nitrogen atmosphere at -78° C. were added in a dropwise fashion a solution of n-butyllithium in hexane (50 ml, 77.4 mmol) over 5 to 10 min. After stirring an additional 20 min at 78° C. 3-phenylpropionyl chloride (12.7 ml, 85.2 mmol) was added neat. The reaction was warmed to room temperature and stirred 1 to 2 h. The reaction was quenched by adding 100 ml of saturated aqueous ammonium chloride and the volatiles removed by rotary evaporation. The resulting aqueous residue was extracted three times with ether and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate provided the title compound (16.6 g, 82%). m.p.=86.5° to 87.5° C. Mass spectrum: (M+NH4)+ =279, (M+H)+ = 262.
Reaction SMILES: [CH2:1]([CH:17]1[CH2:21][CH:20]=[CH:19][O:18]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][CH2:14][CH2:15][CH3:16].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[Cl-:22].[CH2:1]([CH:17]1[CH2:21][CH2:20][CH:19]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N+:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:18]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][CH2:14][CH2:15][CH3:16]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCC1CC=CO1
Reactant: OCCCCCCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCC1CCC(OCCCCCC[n+]2ccccc2)O1
Product: [Cl-]

Procedure:
Analogous to Example 8 but (step a) using dimethylformamide as solvent starting from 2-hexadecyl-2,3-dihydrofuran and 6-chlorohexanol instead of 2-bromoethanol to give the trans and the cis 2-hexadecyl-5-(6'-chloro)-hexyloxy-tetrahydrofuran and (step b) performing the substitution of the chloro atom by pyridine by heating (60°-80° C.) 0.3 g (0.7 mmol) of each chloro compound, pyridine (2 ml) and dimethylformamide (2 ml) overnight with stirring. Evaporation of the excess of pyridine and dimethylformamide leaded to residus which were chromatographed on silica gel using successively 10, 15 and 20% MeOH in CHCl3 as eluents. The title compounds were recovered as waxy solids.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[C:50](=[O:51])[C:49]3[S:48][C:47]4[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=4[C:41]=3[CH:40]=[N:39]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:38]2[C:50](=[O:51])[C:49]3[S:48][C:47]4[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=4[C:41]=3[CH:40]=[N:39]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:32][O:33][CH2:34]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@H]1CN(C2COC2)CCN1c1cnc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)cn1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
A mixture of 230j (80 mg, 0.11 mmol) and lithium hydroxide (27 mg, 1.1 mmol) in i-propanol/THF (1:1, 10 mL) and water (2 mL) was stirred at 35° C. for 0.5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 230 (34 mg, 45%). MS-ESI: [M+H]+ 668.2. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.46 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.34 (d, J=1.5 Hz, 1H), 7.85 (s, 1H), 7.53 (d, J=6.0 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 4.84 (bs, 1H), 4.58-4.54 (m, 2H), 4.50-4.47 (m, 1H), 4.43-4.36 (m, overlap, 4H), 3.78-3.75 (m, 1H), 3.59 (s, 3H), 3.39-3.35 (m, 1H), 3.02-3.0 (m, 1H), 2.98-2.95 (m, 2H), 2.90-2.82 (m, 2H), 2.78-2.76 (m, 1H), 2.60-2.56 (m, 1H), 2.10-2.09 (m, 1H), 1.95-1.88 (m, overlap, 5H), 1.10 (d, J=8.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:26][N:27]4[CH2:28][CH2:29][CH:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:31][CH2:32]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1CN1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(CN3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 30.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.26 g) and 5-amino-2-((4-morpholinopiperidin-1-yl)methyl)benzonitrile (0.3 g), the title compound (0.16 g) was obtained, melting point: 167–168° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>ClCCl.C(Cl)(Cl)Cl>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of N-hydroxyphthalimide (16.31 g, 100 mmol) in dichloromethane (300 ml) was added triethylamine (20.91 ml, 150 mmol) and the mixture was stirred at 0° C. tert-Butyl bromoacetate (14.77 ml, 100 mmol) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with chloroform (100 ml) and washed with water (300 ml). The organic layer was washed with brine (300 ml) and dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. n-Hexane:ethyl acetate (80:20, 100 ml) was added to the residue and the obtained precipitate was collected by filtration to obtain the title compound (26.72 g, 96%).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br-:11].[Li+].CC(=O)CCC>>[Br:11]/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [Br-]
Reactant: CCCCCC(=O)/C=C/Cl
Agent: [Li+]
Solvent: CCCC(C)=O
Product: CCCCCC(=O)/C=C/Br

Procedure:
A mixture of 68.0 g. (0.424 mole) of 1-chloro-trans-1-octen-3 one (Example 723) and 444 g. (4.24 moles) of anhydrous lithium bromide in 900 ml. of 2-pentanone is refluxed for 30 minutes, cooled, and partitioned between ice water and ether. The organic phase is washed with water and saturated brine, dried (NaSO4), and evaporated to an oil. This material is used directly without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])[C:13]1=[O:29].O1CCOCC1.[OH-].[Na+]>O>[CH3:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[C:13]1=[O:29]
Reactant: CCOC(=O)C(C(=O)OCC)c1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CC(=O)O)c1=O
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
The crude product solution of diethyl [1-(2,6-dimethyl-4-nitrophenyl)-2-oxo-1,2-dihydropyridin-3-yl]malonate in dioxane (maximum 108 mmol) was introduced as initial charge in 350 ml of water, and 35 ml of concentrated sodium hydroxide solution were slowly added. The reaction mixture was stirred for 90 min at 45° C. After cooling to RT, 100 ml of water were added, followed by washing three times with dichloromethane, and the aqueous phase (pH=14) was admixed with 270 ml of dichloromethane. At 10-15° C., 59.5 ml of concentrated hydrochloric acid were slowly added until the pH=1. Even at a weakly acidic pH, carbon dioxide started to evolve. The reaction mixture was warmed to RT and stirred for 1 h, until the gas stopped evolving. Following phase separation, the organic phase was dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The residue was stirred with 200 ml of methyl tert-butyl ether for 30 min. The crystalline solid was filtered off with suction, washed with methyl tert-butyl ether and dried in vacuo. 14.8 g (47% over 2 stages) of the desired product were obtained. The mother liquor was largely concentrated, the post-precipitation was filtered off with suction, after-washed and dried in vacuo. A further 5.3 g (17% over 2 stages) of the desired product were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[CH:39](B1OC(C)(C)C(C)(C)O1)=[CH2:40]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[F:38][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][C:28]([C:27]1[CH:26]=[N:25][N:5]3[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:2]([CH:39]=[CH2:40])=[N:3][C:4]=13)=[CH:37]2
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
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: [Na+]
Solvent: C1COCCO1
Product: C=Cc1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
To 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (2.5 g, 4.4 mmol) in 1,4-Dioxane (50 mL) and 2M Na2CO3 (25 mL) was added vinylboronic acid pinacol ester (0.9 ml, 5.2 mmol), and Pd(PPh3)4 (0.5 g, 0.4 mmol). The reaction mixture was heated at 100° C. for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. Following removal of dioxane under reduced pressure, organics were extracted with CH2Cl2 (4×40 mL, dried (Na2SO4) and concentrated in vacuo. Gradient column chromatography on silica eluting with 20 to 50% EtOAc/hexanes gave 3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5-vinylpyrazolo[1,5-a]pyrimidin-7-amine as a yellow solid (2.2 g, 3.89 mmol, 88%). LC/MS: 3.05 mins, m/z=566.3 (MH+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH:12]=[CH2:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 121.4 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-ylcarbamate (95 g, 0.3 mol) and MeI (46.7 mL, 0.75 mol) in DMF (500 mL) was added sodium hydride (60%, 18 g, 0.45 mol) at 0° C. The reaction was stirred at 0° C. for 3 h and LC-MS showed the reaction was complete. The reaction was quenched with saturated NH4Cl solution and filtered. The filtrate was concentrated to remove most of DMF and the residue was dissolved in EtOAc (1.5 L). The organic layer was washed with water and brine, dried over Na2SO4. The above steps were repeated with another 127 g of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-ylcarbamate. The organic layers were combined and concentrated. The resulting residue was purified on silica gel column using a mixture of hexanes and EtOAc to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (120 g, 40% for 4 steps). LRMS (M+H+) m/z 230.2.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16]SC[C@@H](C(O)=O)NC(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NCCC1C=NC=CC=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:43]([O:42][CH2:41][CH:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:16])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) and HBTU (1.2 eq) were stirred in dry DCM (0.1 M) at room temperature. 3-(2-aminoethyl)pyridine (1.2 eq) was then added followed by diisopropylethylamine (2.0 eq) and the reaction was allowed to stir at room temperature for 2 hours. The crude reaction mixture was then loaded directly onto a silica column and purified by purified by flash chromatography on a COMBIFLASH® system (ISCO) using a 100% Hex, 0-50% EtOAc/Hex, 100% EtOAc gradient to give (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-oxo-3-(2-pyridin-3-yl)ethylamino)propylthio)propane-1,2-diyl didodecanoate.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][Cl:27])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCCl
Temperature: 45 °C
Yield: 33.8 %

Procedure:
A mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.2 g, 3.3 mmol), (prepared as described for the starting material in Example 48), 1-bromo-3-chloropropane (1.6 ml, 16 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (25 ml) was heated at 45° C. for 3 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×70 ml). The organic extracts were combined, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with hexantlethyl acetate, collected by filtration and dried under vacuum to give 4-(4-bromo-2-fluoroanihno)-7-(3-chloropropoxy)-6-methoxyquinazoline (492 mg, 34%).