Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]3[C:36](=[C:37]([CH3:39])[CH:38]=2)[N:35]([CH3:40])[N:34]=[CH:33]3)=[O:29])[CH:23]=1>CN(C=O)C>[CH3:40][N:35]1[C:36]2[C:32](=[CH:31][C:30]([C:28]([C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[O:29])=[CH:38][C:37]=2[CH3:39])[CH:33]=[N:34]1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(C)c12
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(cnn5C)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 mg (0.12 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 45 mg (0.13 mmol) (6-chloro-pyrimidin-4-yl)-(1,7-dimethyl-1H-indazol-5-yl)-methanone and 25 μL (0.18 mmol) TEA were combined in 1 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and evaporated down to approx. 10 mL. This residue was neutralised with saturated sodium hydrogen carbonate solution, the precipitate formed was suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Br.O.C[N+]1([O-])CC[O:16]CC1.[NH4+].[Cl-].CCOC(C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[O:16]
Reactant: Fc1ccc(CBr)c(Br)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(F)cc1Br
Temperature: 70 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of the benzyl bromide of Step 1 (59 g, 220 mmol) in dioxane (500 mL) at r.t. was added N-methylmorpholine N-oxide monohydrate (89 g, 660 mmol). The reaction mixture was stirred for 1 hour at 70° C. and poured into a mixture of saturated aqueous NH4Cl and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4 and concentrated to give 44 g of the title compound as a white solid and used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](Cl)=[N:10][OH:11])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH:20]#[C:21][CH2:22][CH3:23]>CCOCC>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:9]2[CH:20]=[C:21]([CH2:22][CH3:23])[O:11][N:10]=2)=[CH:5][N:6]=1
Reactant: ON=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: C#CCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCc1cc(-c2cnc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5,6-Dichloro-N-hydroxy-3-pyridinecarboximidoyl chloride (0.85 g, 3.8 mmol) was dissolved with stirring in ether (60 mL) and a solution of triethylamine (0.8 g, 7.9 mmol) in ether (50 mL) added dropwise to the solution while 1-butyne was bubbled through the reaction mixture. The mixture was stirred at room temperature overnight, filtered, and the filtrate evaporated to dryness under reduced pressure. Recrystallisation of the residue from hexane gave the desired product (0.83 g, 90%) as a cream solid, melting point. 98-9° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:23](OCC)=[O:24].[O-]CC.[Na+].Cl>C(O)C>[OH:24][CH:23]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 71.7 %

Procedure:
N-[3-(2-Oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (0.957 g, 3.25 mmol) and ethyl formate (0.781 mL, 9.75 mmol) were dissolved in anhydrous ethanol (6.50 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (6.07 mL, 16.26 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (0.752 g, 2.33 mmol, 71%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:19](I)[CH2:20][CH3:21]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:19]([NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:20][CH3:21]
Reactant: CCCI
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCNc1c2c(nc3ccccc13)CCCC2=O
Reaction time: 0.5 h
Yield: 63 %

Procedure:
In a mixture consisting of 150 ml of dichloromethane and 100 ml of 50% NaOH were combined 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 0.80 g (0.10 eq) of tetrabutylammonium hydrogensulfate. The biphasic mixture was stirred for 0.5 hour and thereafter 6.9 ml (3 eq) of n-propyl iodide was added and the stirring at room temperature was continued for 2 days during which three more portions of the above quantities of the alkylating agent were added at 12 hour intervals. The reaction was then complete based on thin layer chromatography analysis. The organics were separated and purified by passing through an alumina column (dichloromethane). The product was recrystallized from dichloromethane/Et2O to yield 3.77 g (63%) of a solid, melting point 145° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](OC=C)(=[O:11])[CH3:10].[OH-].[Na+]>O1CCOCC1.O.CO>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([OH:11])=[CH2:10]
Reactant: C=COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C=Cc1ccccc1
Solvent: C1COCCO1
Product: C=CO

Procedure:
12 g. of styrene-vinyl acetate (prepared by General Preparation proceudure described above) were dissolved in 150 ml of dioxane in a reaction flask equipped as described above. To this was added 1.05 g of sodium hydroxide in 15 ml of water. The reaction was heated to reflux overnight. The resulting styrene-vinyl alcohol copolymer was obtained by precipitation in methanol, washed successively with water and excess methanol then dried overnight in a vacuum oven. The product was identified by spectroscopic analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[C:21]([CH3:23])[C:11]([O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15]3)=[C:10]([CH3:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl.O.C(OCC)(=O)C>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[C:21]([CH3:23])[C:11]([O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15]3)=[C:10]([CH3:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2cccc(N)c2)cc(C)c1OCC1CCCN(C)C1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(-c2cc(C)c(OCC3CCCN(C)C3)c(C)c2)c1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of 3-[4-(3-aminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine (513 mg, 1.58 mmol) in dichloromethane at 0° C. was added pyridine (1.3 mL, 16 mmol) and acetic anhydride (0.75 mL, 8.0 mmol). The mixture was stirred overnight at a temperature range from 0° C. to room temperature, and diluted with water and ethyl acetate. The aqueous layer was extracted with dichloromethane (3×), and the organic layers were dried and concentrated. The residue was purified on silica gel, eluting with 10% methanol/dichloromethane containing 0.5% ammonium hydroxide, to give 3-[4-(3-acetylaminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine (479 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27]3)=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=C(NC1CC1)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc(C(=O)NC3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.578 g, 5.25 mmol) in DMA (8.75 mL) was treated with potassium tert-butoxide (0.663 g, 5.90 mmol), stirred at RT for 1 h, treated with a solution of 4-chloro-N-cyclopropylpicolinamide (0.86 g, 4.37 mmol) in DMA (8.75 mL) and stirred at RT for 20 h. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/EtOAc) to afford 4-((6-aminopyridin-3-yl)oxy)-N-cyclopropylpicolinamide (0.674 g, 57%). 1H NMR (400 MHz, DMSO-d6): δ 8.72 (d, J=5.0 Hz, 1H), 8.44 (d, J=5.6 Hz, 1H), 7.82 (d, J=2.9 Hz, 1H), 7.31-7.30 (m, 2H), 7.11 (dd, J=5.6, 2.6 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 2.85-2.84 (m, 1H), 0.65-0.62 (m, 4H); MS (ESI) m/z: 271.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH:14]([O:17][CH3:18])[O:15][CH3:16])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]([OH:29])[N:8]([C:20]([CH3:28])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:9]2=[O:19].CN(CCN(C)C)C.[I:38]I>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]([CH:14]([O:15][CH3:16])[O:17][CH3:18])=[CH:12][C:11]([I:38])=[C:10]2[C:6]=1[CH:7]([OH:29])[N:8]([C:20]([CH3:21])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:28])[C:9]2=[O:19]
Reactant: II
Reactant: COCOc1c(C(OC)OC)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(C(OC)OC)cc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 51.1 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxymethoxy-5-dimethoxymethyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (3.34 g, 8.31 mmol) was dissolved in THF (100 mL), and the solution was treated with TMEDA (4.00 mL, 27.0 mmol), sec-butyl lithium-hexane solution (1.03 mol/L, 25.8 mL, 26.6 mmol) and iodine (3.16 g, 12.5 mmol), followed by purification by slurry using methanol and diisopropylether to obtain 4-methoxymethoxy-5-dimethoxymethyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (2.24 g, yield 51%).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)(=[O:21])[CH3:20]
Reactant: NCc1cccc2ccccc12
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)NCc2cccc3ccccc23)cc1
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
1-Napthalene-methylamine (1.118 g, 7.11 mmol) was dissolved in THF before pyridine (1.725 ml, 21.3 mmol) was added. 4-Acetyl-benzenesulfonyl chloride (1.554 g, 7.11 mmol) was then added as a solid, and the resulting dark solution was stirred for 10 minutes. The volatiles were then removed, and the resulting residue was suspended in THF. Excess Et3N was then added, and the mixture was stirred for several minutes before the solids were filtered. The mother liquor was then evaporated to a solid which was recrystalized in ethylacetate and hexanes to yield 0.5697 g (0.00167 mol, 23%) of desired compound that was pure enough for the next step. LC-MS (ES+): 340 [MH]+ m/e.
Reaction SMILES: [CH2:1](O)C.[NH2:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:11]([F:16])[CH:12]=2)[N:7]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:6]=1.N1(CO)C2C=CC=CC=2N=N1.[BH4-].[Na+]>O>[CH:18]1([NH:17][C:10]2[CH:9]=[C:8]3[C:13]([C:14](=[O:15])[C:5]([NH:4][CH3:1])=[CH:6][N:7]3[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:12][C:11]=2[F:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCC(CC)n1cc(N)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reactant: CCO
Agent: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCC(CC)n1cc(NC)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 4 ml ethanol solution of 220 mg of 3-amino-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one was added 105 mg of 1H-1,2,3-benzotriazol-1-ylmethanol, followed by overnight stirring at room temperature. Next, 48 mg of sodium borohydride was added to the reaction mixture, followed by stirring for 3 hours. By adding water to the resulting reaction mixture and collecting the insoluble materials by filtration, 100 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-3-(methylamino)quinolin-4(1H)-one was obtained.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].C(N(CC)CC)C.O=[S:22]1[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:42])[N:29]([CH2:39][CH2:40][CH3:41])[C:30](=[O:38])[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:23]12>C(Cl)Cl>[OH:4][CH:27]1[S:22][C:23]2=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:30](=[O:38])[N:29]([CH2:39][CH2:40][CH3:41])[C:28](=[O:42])[N:24]2[CH2:25][CH2:26]1
Reactant: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2=O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCC(O)S2
Temperature: 40 °C
Reaction time: 60 h
Yield: 77.5 %

Procedure:
Trifluoroacetic anhydride (3.78 g) and triethylamine (1.82 g) were added to a solution of 1-oxo-9-phenyl-7-propyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (4 g) in methylene chloride (60 ml) and the mixture was stirred at 40° C. for 60 hours. The reaction solution was evaporated to dryness, and the residue was dissolved in methylene chloride-H2O. Then, the organic layer was washed with a saturated aqueous sodium bicarbonate. After drying, the organic solution was concentrated, and the resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystalized from methylene chloride-isopropyl ether to give colorless needles (3.1 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[CH3:27][N:28]([CH3:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([NH:1][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([N:28]([CH3:38])[CH3:27])=[CH:30][CH:31]=5)=[CH:3][CH:4]=4)[N:8]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:13])=[O:12])[CH:7]=3)=[CH:25][CH:24]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: Nc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(N)ccc23)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(NC(=O)c5ccc(N(C)C)cc5)ccc34)cc2)cc1

Procedure:
Compound 991 was prepared according to the procedure described in Scheme IV from 6-amino-3-(4-aminophenyl)-1-(phenylsulfonyl)indole and 4-dimethylaminobenzoic acid. [M+H]+ calcd for C38H35N5O4S: 658.31; found: 658.19.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH:5][CH:6]=[C:7]([C:21]#[N:22])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20])=O.CO.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:20][C:12]1[CH:13]=[C:14]([Cl:19])[C:15]([O:17][CH3:18])=[CH:16][C:11]=1[NH:10][C:8]1[C:23]2[C:4](=[CH:3][C:2]([F:1])=[C:25]([O:26][CH3:27])[CH:24]=2)[N:5]=[CH:6][C:7]=1[C:21]#[N:22]
Reactant: COc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: CC#N
Product: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reaction time: 2 h
Yield: 54.8 %

Procedure:
To a suspension of 3-fluoro-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (360 mg, 0.88 mmol) in 40 mL of acetonitrile was added 0.1 mL of methanol. The reaction mixture was heated to reflux and phosphorous oxychloride (0.65 mL, 7.0 mmol) was added dropwise, via syringe. After 2 hours the mixture became a clear orange solution. This solution was heated at reflux overnight. After 24 hours, the reaction mixture was cooled in an ice-bath and the solid was collected by filtration, washed with cold acetonitrile (20 mL) and then suspended in tetrahydrofuran (50 mL). To both the acetonitrile filtrate and the tetrahydrofuran suspension were added concentrated ammonium hydroxide (2×25 mL) and the mixtures were stirred for 1 hour. Water (2×400 mL) was added and stirring was continued for 2 hours. The resulting solids were combined, washed with hot water and dried under reduced pressure at ˜40° C., overnight, to provide 189 mg (55%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile as orange crystals, mp 219-221° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 4.02 (s, 3H), 7.36 (s, 1H), 7.65-7.80 (m, 2H), 8.08 (d, J=9 Hz, 1H), 8.48 (s, 1H), 9.85 (s, 1H); MS (ES) m/z392.0, 394.0 (M+H)+
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2[C:13]([C:17](=[O:19])[NH2:18])=[C:14]([NH2:16])[S:15][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2[C:13]([C:17](=[O:19])[NH2:18])=[C:14]([NH:16][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)=[O:29])[S:15][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: C=CCOC(=O)N1CCc2c(sc(N)c2C(N)=O)C1
Solvent: c1ccncc1
Product: C=CCOC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Yield: 46 %

Procedure:
Starting material 8 (1 g, 3.6 mmol) was dissolved in 12 ml of pyridine and p-chlorphenyl isocyanate (546 mg, 3.6 mmol) was added. The red solution was stirred over the weekend. The solvent was reduced in a vacuum centrifuge. The crude product was used without further purification (green-brown solid, 1.13 g, 65% content 9, 46% yield).
Reaction SMILES: CC1(C)S[C@@H]2[C@H:7]([NH:10]C([C@H](N)C3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N.OS(O)(=O)=O.CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.CCN1C2N=C(C)C=CC=2C(=O)C(C(O)=O)=C1.C([O-])(=O)CCCCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCCCCCC.C(OCCCCCCCCCC([O-])=O)CC.C(O)C(N)(CO)CO.CCCCCCCCCCCCOS([O-])(=O)=O.[Na+].SCCO.SC[C@H]([C@@H](CS)O)O>OCC(CO)O>[CH2:7]([NH2:10])[C:8]([NH:4][CH2:3][C:21]([OH:23])=[O:22])=[O:9]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CCCCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCCCCCCCCCC(=O)[O-]
Solvent: OCC(O)CO
Product: NCC(=O)NCC(=O)O
Temperature: 37 °C
Reaction time: 0.33 h

Procedure:
Fatty acid labeling of PK-A C-subunit produced in E. coli. Four ml cultures of the double transformants were shaken at 37° C. to an OD600 of 0.5 in LB broth+100 μg/ml ampicillin and 100 μg/ml kanamycin sulfate. Isopropyl-β-D-thiogalactopyranoside (IPTG) was then added to a final concentration of 1 mM to induce NMT production (see Results, below). When the cultures reached OD600 =1.0 (approximately 40 min later), nalidixic acid was added to a final concentration of 50 μg/ml to induce C-subunit production (see Results, below). 3H!Myristate (New England Nuclear; 39.3 Ci/mmol, 113 μCi added per ml of culture), 3H!palmitate (New England Nuclear; 30 Ci/mmol, 143 μCi/ml), or 3H!10-(propoxy)decanoate Heuckeroth and Gordon, Proc. Natl. Acad. Sci. USA 86, 5262-5266 (1989)! (31.7 Ci/mmol, 800 μCi/ml) was added simultaneously with the nalidixic acid. Cultures were shaken for an additional 20 min at 37° C. and the cells were harvested by centrifugation. Lysates were prepared by boiling E. coli contained in the pellet for 10 min in 40 μL of a solution of 125 mM Tris, pH 8.0, 4% SDS, 20% glycerol, 10% β-mercaptoethanol, and 0.2M dithiothreitol. Cell debris was removed by centrifugation and 15 μl aliquots of the supernatant were subjected to SDS-PAGE Laemmli, Nature 227, 680-685 (1970)! and subsequent fluorography using EN3HANCE (New England Nuclear) autoradiography enhancer. For Western blot analyses, 50 μg of reduced and denatured lysate proteins, prepared from unlabeled E. coli producing Gly2 -C-subunit or Ala2 -C-subunit, were separated by SDS-PAGE, electroblotted onto nitrocellulose Burnette, Anal. Biochem. 112, 195-230 (1981)!, and the filters probed with polyclonal, monospecific rabbit antisera raised against purified mouse C-subunit. Antigen-antibody complexes were visualized with 125I-protein A Burnette, supra.!.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[C:22]([CH2:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:24])=[O:23]>C1COCC1.O>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:26]/[CH2:25][C:22]([OH:24])=[O:23]
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(C=O)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(/C=C/CC(=O)O)c1C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a solution of 2,3-dimethylbenzaldehyde (17.0 g, 41.0 mmol) in THF (40 mL) was added NaHMDS (41.1 mL, 82.1 mmol) at −20° C., and the reaction was stirred for 20 min. (2-Carboxyethyl)triphenylphosphonium bromide (5.0 g, 37.3 mmol) was added to the reaction at −78° C., and reaction was stirred while warming to rt overnight. The solution was diluted with water (50 mL) and extracted with EtOAc (50×3 mL). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated to give 7.00 g (99%) of the crude title compound as a yellow solid. [M+H] calc'd for C12H14O2, 191. Found 191.
Reaction SMILES: [Si:1]([O:14][CH2:15][CH2:16]C)([O:10][CH2:11][CH2:12]C)([O:6][CH2:7][CH2:8]C)[O:2][CH2:3][CH2:4]C.[Si](OC(C)C)(OC(C)C)(OC(C)C)OC(C)C.[Si](OCCOC)(OCCOC)(OCCOC)OCCOC.C[Si](OC)(OC)OC.C=C[Si](OC)(OC)OC.C[Si](OCCOC)(OCCOC)OCCOC.ClC[Si](OCC)(OCC)OCC.C=C[Si](OCCOC)(OCCOC)OCCOC>>[Si:1]([O:6][CH2:7][CH3:8])([O:10][CH2:11][CH3:12])([O:14][CH2:15][CH3:16])[O:2][CH2:3][CH3:4]
Reactant: CCCO[Si](OCCC)(OCCC)OCCC
Agent: C=C[Si](OC)(OC)OC
Agent: C=C[Si](OCCOC)(OCCOC)OCCOC
Agent: CC(C)O[Si](OC(C)C)(OC(C)C)OC(C)C
Product: CCO[Si](OCC)(OCC)OCC

Procedure:
Si(O-n-C3H7)4; Si(O—isoC3H7)4; Si(OC2H4OCH3)4; CH3Si(OCH3)3; CH2═CHSi(OCH3)3; CH3Si(OC2H4OCH3)3; ClCH2Si(OC2H5)3; CH2═CHSi(OC2H4OCH3)3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1>N1C=CC=CC=1>[CH2:1]([N:8]1[C@H:9]([CH3:15])[CH2:10][N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:28])[F:27])[CH:18]=2)[C@@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1Cc1ccccc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A 15 ml portion of pyridine solution containing 0.63 g of (2R,5S)-1-benzyl-2,5-dimethylpiperazine was mixed with 0.7 g of 4-fluoro-2-trifluoromethylbenzonitrile and stirred at 90° C. for 2 days. The reaction mixture was concentrated and the residue was purified by a silica gel column chromatography to obtain the title compound from n-hexane-ethyl acetate (9:2, v/v) as a white solid.