Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Si:13]([O:20][CH2:21][CH2:22][NH:23][CH3:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl.[OH-].[Na+]>[CH3:19][C:16]([Si:13]([CH3:14])([CH3:15])[O:20][CH2:21][CH2:22][N:23]([CH3:24])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])([CH3:17])[CH3:18]
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
2,3,4-Trifluorobenzoyl chloride (2.32 mL, 18.16 mmol) was added slowly to a stirred mixture of (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)methylamine (3.44 g, 18.16 mmol) in DCM (200 mL) and 10% aqueous sodium hydroxide solution (200 mL) at 0° C. The reaction was allowed to warm to RT and stirred for a further 24 hours. The phases were separated and the aqueous phase further extracted with DCM (3×100 mL), the combined organics dried (MgSO4), filtered and the solvent removed in vacuo to give a pale yellow oil. The residue was chromatographed on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a colourless oil (5.22 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:26])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cccc(NC(=O)C(F)(F)F)c1Br
Solvent: C1COCCO1
Product: COc1cccc(NC(=S)C(F)(F)F)c1Br
Temperature: 25 °C

Procedure:
A solution of N-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroacetamide (C24) (776 mg, 2.6 mmol) and Lawesson's reagent (1.07 g, 2.6 mmol) in 1,4-dioxane (13 mL) was heated to 135° C. overnight. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. Purification via silica get chromatography (Gradient: 0% to 20% ethyl acetate in heptanes) afforded the title compound as an oil. Yield: 839 mg, 2.60 mmol, quantitative. LCMS m/z 314.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H), 6.92 (dd, J=8.3, 1.1 Hz, 1H), 7.39 (dd, J=8.4, 8.3 Hz, 1H), 8.28 (dd, J=8.2, 0.8 Hz, 1H), 9.75 (br s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][CH:5]1[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[C:34](B(O)O)=[C:33]([CH3:38])[O:32][N:31]=1.C(O)C>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.C1(C)C=CC=CC=1>[CH3:19][CH:18]([O:17][C:16](=[O:21])[NH:15][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:34]3[C:30]([CH3:29])=[N:31][O:32][C:33]=3[CH3:38])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:22])[CH2:6]1)[CH3:20]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)N1c2ccc(Br)cc2C(NC(=O)OC(C)C)CC1C
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3c(C)noc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 38 %

Procedure:
A flask was charged with 1-methylethyl (1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol), potassium carbonate (74.9 mg, 0.542 mmol), 3,5-dimethyl-4-isoxazolylboronic acid (45.8 mg, 0.325 mmol), and tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) then filled with ethanol (1 mL) and toluene (1 mL) and the resulting mixture was refluxed under nitrogen for 20 h. tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) was then added and the mixture refluxed for 40 h then cooled to room temperature and partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and the aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 66% AcOEt in Hexanes) gave 1-methylethyl[(cis)-1-acetyl-6-(3,5-dimethyl-4-isoxazolyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (42 mg, 0.103 mmol, 38%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C(OP([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Br:26])(=O)OCC)C.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[Br:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1/[CH:19]=[CH:7]/[C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:10]
Reactant: CCOP(=O)(Cc1ccccc1Br)OCC
Reactant: O=Cc1cc(Cl)ccc1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Cl)cc1/C=C/c1ccccc1Br
Yield: 81.3 %

Procedure:
5-Chlorosalicylaldehyde (188 g, 1.2 mol) was added to a solution of (2-bromo-benzyl)-phosphonic acid diethyl ester (369 g, 1.2 mol) in tetrahydrofuran (1500 ml) under nitrogen. A solution of potassium tert-butoxide (300 g, 2.68 mol) in tetrahydrofuran (3000 ml) was added while keeping the temperature at 33° C. After completion of the reaction water (1800 ml) was added followed by 4N HCl (450 ml). The organic layer was washed with sodium carbonate solution (500 ml) and saturated NaCl solution. The organic layer was evaporated under reduced pressure at 50° C. to give trans-2-bromo-5′-chloro-2′-hydroxystilbene (301.9 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:34])[CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:34]=[C:30]([CH2:31][CH2:32][CH3:33])[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CCCC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 3.5 g, 16.80 mmol) was dissolved in dry DMF (35 mL). 1,1′-Carbonyldiimidazole (CDI) (3.0 g, 18.48 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-butyramidine (1.88 g, 18.48 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After completion of the reaction, additional CDI (2.99 g, 18.48 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 7 h to effect cyclodehydration. DMF was evaporated and the residue obtained was cooled to room temperature followed by addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[CH:13]=2)(=[O:20])=[O:19])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 3-methylbenzenesulfonyl chloride (1.60 g, 8.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×40 mL). The organic phase was washed with brine (2×30 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a yellow oil (2.1 g, 76%). 1H-NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 6.32 (s, 1H), 5.33 (s, 1H), 2.41 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=1.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=3)[CH2:8][CH2:9]2)=[O:25])=[CH:22][N:21]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(N)nc3)CC2)ccc1Cl
Temperature: 60 °C
Yield: 30.9 %

Procedure:
1-(4-Chloro-3-ethoxy-benzyl)piperidin-4-ylamine (0.33 g, 1.0 mmol), 6-amino-nicotinic acid (0.17 g, 1.0 mmol) and EDCI (0.28 g, 1.2 mmol) were mixed with DMF (5 ml) and heated to 60° C. for 24 h, after which time the reaction was allowed to cool, poured into dilute NaHCO3 and extracted with EtOAc. The combined organic was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (DCM:MeOH 9:1-4:1) affording the title product (0.12 g, 24%).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]2[CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]([OH:19])=O)[C:11]2=[O:20])=[CH:7][CH:6]=1.Cl.[CH3:24][O:25][C:26](=[O:39])[C@H:27]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH2:28]>>[CH3:24][O:25][C:26](=[O:39])[C@H:27]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH:28][C:17](=[O:19])[CH2:16][N:12]1[C:13](=[O:15])[CH2:14][CH:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:22][CH:21]=2)[C:11]1=[O:20]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: NN=Cc1ccc(CC2CC(=O)N(CC(=O)O)C2=O)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CN1C(=O)CC(Cc2ccc(C=NN)cc2)C1=O

Procedure:
403 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acid hydrochloride are coupled with 356.6 mg of L-tryptophan methyl ester hydrochloride by the process described above. After working up and chromatographic purification, 270 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptophan methyl ester are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]2=[O:22])[N:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:23][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[N:3][C:4]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11][C:10]1=[O:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(O)n2)C(=O)C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc(O)ccc2Br)C(=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step A (511 mg, 1.66 mmol) in 10 mL of chloroform at 0° C. was added N-bromosuccinimide (296 mg, 1.66 mmol). After 30 minutes, the solution was concentrated in vacuo. The resulting product was purified by silica gel chromatography (3-4% MeOH/CH2Cl2) to provide the desired product.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:33])[N:25]([CH2:29][CH2:30][CH2:31][NH2:32])[CH:26]([CH3:28])[CH3:27])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.ClCCl.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:32][CH2:31][CH2:30][CH2:29][N:25]([CH:26]([CH3:28])[CH3:27])[C:24](=[O:33])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: CC(C)N(CCCN)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCCN)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (2-{3-[(3-amino-propyl)-isopropyl-carbamoyl]-5-chloro-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.025 g) in dichloromethane (1 ml) was treated with dichloromethane:trifluoroacetic acid (1:1 v/v) (1 ml), stirred for 3 h at room temperature and concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.018 g) as a light brown oil.
Reaction SMILES: [CH3:1][O:2]C1C(OC)=CC(N)=CC=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[NH:21][C:22](=[O:24])[CH3:23]>>[CH3:1][O:2][C:18]1[CH:13]=[C:14]([NH:21][C:22](=[O:24])[CH3:23])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=1
Reactant: COc1ccc(Cl)c(NC(C)=O)c1
Reactant: COc1ccc(N)cc1OC
Product: COc1cc(NC(C)=O)cc(OC)c1

Procedure:
Prepared from 4,5-dimethoxyaniline in analogy to the methods described for N-(2-chloro-5-methoxy-phenyl)-acetamide.
Reaction SMILES: [CH3:1][NH2:2].Br[C:4]1[C:5]([NH2:11])=[N:6][CH:7]=[C:8]([Br:10])[N:9]=1>C(O)C>[NH2:11][C:5]1[C:4]([NH:2][CH3:1])=[N:9][C:8]([Br:10])=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CN
Solvent: CCO
Product: CNc1nc(Br)cnc1N
Temperature: 130 °C
Reaction time: 17 h
Yield: 40 %

Procedure:
1.55 g (50 mmol) of 40% strength aqueous methylamine solution is added to a solution of 2.53 g (10 mmol) of 3,5-dibromo-2-aminopyrazine in ethanol. The mixture is stirred in an autoclave at 130° C. for 17 hours. After evaporation of the solvent under reduced pressure, the product is purified by chromatography on a silica column (eluant=CH2Cl2, to which 3% of CH3OH has been added). 0.8 g (Yld=40%) of 2-amino-5-bromo-3-methylaminopyrazine (m.p. 121° C.) is obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[I:19].Cl[S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:33])[CH:25]=1)(=[O:23])=[O:22]>C1COCC1>[I:19][C:3]1[CH:4]=[C:5]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[C:7]([I:8])[C:2]=1[O:1][S:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([OH:33])[CH:25]=1)(=[O:23])=[O:22]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: COc1ccc(C(=O)c2cc(I)c(O)c(I)c2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cc(I)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(I)c2)cc1
Yield: 15.7 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (4-hydroxy-3,5-diiodo-phenyl)-(4-methoxy-phenyl)-methanone (0.202 g, 0.421 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.398 g, 1.68 mmol) in THF (5 mL). Purification by preparative HPLC (C18, eluting with 70% CH3CN/H2O containing 0.1% TFA) gave 0.045 g (16%) of the title compound as a white solid, mp 214-215° C. 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.11 (d, 2H), 7.44-7.48 (m, 2H), 7.73 (d, 2 H), 8.04-8.07 (m, 3H). IR (KBr) 3400, 3050, 1690, 1600, 1260 and 1175 cm-1. mass spectrum (-ESI) m/z 679 (M-H). Anal. Calcd. for C21H14I2O8S: C,37.08; H,2.07; N,0.00. Found: C,37.43; H,2.24; N,0.00.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>>[C:14]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 4-cyano-3-trifluoromethylaniline and methacryloyl chloride as starting materials, the title compound is prepared according to the method described in J. Med. Chem., 1988, 954–959.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[C:5](=O)[NH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[C:2]([F:1])=[CH:3][N:4]=1
Reactant: O=c1[nH]cc(F)c2cc([N+](=O)[O-])ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2c(Cl)ncc(F)c2c1
Temperature: 115 °C
Yield: 104.2 %

Procedure:
To Intermediate 3E (8.8 g, 36.0 mmol) was added phosphoryl trichloride (59.3 mL, 648 mmol). The suspension was heated at 115° C. for 1.0 h. Solvent was removed under high vacuum. The residue was diluted with EtOAc, washed with sat. sodium bicarbonate, brine and dried over sodium sulfate. After evaporation of solvent, the crude product was dissolved in a small amount of chloroform and charged to a 120 g silica gel cartridge which was eluted with 2% EtOAc in hexanes for 6 min, then a 15 min gradient from 2% to 25% EtOAc in hexanes. The desired fractions were combined and concentrated to give Intermediate 3F (8.5 g, 37.5 mmol, 104% yield) as a slightly yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 9.01 (s, 1H) 8.46-8.56 (m, 2H) 8.34 (s, 1H); 19F NMR (376 MHz, chloroform-d) δ ppm −136.54 (s, 1F); MS (ESI) m/z: (M+H)+ 227.1.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[N:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[S:26][C:25]=1[NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:33][C:25]3[S:26][C:27]4[C:32]([N:24]=3)=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1nc2cccnc2s1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1nc2cccnc2s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Yield: 63.7 %

Procedure:
The compound of example A79 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.2 g, 0.58 mmol), thiazolo[5,4-b]pyridin-2-ylamine (0.133 g, 0.88 mmol), HOBt (0.119 g, 0.88 mmol), and EDCI (0.168 g, 0.88 mmol), N-methyl morpholine (0.178 g, 0.88 mmol) in DMF (10 mL) to provide the title compound (0.175 g).
Reaction SMILES: [H-].[K+].N#N.[CH2:5]([N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:26]I>C1COCC1>[CH2:19]([N:12]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][CH2:14][C:15]([O:17][CH3:26])([CH3:18])[CH3:16])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Reactant: CI
Agent: N#N
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(C)(C)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
Add potassium hydride (30%, 2.6 g, 19.4 mmol) portion wise under N2 to a cooled solution (0° C.) of 4-(dibenzylamino)-2-methylbutan-2-ol (5 g, 17.6 mmol) in THF (50 mL). Stir the mixture at 0° C. for 0.5 h, treat with MeI (2.76 g, 19.4 mmol) dropwise, allow the mixture to warm to RT and stir for 3 h. Re-cool the mixture to 0° C., treat with saturated. NH4Cl, and remove the organics under reduced pressure. Extract the residue with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography (Pet ether/EtOAc, 50:1) to afford the title compound (3.0 g, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.29 (m, 10H), 3.58 (s, 4H), 3.05 (s, 3H), 2.50 (m, 2H), 1.73 (m, 2H), 1.07 (s, 6H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][CH:24]([C:28]([F:31])([F:30])[F:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>ClCCl>[F:29][C:28]([F:30])([F:31])[CH:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:19])[CH3:18])[C:25](=[O:26])[NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:8])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)Nn1cccc1C(=O)Nc1ccccc1)C(F)(F)F
Reaction time: 8 h
Yield: 47 %

Procedure:
1-Amino-N-phenyl-1H-pyrrole-2-carboxamide (570 mg, 2.83 mmol), 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid (826 mg, 3.40 mmol), HATU (1.29 g, 3.40 mmol) and N-methylmorpholine (685 μl, 6.23 mmol) were suspended in 20 mL of dichloromethane and stirred overnight. The reaction mixture was diluted with more dichloromethane and the solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to obtain the title compound in a 47% yield (562 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH2:11]([O:13][C:14](=O)[O:15]CC)[CH3:12]>>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH2:1][C:14]([O:13][CH2:11][CH3:12])=[O:15])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)OCC
Product: CCOC(=O)CC(=O)c1ccc(O)cc1

Procedure:
This novel compound was synthesized by the acylation of 4-hydroxyacetophenone with diethylcarbonate to yield ethyl 4-hydroxybenzoylacetate. Treatment with acetic anhydride and subsequent catalytic hydrogenation yielded the desired product. The experimental details are given below:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.Cl[C:44]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:45]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:45])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC(C)COC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OCC(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl) phenyl)urea (0.0867 g, 0.227 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) at 0° C. was added N,N-Diisopropylethylamine (0.1190 mL, 0.6832 mmol) followed by Isobutyl chloroformate (0.0442 mL, 0.341 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.52 (s, 2H), 3.86 (d, J=6.5, 2H), 3.77-3.68 (m, 4 H), 3.58 (s, 2H), 3.47 (d, J=4.3, 4H), 3.17-3.06 (m, 2H), 2.73-2.62 (m, 2H), 1.92 (dp, J=13.2, 6.6, 1H), 1.06 (t, J=7.2, 3H), 0.93 (d, J=6.7, 6H). LC/MS-m/z+483.3 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH3:2].C([C:14]1C=C(CC(N)=O)C=C[C:19]=1[O:20]C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:11][C:19](=[O:20])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH3:2]
Reactant: CCc1cc(CC(N)=O)ccc1OC
Reactant: CCc1cc(N)ccc1OC
Product: CCc1cc(NC(C)=O)ccc1OC

Procedure:
By proceeding in a manner similar to Reference Example 33(a) but using 3-ethyl-4-methoxy-phenylamine [2.5 g, Reference Example 30(aa)] there was prepared N-(3-ethyl-4-methoxy-phenyl-acetamide (2.9 g) was prepared as a light brown solid. LC-MS (METHOD K): RT=3.92 minutes, 194.16 (M+H)+.