Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(F)=CC=CC=1C1C=C[C:12]([O:15]CCCCCCOC(=O)C=C)=[CH:11][CH:10]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40].BrCCCCCCO>>[C:12]([O:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][Br:27])(=[O:15])[CH:11]=[CH2:10]
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: OCCCCCCCCCCCCBr
Agent: OCCCCCCBr
Product: C=CC(=O)OCCCCCCCCCCCCBr
Yield: 75.1 %

Procedure:
The same procedure as in the synthesis (a) of Example 2 was repeated except that 44.0 g of 12-bromo-1-dodecanol were used instead of 30 g of 6-bromo-1-hexanol to give 39.8 g (Y., 75.1%) of 12-bromododecyl acrylate.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:18]([C:29]#[N:30])[CH:17]=1.O>CN(C)C(=O)C>[C:23]1([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:17][C:18]=2[C:29]#[N:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: N#Cc1cc(N)ccc1Sc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(Sc2ccccc2)c(C#N)c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 158.7 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (2.16 g 13.7 mmol) in N,N-dimethylacetamide (20 mL) was rapidly added thionyl chloride (1.73 g, 14.5 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -20° C. to -10° C. for 1 hour. (4-Amino-2-cyanophenyl)phenyl sulfide (2.08 g, 9.2 mmol) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into 500 mL of water and extracted with two 100 mL portions of ethyl ether. The oil obtained in removal of the ethyl ether was chromatographed on 325 g of silica gel using an ethyl ether (0%, 5%, 10% and 20%) in methylene chloride gradient. The proper fractions were combined, the solvent removed in vacuo and the residue heated overnight at 60° C./0.1 mm to yield 5.35 g (93%) of N-(4-phenylthio-3-cyanophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide, mp 124°-126° C. 1H-NMR (300 MHz, d6 -DMSO): 1.59 (s, 3H, CH3), 7.32-7.47 (m, 6H, aromatic), 7.59 (s, 1H, OH), 8.07 (dd 1H, J=8.8, 2.3 Hz, aromatic), 8.33 (d, 1H, J=2.3 Hz, aromatic), 10.48 (s, 1H, NH). MS (CI, CH4): 367(M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Cl.[NH2:17]O>C(O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:17])[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: NO
Reactant: CCCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCCC(N)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
To a solution of 1-[4-(trifluoromethyl)phenyl]butan-1-one (6 g, 27.8 mmol) in ethanol (60 ml) was added hydroxylamine hydrochloride (5.79 g, 83.3 mmol) and the reaction heated to reflux and stirred for 16 h. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed twice with water, dried over sodium sulfate and concentrated in vacuo. The crude oxime was then dissolved in ethanol (100 ml) and Raney nickel (approx 1 g) added. The reaction was stirred under a balloon of hydrogen for 72 h. The reaction was filtered though celite (washing with ethanol) concentrated in vacuo, adsorbed onto silica gel and purified by flash column (50-80% ethyl acetate in hexanes) to yield the title compound (5 g, 83%) as colourless crystals.
Reaction SMILES: C[O-].[Na+].[Na].[Cl-].[OH:6][NH3+:7].[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]=[C:11]([C:15]#[N:16])[CH2:10]1>CO>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]=[C:11]([C:15](=[N:7][OH:6])[NH2:16])[CH2:10]1
Reactant: CN1CCC=C(C#N)C1
Reactant: [NH3+]O
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC=C(C(N)=NO)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of sodium methoxide, prepared from sodium (575 mg; 25 mmol) in methanol (30 ml), hydroxylammonium chloride (1,74 g; 25 mmol) was added. The mixture was stirred at room temperature for 30 min. and filtered. A solution of 1-methyl-3-cyano-1,2,5,6-tetrahydropyridine (Liberatore et al, Tetrahedron Letters 46, 4735 (1968)) (1.65 g; 13.5 mmol) in methanol (20 ml) was added to the filtrate. The reaction was stirred at room temperature for 20 hours and evaporated. The residue was extracted with ethanol (50 ml), filtrated, and evaporated to give the title compound in 25% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:5][CH2:4][CH2:3][CH2:2][N:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1
Reactant: OCCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(CCCO)CC1
Temperature: 25 °C

Procedure:
A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29 ml), potassium carbonate (83 g) and ethanol (200 ml) was stirred and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under diethyl ether. The resultant mixture was filtered and the filtrate was evaporated. The residue was purified by distillation at about 60-70° C. under about 0.2 mm Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine (17 g); NMR Spectrum: (CDCl3) 1.72 (m, 2H), 2.3 (s, 3H), 2.2-2.8 (m, 8), 2.6 (t, 2H), 3.8 (t, 2H), 5.3 (br s, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][CH2:18][C:19]1[O:24][C:23](=[O:25])[C:22]([CH3:26])=[C:21]([OH:27])[C:20]=1[CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:29][O:30][CH2:31]Cl>C1COCC1>[CH2:10]([O:17][CH2:18][C:19]1[O:24][C:23](=[O:25])[C:22]([CH3:26])=[C:21]([O:27][CH2:29][O:30][CH3:31])[C:20]=1[CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(COCc2ccccc2)oc(=O)c(C)c1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1c(C)c(COCc2ccccc2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (2.1 ml) was added to a solution of 6-(benzyloxy)methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (2.60 g) in THF (50 ml), and after stirring the mixture at room temperature for one hour, chloromethyl methyl ether (921 μl) was added at 0° C. and the mixture was stirred at room temperature for one hour. After concentrating the reaction solution under reduced pressure, water was added to the residue, extraction was performed with AcOEt, and the organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→1/1) to obtain 6-(benzyloxy)methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[C:8]([N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]2[N:27]=[CH:28][CH:29]=[C:6]2[N:5]=1)[CH3:3].[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.CC(O)=O.[BH3-]C#N.[Na+]>ClCCCl.C(O)C.C(Cl)Cl>[O:30]1[CH2:35][CH2:34][CH:33]([NH:1][CH:2]([C:4]2[CH:9]=[C:8]([N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])[N:7]3[N:27]=[CH:28][CH:29]=[C:6]3[N:5]=2)[CH3:3])[CH2:32][CH2:31]1
Reactant: CC(N)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To crude 5-(1-aminoethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.6 g) in DCE (20 ml) and Ethanol (20 ml) was added tetrahydro-4H-pyran-4-one (0.6 ml, 7 mmol) followed by AcOH (0.08 ml, 1.4 mmol). After stirring for 30 minutes at room temperature, NaBH3CN (0.18 g, 2.8 mmol) was added and stirring was continued further for 30 minutes more. LC/MS showed no starting material (M.W=437) remaining. After the solvent was rotoevaporated, the crude was dissolved with DCM (60 ml), washed with sat. NaHCO3 (1×5 ml), water (1×5 ml), brine (1×5 ml), dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with MeOH/EtOAC (0-20%) gave desired product, 5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([S:10]([N:13]([CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[CH3:14])(=[O:12])=[O:11])=[C:8]([C:21](OC)=[O:22])[S:7][C:6]=2[CH:25]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[S:10](=[O:12])(=[O:11])[N:13]([CH3:14])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:21]([OH:22])[C:8]=3[S:7][C:6]=2[CH:25]=1
Reactant: CCOC(=O)CN(C)S(=O)(=O)c1c(C(=O)OC)sc2cc(Cl)ccc12
Solvent: CO
Product: COC(=O)C1=C(O)c2sc3cc(Cl)ccc3c2S(=O)(=O)N1C
Yield: 35 %

Procedure:
Prepared analogous to Example 1(e) from methyl 6-chloro-3-{[(ethoxycarbonyl-methyl)-methylamino]sulfonyl}-benzo[b]-thiophene-2-carboxylate by reaction with sodium methylene in anhydrous methanol with a yield of 35% of theory.
Reaction SMILES: C([O:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10](F)=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)C=C.[CH3:18][O-:19].[Na+].Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].CO>[OH:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:18])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1
Reactant: C=CCOc1cn(C)c2cc(F)ccc2c1=O
Reactant: C[O-]
Agent: [Rh]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: COc1ccc2c(=O)c(O)cn(C)c2c1

Procedure:
A mixture of 3-allyloxy-7-fluoro-1-methyl-4quinolone (2.1 g), prepared as described in Example 8(a), sodium methoxide (3 g) and dry methanol (50 ml) was heated under reflux for 4 days. Methanolic hydrochloric acid was added to neutralise the solution and tris(triphenylphosphine)rhodium chloride (0.2 g) was added. The mixture was heated under reflux for 3 days and then acidified with methanolic hydrochloric acid to pH 1. The solvent was removed by distillation under reduced pressure and the residue stirred with aqueous sodium hydroxide (0.5M, 50 ml) and filtered. The filtrate was neutralised with hydrochloric acid (5M, 5 ml), the precipitate was collected by filtration and washed with water (2×10 ml) to give the novel compound 3-hydroxy-7-methoxy-1-methyl-4-quinolone, m.p. 228°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1>CN(C=O)C.O>[O:17]=[C:16]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10]1
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74.2 %

Procedure:
To a solution of 3-amino-4-hydroxybenzonitrile (730 mg) in DMF (10 ml) was added CDI (1.06 g) at 0° C., followed by stirring at room temperature for 3.5 hours. The reaction solution was diluted with water (10 ml), and extracted with EtOAc (200 ml). The organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=98:2 to 93:7) to obtain 2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile (647 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:18]([C:20]1[NH:21][C:22]([CH3:30])=[CH:23][C:24]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12](=[CH:18][C:20]4[NH:21][C:22]([CH3:30])=[CH:23][C:24]=4[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:13](=[O:17])[NH:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2ccc(-c3ccc(F)cc3)cc2N1
Product: Cc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cc(-c4ccc(F)cc4)ccc32)[nH]1

Procedure:
6-(4-Fluorophenyl)-1,3-dihydroindol-2-one (70 mg, 0.31 mmol) was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (56 mg) to give the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([C:9](=O)[CH2:10][C:11]#[N:12])[CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[CH:4]1([C:9]2[CH:10]=[C:11]([NH2:12])[O:3][N:2]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NO
Reactant: N#CCC(=O)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(C2CCCC2)no1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
Hydroxylamine hydrochloride (6 g, 86 mmol) and 3-cyclopentyl-3-oxopropanenitrile (10 g, 73 mmol) were added to a solution of NaOH (9 g, 225 mmol) in water (100 mL) and the resulting mixture was heated at 50° C. overnight. The precipitate was collected by filtration, washed with water, and dried to give 3-cyclopentylisoxazol-5-amine (6.7 g, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 6A3 (s, 2 H), 4.77 (s, 1 H), 2.84 (m, 1 H), 1.87-1.51(m, 8 H); MS (ESI) m/z: 153.1 (M+H+).
Reaction SMILES: [F-].C([NH3+])(C)(C)C.[Si]([O:24][CH2:25][C:26]1[C:27]([N:42]2[CH2:47][C@H:46]([CH3:48])[O:45][C@H:44]([CH3:49])[CH2:43]2)=[C:28]([F:41])[C:29]([F:40])=[C:30]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[CH:31]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:48][C@H:46]1[O:45][C@@H:44]([CH3:49])[CH2:43][N:42]([C:27]2[C:26]([CH2:25][OH:24])=[CH:31][C:30]([C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:33])=[C:29]([F:40])[C:28]=2[F:41])[CH2:47]1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(CO)cc(C(=O)c3ccccc3)c(F)c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl ammonium fluoride (435 mg, 0.002 mmol) was added in small portions to a stirred solution of {5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorophenyl}(phenyl)methanone (Intermediate 20, 1 g, 0.002 mmol) in anhydrous THF (10 mL) at 0° C. and stirring was continued for 1 h with warming to room temperature. The solvent was removed and the residue was purified over a silica gel chromatography column using ethyl acetate-pet. ether gradient, providing the title compound. Yield: 450 mg, (75%)
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([NH:10][C@H:11]3[CH2:15][CH2:14][CH2:13][C@@H:12]3[NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]3[N:28]=[CH:27][CH:26]=[N:25]3)=[N:8][CH:9]=2)C[CH2:2]1.BrC1N=CC(N[C@H]2CCC[C@@H]2NC(=O)C2C=CC=CC=2N2N=CC=N2)=NC=1.ClC1N=CC(N[C@H]2CCC[C@@H]2NC(=O)C2C=CC=CC=2N2N=CC=N2)=NC=1.C(B1OC(C)(C)C(C)(C)O1)=C>>[CH2:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[N:25]=[CH:26][CH:27]=[N:28]2)=[N:8][CH:9]=1)[CH3:2]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C2CC2)cn1)c1ccccc1-n1nccn1
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(Br)cn1)c1ccccc1-n1nccn1
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(Cl)cn1)c1ccccc1-n1nccn1
Product: CCc1cnc(N[C@H]2CCC[C@@H]2NC(=O)c2ccccc2-n2nccn2)cn1
Reaction time: 2 h

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-[(5-cyclopropylpyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 112) from N-[(1S,2S)-2-[(5-bromopyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide and N-[(1S,2S)-2-[(5-chloropyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30a and 30b; 100 mg, 0.23 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS number 75927-49-0; 151 mg, 0.98 mmol) except this was purified only by column chromatography (silica, 0-100% ethyl acetate/petrol) and then was dissolved in ethanol (1.4 ml). To this was then added palladium on carbon (10% wt, 50% wet) (15 mg, 0.014 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo. This was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4](Cl)=[O:5].CN(C)C1C=CC=CC=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.[OH-].[K+]>C(Cl)Cl.C(Cl)Cl.C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:19]=[CH:20][C:21]([N:22]2[CH2:2][CH2:3][C:4]2=[O:5])=[CH:23][CH:24]=1
Reactant: O=C(Cl)CCBr
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: O=C1CCN1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
3-Bromopropanoyl chloride (3.13 mL, 31.0 mmol) and N,N-dimethylaniline (3.91 mL, 31.0 mmol) were dissolved in methylene chloride (30 ml), 4-trifluoromethylaniline (5 g, 31.0 mmol) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 hrs. Work-up of the reaction mixture according to a conventional method gave a crude product. The obtained crude product was dissolved in a mixed solvent (100 mL) of methylene chloride/acetonitrile (20/1), potassium hydroxide (2.28 g, 40.6 mmol) and tetrabutylammonium bromide (3.26 g, 6.76 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated and, after work-up according to a conventional method, the mixture was purified by silica gel column chromatography to give the title compound (4.6 g, 21.4 mmol, 71%).
Reaction SMILES: [F:1][CH2:2][CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][CH:29]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][CH:29]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:3][CH2:2][F:1])=[CH:42][CH:43]=1)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: FCCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 54 mg 1-fluoro-2-iodoethane (0.31 mmol) in N,N-dimethylformamide (10 mL) was subsequently added 101 mg potassium carbonate (0.73 mmol), followed by 100 mg di-tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(4-hydroxybenzyl)-hexanedioate (from example 12d; 0.21 mmol), and the resulting mixture was stirred for 4 h at room temperature. The mixture was then partitioned between water and ethyl acetate, the aqueous layer was than extracted with ethyl acetate again. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC, method A to give 85 mg (62% purity adjusted yield) of the target compound in approx. 80% purity.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+:16]([O-])=O)[CH:7]=1>CCOC(C)=O.[Pd]>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[NH2:16]
Reactant: CN(C)CCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)CCOc1cc(N)cc(C(F)(F)F)c1
Yield: 82.3 %

Procedure:
A mixture of N,N-dimethyl-2-[3-nitro-5-(trifluoromethyl)phenoxy]-ethanamine (490 mg, 1.61 mmol) and Pd/C (10 wt %, 49 mg) in EtOAc (15 mL) was stirred under an atmosphere of hydrogen until reaction complete was judged to be complete by LCMS. The mixture was filtered through Celite and rinsed with EtOAc. The filtrate was concentrated to yield the desired product as a brown solid (329 mg, 71%). LCMS: (FA) ES+ 275.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][C@H:33]([CH3:35])[O:32][C@H:31]([CH3:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:37][N:38]([CH3:45])[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40].CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:44]#[C:43][CH2:42][NH:41][C:39](=[O:40])[N:38]([CH3:45])[CH3:37])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][C@H:33]([CH3:35])[O:32][C@H:31]([CH3:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1C[C@@H](C)O[C@@H](C)C1
Reactant: C#CCNC(=O)N(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1C[C@@H](C)O[C@@H](C)C1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
N-(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)-7-[3-(cis-2,6-dimethylmorpholin-4-yl)propoxy]-6-methoxyquinazolin-4-amine (250 mg, 0.40 mmol) and N,N-dimethyl-N′-prop-2-yn-1-ylurea (100 mg, 0.79 mmol) in ethyl acetate (8 ml) stirred at room temperature, under an atmosphere of nitrogen, and treated with bis(triphenylphosphine)palladium(II) dichloride (28 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamnine (81 mg, 0.81 mmol). The reaction was stirred 1 hr then DMF (4 ml) added and the reaction stirred for a further 1 hr. The resulting orange solution was evaporated in vacuo then treated with dilute aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulphate and evaporated to an orange oil. Purification was by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent gave the title compound (211 mg, 85%) as a pale orange solid;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[OH:13].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>CN1CCCC1=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[N:8]=[C:7]([OH:13])[C:6]3[C:11](=[C:2]([Br:1])[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=3)[N:10]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(Cl)nc(O)c2c1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 8-bromo-2-chloro-6-nitroquinazolin-4-ol (2.96 g) and 3,4-dichloroaniline (4.72 g) in 1-methyl-2-pyrrolidinone (70 mL) was heated at 140° C. for 3 h. The mixture was cooled to room temperature and poured onto ice/water (600 mL). The precipitate which formed was filtered, washed with water (50 mL), diethyl ether (150 mL) and dried in vacuo to afford the title compound (4.18 g). 1H NMR (300 MHz, DMSO-d6) δ11.62 (s, 1H), 9.64 (s, 1H), 8.72-8.65 (m, 3H), 7.61 (s, 1H), 7.60 (5, 1H); HPLC (Method B): 10.56 min. MS (APCI−): m/z 429, 431.