Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([Cl:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:20][C:9]1[C:8]2[C:7](=[O:21])[C:6]3[CH:5]=[C:4]4[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]4=[C:16]([Cl:19])[C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: C=CCc1cc2c(=O)c3c(Cl)cccc3oc2c(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2cc3c(=O)c4c(Cl)cccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
A mixture of 2-allyl-4,8-dichloro-3-hydroxy-9-oxo-9H-xanthene (14 g), m-chloroperbenzoic acid (11 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and to the stirred solution, a mixture of chromium trioxide (17 g), water (100 ml) and concentrated sulfuric acid (30 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 5.0 g of 6,11-dichloro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 291°-294° C. This compound showed a mass spectrum having a molecular ion peak at m/e 350.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2].C(OCC)(=O)C.Cl.P([S-])(OCC)(OCC)=[S:23]>>[NH2:2][C:1](=[S:23])[CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cccc(CC#N)c1
Reactant: CCOP(=S)([S-])OCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(CC(N)=S)c1
Yield: 78.8 %

Procedure:
By a method similar to that in Example 178a and using the compound (4.23 g, 22.4 mmol) obtained in Example 180a, 4M hydrogen chloride-ethyl acetate solution (42 mL) and O,O-diethyl dithiophosphate (4.50 mL, 26.8 mmol), the title compound (3.94 g, 79%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:36])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Cn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 306 (99mg, 0.29 mmol) and 2-phenylacetyl isocyanate (97 mg, 0.60 mmoL) [A. J. Hill, et al. JACS, 62, 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and gradient eluted with EtOAc, to MeOH/EtOAc (10:90) to afford the title compound 307 (42% yield) as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.11(s, 1H), 10.68(s, 1H, J=5.5 Hz), 8.49(d), 7.85(s, 1H), 7.82(dd, 1H, J1=12.9 Hz, J2=2.4Hz), 7.76(s, 1H), 7.43(m, 2H), 7.40(s, 1H), 7.32(m, 4H), 7.28(m, 1H), 6.61(d, 1H, J=5.5 Hz), 3.89(s, 3H), 3.74(s, 2H). MS (m/z):502.4 (M+H) (found).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[N:6][C:5]=1[Cl:12].[C:14](OC(=O)C)(=[O:16])C>C(O)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:14]=[O:16])=[N:6][C:5]=1[Cl:12]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(CN)nc1Cl
Solvent: O=CO
Product: COC(=O)c1ccc(CNC=O)nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 6-aminomethyl-2-chloro-nicotinic acid methyl ester (740 mg, 3.7 mmol) in formic acid (18.5 mL) was added acetic anhydride (3.7 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and azeotroped three times with toluene to afford the title compound as a yellow oil (757 mg, 90%) which was used without purification in the next step. LCMS (method B): RT=2.20 min, [M+H]+=229.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([S:30][CH3:31])=[N:28]2)=[CH:23][CH:22]=1>>[CH3:31][S:30][C:27]1[N:26]=[CH:25][C:24]2=[CH:23][CH:22]=[C:21]([C:6]3[CH:11]=[N:10][CH:9]=[CH:8][N:7]=3)[N:29]2[N:28]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: CSc1ncc2ccc(-c3cnccn3)n2n1
Yield: 44.9 %

Procedure:
Analogous to Example 1562a, 2-Tributylstannanyl-pyrazine (0.650 mL, 2.06 mmol) and 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.224 g, 0.916 mmol) were reacted to afford 2-Methylsulfanyl-7-pyrazin-2-yl-pyrrolo[2,1-f][1,2,4]triazine (0.100 g, 44%). 1H-NMR (DMSO-d6): 9.87 (s, 1H), 9.50 (s, 2H), 9.15 (s, 1H), 8.80 (m, 6H), 8.62 (s, 1H), 7.64 (d, 1H, J=4.96 Hz), 7.17 (d, 1H, J=4.96 Hz), 2.66 (s, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.Cl[CH2:15][C:16]#[N:17]>O1CCCC1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:11]([C:7]([CH2:8][CH2:9][NH:10][CH2:15][C:16]#[N:17])=[CH:6][NH:5]2)=[CH:12][CH:13]=1
Reactant: N#CCCl
Reactant: Cc1ccc2c(CCN)c[nH]c2c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2c(CCNCC#N)c[nH]c2c1
Reaction time: 15 h

Procedure:
17 g of 6-methyltryptamine were dissolved at 40° C. under inert atmosphere in 500 ml of tetrahydrofuran, and the solution was allowed to return to ambient temperature. 14.6 ml of 1,5-diaza[5,4,0]undec-5-ene were added followed by 6.2 ml of chloroacetonitrile and stirring for 15 hours. The solvent was eliminated under reduced pressure and the residue was taken up in 250 ml of methylene chloride, washed with water, dried and concentrated to dryness. The 25 g of crude product was purified by chromatography on silica (eluent: methylene chloride-ethyl acetate 3-7) to obtain 13.2 g of the expected product melting at 92° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(OCC)(=O)C>[CH2:1]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCBr
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCBr)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzylamine (6.49 ml) and triethylamine (8.26 ml) in ethyl acetate (60 ml) was added dropwise to a solution of 3-bromopropionyl chloride (6 ml) in ethyl acetate (10 ml) at 0° C. The reaction mixture was stirred to room temperature for 1 hr. The organic phase was washed with water (2×150 ml), saturated brine (150 ml) and dried over magnesium sulphate. Removal of the solvent produced the amide as a crystalline solid.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:7]2[C:6]([CH3:32])=[N:5][CH:4]=1.[CH2:33]([N:35]1[C:39]([CH:40]=O)=[N:38][C:37]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[N:36]1)[CH3:34].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:33]([N:35]1[C:39]([CH:40]=[CH:12][C:10]2[N:11]=[C:7]3[C:6]([CH3:32])=[N:5][CH:4]=[C:3]([CH3:2])[N:8]3[N:9]=2)=[N:38][C:37]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[N:36]1)[CH3:34]
Reactant: CCn1nc(N2CCCC2)nc1C=O
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1nc(N2CCCC2)nc1C=Cc1nc2c(C)ncc(C)n2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
A mixture of ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (125 mg, 272 μmol, Eq: 1.00), 1-ethyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (52.9 mg, 272 μmol, Eq: 1.00) and 1,8-diazabicyclo[5.4.0]undec-7-ene (104 mg, 103 μl, 681 μmol, Eq: 2.5) in tetrahydrofuran (6 ml) was stirred for 18 hours at 25° C. under nitrogen atmosphere. The crude material was applied on silicagel and purified by flash chromatography over a 50 g silicagel column using ethyl acetate methanol 0-10% as eluent affording 2-[2-(2-ethyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (37 mg/40.1%) as a bright yellow viscous oil. MS: m/e=339.5 (M+H+)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][N:10]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:4][CH2:3]1.SCCO>FC(F)(F)C(O)=O.C(OCC)(=O)C>[SH:14][C@@H:12]1[CH2:11][N:10]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[C@H:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:13]1
Reactant: CN1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: OCCS
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CN1CCN(C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a solution of (2S,4S)-2-(4-methylpiperazin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (6.85 g) in trifluoroacetic acid (35 ml) was added 2-mercaptoethanol (1.13 ml) under ice-cooling and the mixture was stirred at ambient temperature for 15 minutes. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in toluene (40 ml) and the solution was evaporated in vacuo to give a syrup. The syrup was dissolved in ethyl acetate (100 ml) and washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (10:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-2-(4-methylpiperazin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.14 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:31]([C:33]2[C:42]([NH:43]C(=O)OCC3C=CC=CC=3)=[CH:41][C:40]3[C:35](=[CH:36][C:37]([C:54]4[CH2:55][CH2:56][O:57][CH2:58][CH:59]=4)=[CH:38][CH:39]=3)[N:34]=2)=[O:32])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:43][C:42]1[C:33]([C:31]([NH:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][C:24]=2[N:11]2[CH2:12][C@H:13]([CH3:23])[C@@H:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]2)=[O:32])=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([CH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)[CH:36]=2
Reactant: [H][H]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4CCOCC4)ccc3cc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 62 %

Procedure:
A mixture of benzyl [2-({[4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (0.023 g, 0.028 mmol) in 1.5 mL of MeOH was hydrogenated in the presence of 10% Pd on carbon (10 mg) under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford a hydrogenated intermediate tert-butyl ((3R,4R,5S)-1-[3-({[3-amino-7-(tetrahydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.012 g, 62%). LCMS calc. for C37H55N6O5Si [M+H]+: m/z=691.4. found: 691.5.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:29]([O:42][CH3:43])[CH:28]=3)[S:26][C:19]=12)[NH2:13].C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[C:29]([O:42][CH3:43])[CH:28]=3)[S:26][C:19]=12
Reactant: COc1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1OCCN1CCOCC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
Ethyl chlorooxoacetate (0.11 mL, 0.95 mmol) was added to a solution of the amine 139 (313 mg, 0.63 mmol) and triethylamine (0.18 mL, 1.26 mmol) in dichloromethane (16 mL). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (eluent: 5% MeOH/95% DCM to 7% MeOH/93% DCM) to afford title compound 140 as a yellow solid (178 mg, 47% yield). MS (m/z): 596.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 11.64 g. of p-benzyloxybenzyl chloride and 50 ml. of hexamethylphosphoramide are heated in an oil bath at 110° C. for 20 hours. The mixture is chilled, diluted with 25 ml. of water, chilled and the solid mass diluted with additional water in order to filter. The solid is washed with water and recrystallized from ethanol to give off-white crystals, m.p. 144°-146° C. A sample is recrystallized from ethanol to give off-white crystals, m.p. 146°-147° C.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11](I)=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:3]12.N1CCCCC1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C@:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:29]=1>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.[Cu]I>[F:1][C:2]1([F:20])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:36]#[C:35][C@@:33]([OH:37])([C:30]3[CH:29]=[C:28]([CH3:27])[O:32][N:31]=3)[CH3:34])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:3]12
Reactant: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2(F)F
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2C(F)(F)CO3)no1
Temperature: 60 °C
Yield: 48.3 %

Procedure:
To a pressure tube was added 4,4-difluoro-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide (65 mg, 0.17 mmol) followed by piperidine (1.5 ml), tetrakis(triphenylphosphine)palladium (0) (19.2 mg, 0.02 mmol), copper(I) iodide (3.2 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (38 mg, 0.25 mmol). The reaction vessel was sealed and heated at 60° C. for 40 minutes. The reaction mixture was cooled and concentrated in vacuo. and then co-evaporated with dichloromethane (2×10 ml). The crude material was purified by FCC (silica, 1-8% methanol in dichloromethane) to provide 34 mg (49%) of the title compound as a pale brown solid. 1H-NMR (500 MHz, DMSO-d6): 1.81 (3H, s), 2.41 (3H, d, J=0.7 Hz), 4.85 (2H, t, J=11.7 Hz), 6.36 (1H, d, J=0.8 Hz), 6.56 (1H, s), 7.33 (1H, d, J=8.4 Hz), 7.35 (1H, s), 7.43 (1H, dd, J=8.4, 2.0 Hz), 7.60 (1H, s), 8.16 (1H, s), 8.37 (1H, d, J=2.0 Hz); M+23=437.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[C:67]([C:70](O)=[O:71])[CH:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:67]5[CH:66]=[C:65]([CH3:64])[O:69][N:68]=5)=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2cc(C)on2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 5-methyl-3-isoxazolecarboxylic acid (0.127 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.115 g). 1H NMR Spectrum: (DMSO d6 373K) 1.87 (m, 2H), 2.08 (m, 2H), 2.48 (s, 3H), 3.61 (m, 2H), 3.89 (m, 2H), 3.96 (s, 3H), 4.80 (m, 1H), 6.40 (s, 1H), 7.22 (m, 1H), 7.22 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.90 (s, 1H), 8.39 (s, 1H), 9.26 (br s, 1H); Mass Spectrum: (M+H)+ 512.
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:12]=1)[CH:10]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:13])=[C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])[CH:12]=1
Reactant: Cc1ccc(Cl)cc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(Cl)ccc1C
Reaction time: 1 h

Procedure:
To a mixture of acetone (80 ml), sodium hydroxide (1.2 g) and water (80 ml) was added dropwise at 0° C. a solution of 5-chloro-2-methylbenzaldehyde (4.1 g) in acetone (10 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(5-chloro-2-methylphenyl)-3-buten-2-one (5.5 g) as oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][C@@H:11]([OH:16])[CH2:12][C:13]([NH2:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][C@@H:11]([O:16][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:12][C:13]([NH2:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)C[C@H](O)CC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-hydroxyglutaramate (100 g) was dissolved in dimethyl formamide. To this Imidazole (35 g) was added and the solution was cooled to 5° C. To this a solution of tert-butyldimethylsilylchloride (68.5 g) dissolved in dimethyl formamide (250 ml) was added under cooling. The mixture was warmed to 20-25° C. and stirred. The reaction mixture was cooled and quenched with water. To the reaction mixture ethyl acetate and water was added and stirred. The layers were separated and the organic phase was washed thrice with water. The organic phase was evaporated under reduced pressure to yield (S)-benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate as oil.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[N:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42](O)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]>CN(C)C=O>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42]([NH:29][C:26]2[CH:27]=[CH:28][N:23]=[N:24][CH:25]=2)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: Nc1ccnnc1
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)O)c1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2ccnnc2)c1
Temperature: 25 °C

Procedure:
EDC (0.79 g, 4.11 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmorpholine (0.87 mL, 6.84 mmol) and 4-pyridazinamine (0.49 g, 5.13 mmol) were added to a solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 101; 1 g, 3.42 mmol) in N,N-dimethylformamide (DMF; 25 ml) and the mixture was stirred at room temperature. The DMF was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml) and the organic layer washed with saturated sodium hydrogencarbonate (2×50 ml) and water (2×50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a dark yellow solid. 0.98 g.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[NH:14]1[CH2:15][CH2:16][CH:11]([CH2:10][N:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: NCC1CCNCC1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Benzaldehyde (28.0 g; 0.264 mol) was added, dropwise, to a solution of 4-aminomethylpiperidine (30.2 g; 0.264 mol) in toluene (100 ml). The solution thus obtained was kept stirred at room temperature. After 3 h, the solvent was removed by evaporation at reduced pressure and the residue was taken up twice in toluene. 53.4 g of N-hexahydro-4-pyridinylmethyl-N-phenylmethylidenamine was thus obtained, and was used in subsequent reaction without further purification.