Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:35])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(CO)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 91.6 %

Procedure:
To a suspension of 6-benzyloxy-4-(3-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (3.88 g, 9 mmol) in toluene (30 mL) was added thionyl chloride (1.3 mL, 18 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.71 g, 91.8%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([O:30]C)=[C:25]([CH3:32])[CH:24]=2)([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:6]1=[O:33].Cl.N1C=CC=CC=1.Cl>[Cu].C(OCC)(=O)C>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:24]=[C:25]([CH3:32])[C:26]([OH:30])=[C:27]([CH3:29])[CH:28]=2)([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[C:6]1=[O:33]
Reactant: COc1c(C)cc(C2(c3ccc([N+](=O)[O-])cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(C2(c3ccc([N+](=O)[O-])cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O
Temperature: 190 °C
Yield: 40.1 %

Procedure:
Evaporate 1-(2-chloro-benzyl)-3-(4-methoxy-3,5-dimethyl-phenyl)-3-(4-nitro-phenyl)-1,3-dihydro-indol-2-one (62 mg, 0.12 mmol) into a vial and add pyridine hydrochloride (300-500 mg). Suspend the vial, by means of a copper wire, in an oil bath heated to 180-200° C. so that the entire vial, except the cap, is immersed in the bath. When the pyridine hydrochloride melts, stir to effect a homogeneous solution. Heat for 1.5 h and then allow to cool. Treat the resulting solid with 1N HCl solution and ethyl acetate until all solids are dissolved and transferred to a separatory funnel. Extract the aqueous portion with ethyl acetate (2×). Combine the organic portions and wash with brine, then dry (MgSO4), filter and concentrate in vacuo to give a yellow gum. Purify by flash chromatography (gradient of 10% EtOAc/hexanes to 33% EtOAc/hexanes) followed by trituration in diethyl ether and drying under house vacuum to obtain 24 mg (40%) of the title compound as a pale yellow solid. MS (ES): m/z=499 (M+1), 497 (M−1); 1H NMR(DMSO-d6): δ8.43 (s, 1H), 8.24 (d, J=9 Hz, 2H), 7.57-7.43 (m, 4H), 7.37-7.23 (m, 3H), 7.15 (t, J=8 Hz, 1H), 7.01 (m, 2H), 6.76 (s, 2H), 5.11 (s, 2H), 2.12 (s, 6H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=2)[CH2:20][CH3:21])=[CH:15][CH:14]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]([OH:39])=[O:4])=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccccc3CC(=O)OC)cc2)cc1C)CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccccc3CC(=O)O)cc2)cc1C)CC
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 74.7 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.160 mL, 0.160 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-biphenyl-2-yl)-acetic acid methyl ester (Example 126-(2); 26.6 mg, 0.053 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred at 60° C. for 2.5 hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:1:0.3) to give the target compound as a colorless oil (19.2 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:39])[CH2:20][CH2:19][N:18]([CH:21]3[CH:25]([OH:26])[CH2:24][N:23]([C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:22]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:39])[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][N:23]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:37])([F:36])[F:38])[CH2:24][CH:25]3[O:26][C:40](=[O:42])[CH3:41])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC(O)C(N2CCC(O)(c3ccc(Cl)cc3)CC2)C1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC1CN(C(=O)c2ccccc2C(F)(F)F)CC1N1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
A mixture of (3R,4R; 3S,4S)-{3-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl)-methanone trifluoroacetate (2.2 mg, 0.005 mmol, see Example 43 for preparation) was dissolved in DMF (0.4 mL) and acetic anhydride was added. The reaction mixture was shaken for 2 h and directly used for LC-MS purification, to yield 1.1 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 511.2 (100).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][NH:5][CH:6]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.[H-].[Na+]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)[C:3]=1[C:7]#[N:8]
Reactant: C1=COCCC1
Reactant: N#Cc1n[nH]cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(Br)cnn1C1CCCCO1
Temperature: 95 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
4-Bromo-1H-pyrazole-3-carbonitrile (150 mg, 0.87 mmol) is dissolved in 3,4-dihydro-2H-pyran (25 mL, 2.6 mmol) in the presence of a catalytic amount of TFA (1 mg, 0.009 mmol). The reaction mixture is stirred at 95° C. for 1 hour, cooled and then quenched using NaH (1.2 mg, 0.052 mmol). After removing the solvent, the residue is purified by silica gel column chromatography eluting with a mixture of 3:1 petroleum ether-dichloromethane, followed by 10:1 petroleum ether-ethyl acetate. The fractions containing the desired compounds are collected and concentrated in vacuo to afford the title compound as a colorless oil (90 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1.C[Al](C)C.C([O:20][C:21]([C:23]1[C:28]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:27][CH:26]=[C:25]([CH3:36])[N:24]=1)=O)C.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:21]([C:23]3[C:28]([NH:29][C:30]4[CH:35]=[N:34][CH:33]=[N:32][CH:31]=4)=[CH:27][CH:26]=[C:25]([CH3:36])[N:24]=3)=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncnc1
Reactant: Nc1ccn(-c2ccc(F)cc2)n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ccn(-c3ccc(F)cc3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-Fluoro-phenyl)-1H-pyrazol-3-ylamine (55 mg, 0.31 mmol) was dissolved under inert gas atmosphere in dioxane (2 ml) and trimethylaluminium (0.154 ml, 2M toluene solution) was added. After stirring for 30 min at ambient temperature, 6-methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (A-1; 20 mg, 0.08 mmol) was added and the reaction mixture was heated at reflux for 18 hours. Upon cooling to room temperature water (0.5 ml) was added and intensive stirring was continued for 5 min. Sufficient sodium sulfate for water absorption and dichloromethane were added while stirring is continued. The resulting solution was then filtered through decalite and washed with dichloromethane. The solvent was evaporated and the final product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as off-white solid (5 mg, 16%).
Reaction SMILES: C[Li].[CH3:3]COCC.[C:8]([O:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[C:18](=[O:27])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCCCCC.CCOC(C)=O>C1COCC1.CCOC(C)=O>[C:8]([O:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[C:18]([OH:27])([CH3:3])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOCC
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2=O
Agent: [Li]C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)O
Temperature: 140 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a flame dried 250 mL 3-necked rb flask equivuipped with a magnetic stir bar was added Ce(III)Cl-7 H2O (2.74 g, 7.35 mmol, 2 equiv). The flask was heated in a 140° C. oil bath under reduced pressure (~1 torr) for 2.5 h. The flask was cooled to rt and slowly filled with N2G. The white powder was suspended in dry THF (30 mL), stirred at rt for 1 h and then cooled to -78° C. To the white suspension was added a 1.4M solution of methyl lithium (MeLi) in Et2O (5.25 mL, 7.35 mmol, 2 equiv) by syringe. The dark yellow/brown solution stirred at -78° C. for 1 h and then 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-7-methoxy-4-quinolone dissolved in 3 mL THF was added. The solution stirred at -78° C. for 3 h and was warmed to 0° C. for 2 h. The reaction did not go to completion and starting material was observed by TLC (silica gel, hexane/EtOAc, 3:1). The reaction was quenched with H2O (1 mL) and allowed to warm to rt. The solution was neutralized with sat NH4Cl solution (5 mL), extracted with EtOAc (3×100 mL), washed with brine (1×100 mL), dried over Na2SO4 and concentrated in vacuo to give a mix of the desired alcohol and starting material. The mixture was taken up in EtOAc and concentrated on Celite™ to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 3:1) to give 796 mg (74%) of the desired product as a vicious clear colorless oil. Data for 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methyl-7-methoxy-quinoline: Rf =0.20 (hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 7.42 (d, J=8.7, 1H), 7.33 (d, J=2.5, 1H), 6.66 (dd, J=2.5, 8.6, 1H), 3.98 (m, 1H), 3.79 (s, 3H, OCH3), 3.61 (m, 1H), 1.98 (m, 2H), 1.58 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC.C(OCCOCC)C>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[F:18][C:13]1[CH:12]=[C:11]([C:8]2[O:9][C:10]3[C:2]([CH:20]=[CH2:21])=[CH:3][C:4]([OH:19])=[CH:5][C:6]=3[N:7]=2)[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Oc1cc(Br)c2oc(-c3ccc(O)c(F)c3)nc2c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCOCCOCC
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 115 °C
Reaction time: 48 h
Yield: 72.6 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (0.87 g, 1.1 mmol) was added into a mixture of 7-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol (7.16 g, 22.1 mmol), tributyl(vinyl)tin (10.5 g, 33.25 mmol) and ethylene glycol diethyl ether (65 mL). The reaction mixture was stirred at 115° C. for 48 h, cooled to room temperature and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography, on acidic silica gel (hexanes/EtOAc/CH2Cl2 1/1/1), gave a white solid (4.35 g, 72% yield, m.p. 250–252° C.); MS m/e 272 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: Cn1cnc2c(Cl)nc3ccccc3c21
Product: CCCCNc1nc2ccccc2c2c1ncn2C

Procedure:
Using the general method exemplified in Example 151, 4-chloro-1-methyl-1H-imidazo[4,5-c]quinoline (from Example 114) was reacted with n-butylamine to provide N-butyl-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 98°-100° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][OH:17])[C@H:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@H:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)OCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-(hydroxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 217, 13.7 g, 36.67 mmol) in dichloromethane (20 mL) at 0° C. was added pyridine (5.93 mL, 73.35 mmol) followed by dropwise addition of ethyl chloroformate (3.87 mL, 40.34 mmol). The reaction was allowed to warm to room temperature over 3 hours. Diluted with dichloromethane and washed with saturated NH4Cl. Extracted with dichloromethane three times, combined and dried over Na2SO4. Removed solvent to give title compound as a yellow oil (14.5 g, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([CH:13]=[N:22][N:17]2[CH2:18][C@@H:19]([OH:21])[CH3:20])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: C[C@H](O)CNc1cc(OCc2ccccc2)ccc1C=O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 44.3 %

Procedure:
To a mixture of the product from Step C (16.0 g, 56.1 mmol) in acetic acid/water (150 mL/30 mL) at 0° C. was added sodium nitrite (7.75 g, 112 mmol) in portions over 40 min. The mixture was stirred for 50 min, cooled (ice bath), and zinc (14.7 g, 224 mmol) was added in portions. After 1 h the suspension was warmed to room temperature and more zinc was added (14.7 g, 224 mmol). The mixture was stirred for 1 h, concentrated, and extracted with EtOAc (2×300 mL). The extracts were filtered through a filter-aide, and the filtrate was washed with saturated aqueous disodium hydrogen phosphate (to pH 8) and brine, dried, and purifed by chromatrography (silica, 25% EtOAc/hexane) to afford an oil (7.01 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1C
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1C
Yield: 89 %

Procedure:
A mixture of 0.074 g (0.38 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-methyl-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 132 mg of N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 88%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19]>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])=[O:19]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)C=Cc1ccccc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(2-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (19.5 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (16 g) as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]([C@@H:11]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])[CH2:14][CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10]>C(Cl)Cl>[Cl:37][C:33]1[C:32]([F:38])=[C:31]([NH:30][C:21]2[C:20]3[C:25](=[CH:26][C:27]([O:28][CH3:29])=[C:18]([O:17][C@H:15]4[CH2:14][CH2:13][NH:12][C@H:11]([C:9]([NH2:8])=[O:10])[CH2:16]4)[CH:19]=3)[N:24]=[CH:23][N:22]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
TFA (15 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2S,4S)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (4) (5 g, 9.16 mmol) in DCM (15 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 5%) to give (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxamide (5) (3.1 g, 76%) as a white solid: 1H NMR Spectrum: (DMSO d6) 1.72-1.89 (m, 2H), 1.91 (m, 1H), 2.03 (m, 1H), 2.78 (m, 1H), 2.92 (m, 1H), 3.47 (m, 1H), 3.95 (s, 3H), 4.84 (m, 1H), 7.06 (s, 1H), 7.27 (s, 1H), 7.30 (m, 2H), 7.49-7.55 (m, 2H), 7.84 (s, 1H), 8.37 (s, 1H), 9.56 (s, 1H), Mass Spectrum: (M+H)+ 446.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([CH:11]2[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)[OH:10])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[OH:10])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C2CCNCC2)cc1
Yield: 29.8 %

Procedure:
A solution of 36.7 g (0.088 mole) of α,α-bis(4-methoxyphenyl)-1-(phenylmethyl)-4-piperidinemethanol in 500 ml of absolute ethanol was hydrogenated over palladium on carbon at 60° C. in a Parr apparatus over the weekend. The mixture was cooled, filtered through Celite®, fresh catalyst added to the filtrate and the mixture hydrogenated. This process was repeated so that no starting material was present by mass spectral analysis. The filtrate was concentrated and the residue was partitioned between methylene chloride and a 5% sodium hydroxide solution. The organic layer was dried over sodium sulfate and concentrated to give a solid residue. The solid was recrystallized from 2-propanol to yield 8.6 g (30%) of white solid, m.p. 153°-155° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]([CH3:17])=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].[OH-].[Na+]>CO.O>[CH3:17][C:4](=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:3]([OH:18])=[O:2]
Reactant: COC(=O)C(C)=CC=CCC(C)CCC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)=CCCC(C)CC=CC=C(C)C(=O)O
Temperature: 0 °C

Procedure:
22.8 g. of 2,7,11-trimethyl-2,4,10-dodecatrienoic acid methyl ester is dissolved in 150 ml of methanol and mixed with 22.8 g. of sodium hydroxide dissolved in 35 ml of water. The mixture is boiled under reflux for 3 hours, poured on to ice-water and extracted with diethyl ether. The ether extracts are discarded and the aqueous phase acidified with dilute sulphuric acid. The acidic aqueous solution is extracted with diethyl ether and the ether extract is washed repeatedly with aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. There is obtained 2,7,11-trimethyl-2,4,10-dodecatrienoic acid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].O>ClCCl>[C:1]([NH:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=1)(=[O:14])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CC(C)(C)N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butylamine (5.1 g, 70 mmol) in dichloromethane (200 mL) was added dropwise a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (17.9 g, 70 mmol) in dichloromethane (100 mL) at room temperature over a period of 30 min, and then the reaction mixture was stirred for 2 h. The reaction mixture was poured into water (100 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried (Na2SO4), and concentrated to give 21.3 g (quant.) of the title compound as yellow solids: 1H-NMR (CDCl3) δ 8.38 (1H, d, J=2.0 Hz), 8.02 (1H, dd, J=2.0, 8.6 Hz), 7.70 (1H, d, J=8.6 Hz), 4.95 (1H, br.s), 1.28 (9H, s).