Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[OH:8].N.OO.Cl.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[OH:22]>O>[NH2:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:21][C:19]2[CH:18]=[CH:17][C:16]([OH:22])=[C:15]([Cl:14])[CH:20]=2)[C:4](=[O:9])[CH:3]=1
Reactant: Nc1cc(O)ccc1O
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Cl
Agent: N
Agent: OO
Solvent: O
Product: NC1=CC(=O)C(Nc2ccc(O)c(Cl)c2)=CC1=O
Reaction time: 5 h

Procedure:
0.02 mole (2.78 g) of 3-amino-4-hydroxy phenol is dissolved in 200 cc of water to which have been added 20 cc of ammonia (22° Be'). To this solution there are initially added 100 cc of H2O2 (20 volumes) and then immediately thereafter, which good agitation, 0.02 mole (3.60 g) of 2-chloro-4-amino phenol hydrochloride in 200 cc of water. The reaction mixture is left to stand for 5 hours at ambient temperature at which time it is filtered to recover the 2-amino-5-(3'-chloro-4'-hydroxyanilino)-1,4-benzoquinone which is then washed with water, recrystallized in a mixture of dimethylformamide and water and dried for 5 hours under a vacuum with a boiling water bath. The product is chromatographically pure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.[C:28]1([S:34]([OH:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN1CCN(C(OC2N(C3C=CC(Cl)=CN=3)C(=O)C3N=CC=NC2=3)=O)CC1>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C@@H:11]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:18](=[O:19])[C:13]3[N:14]=[CH:15][CH:16]=[N:17][C:12]2=3)=[O:9])[CH2:4][CH2:3]1.[S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-:37])(=[O:36])=[O:35]
Reactant: O=S(=O)(O)c1ccccc1
Agent: CN1CCN(C(=O)OC2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Agent: CN1CCN(C(=O)O[C@H]2c3nccnc3C(=O)N2c2ccc(Cl)cn2)CC1
Solvent: C1CCOC1
Product: O=S(=O)([O-])c1ccccc1
Temperature: 35 °C

Procedure:
A 2000 mL reactor was charged with 10.0 g (S)-zopiclone and 400 mL tetrahydrofuran (THF). The contents were heated to 35° C. Into a 1000 mL reactor was charged 4.4 g benzenesulfonic acid and 400 mL THF, and stirred until a solution was formed. The acid solution was transferred slowly to the zopiclone solution. The reaction was cooled to 15° C. and stirred for 18 hr at 20-25° C. The reactor slurry was filtered and washed with THF in an appropriate filter. The wet cake was dried under vacuum at 60-65° C. and packaged in an appropriate container. Isolated yield=92.7%.
Reaction SMILES: [OH-:1].[Na+].OO.CS(C)=O.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[N:18]=1>O.C(O)C>[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]([NH2:22])=[O:1])=[C:19]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[N:18]=1
Reactant: N#Cc1cc(F)c(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc2ncccc12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5M sodium hydroxide aqueous solution (0.1 ml) and a 30% hydrogen peroxide solution (0.1 ml) were added to a solution of dimethyl sulfoxide (1 ml) and ethanol (0.5 ml) containing 6-(((1R,2S)-2-aminocyclohexyl)amino)-5-fluoro-2-(quinolin-5-ylamino)nicotinonitrile (20 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. 4M hydrogen chloride/1,4-dioxane (0.5 ml) was added to the obtained residue, the resulting precipitate was collected by filtration, and a red solid of 6-(((1R,2S)-2-aminocyclohexyl)amino)-5-fluoro-2-(quinolin-5-ylamino)nicotinamide (12 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31]C1C=CC(F)=CC=1C=O>>[F:31][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[O:9]1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: O=Cc1cc(F)ccc1F
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2cc(F)ccc2F)Oc2ccc(O)cc21

Procedure:
2-(2,5-Difluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.57 ml of 2,5-difluorobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (300 MHz, d6-DMSO) δ: 9.46 (s, 1H), 7.53 (m, 1H), 7.36-7.30 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 5.76 (dd, 1H, J 13.6, 2.7 Hz), 3.26 (dd, 1H, J −16.8, 13.6 Hz), 2.76 (dd, 1H, J −16.8, 2.7 Hz).
Reaction SMILES: C([N:3](CC)CC)C.[CH3:8][NH:9][C:10](=[O:13])[CH2:11][SH:12].O1[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[C:18]([CH2:17][CH:16]1[N:9]([CH3:8])[C:10](=[O:13])[CH2:11][S:12][CH2:15]1)#[N:3]
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Reactant: CNC(=O)CS
Solvent: O
Product: CN1C(=O)CSCC1CC#N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of omega-cyano-allyl bromide (9.07 g) in tetrahydrofurane (60 ml) cooled at -65° C. is added a mixture of triethylamine (9.5 ml) and thioglycolic methylamide (6.13 ml). After 15 minutes, cooling is stopped and the mixture is warmed to 0° C. The mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated to give 5-cyanomethyl-4-methyl-3-oxothiomorpholine (6.86 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[C:23]([S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH:22]=3)(=[O:20])=[O:19])=[N:15][N:16]=[C:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:31]1([CH2:30][CH2:29][C@@H:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:14]3[N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]4[NH:16][N:15]=3)(=[O:19])=[O:20])=[CH:22][C:23]=2[S:45]([C:48]([F:50])([F:51])[F:49])(=[O:47])=[O:46])[CH2:37][S:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2NS(=O)(=O)c2ccc(N[C@H](CCN3CCOCC3)CSc3ccccc3)c(S(=O)(=O)C(F)(F)F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NC1=NNC2CNCCN12)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
To a solution of 3-[4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonylamino]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylic acid tert-butyl ester (130 mg, 0.168 mmol) in dichloromethane (3 mL) under nitrogen was added trifluoroacetic acid (0.323 mL, 4.19 mmol), and the reaction was stirred for 2.5 hours. The reaction mixture was then concentrated and diluted with water and CH2Cl2. It was then basified to pH approximately 8 with saturated Na2CO3. The organics were extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (112 mg, 99% yield). MS [m/z; (M+1)+]: 676.5
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6]CO)=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:11]([CH2:15][CH3:14])[CH2:12][CH3:13])=[CH:9][CH:10]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: C1=CCNC1
Product: CCN(CC)Cc1ccc(Br)cc1

Procedure:
The procedure of step (i) of Reference Example 2 was repeated, except that 4-bromophenethyl alcohol was used instead of 4-bromobenzylalcohol and various amines were used instead of 2,5-dihydro-1H-pyrrole. The following compounds thus synthesized were used in the Examples.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:6]2[C:7]([N:9]([C:12]3([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]3=[O:19])[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>CC(C)=O.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:23]=[CH:22][CH:21]=[C:6]2[C:7]([N:9]([C:12]3([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]3=[O:19])[C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: CC1(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CCC(=O)NC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 82 %

Procedure:
3-(3-Nitrophthalimido)-3-methylpiperidine-2,6-dione (0.5 g, 1.57 mmol) was dissolved in acetone (250 mL) with gentle heat and then cooled to room temperature. To this solution was added 10% Pd/C (0.1 g) under nitrogen. The mixture was hydrogenated in a Parr apparatus at 50 psi of hydrogen for 4 hours. The mixture then was filtered through Celite and the pad washed with acetone (50 mL). The filtrate was concentrated in vacuo to yield a yellow solid. The solid was slurried in ethyl acetate (10 mL) for 30 minutes. The slurry then was filtered and dried (60° C., <1 mm) to afford 0.37 g (82%) of 3-(3-aminophthalimido)-3-methylpiperidine-2,6-dione as a yellow solid: mp 268–269° C.; 1H NMR (DMSO-d6) δ 10.98 (s, 1H), 7.44 (dd, J=7.1 and 7.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.94 (d, J=6.9 Hz, 1H), 6.52(s, 2H), 2.71–2.74(m, 3H), 2.08–1.99 (m, 1H), 1.87 (s, 3 H); 13C NMR (DMSO-d6) δ 172.48, 172.18, 169.51, 168.06, 146.55, 135.38, 131.80, 121.51, 110.56, 108.30, 58.29, 29.25, 28.63, 21.00; HPLC Water Nova-Pak/C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 5.62 min (99.18%). Anal. Calcd For C14H13N3O4: C, 58.53; H, 4.56; N, 14.63. Found: C, 58.60; H, 4.41; N, 14.36.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C.O>ClCCl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:24][CH2:25]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0-5° C.) suspension of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (50.2 g, 186 mmol) in dichloromethane (200 mL) was slowly added a solution of tert-butyl piperidin-4-ylcarbamate (39.0 g, 195 mmol) and triethylamine (56 mL, 390 mmol) in dichloromethane (200 mL). The resulting mixture was stirred overnight at room temperature. Water (400 ml) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane (2×200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, eluent: dichloromethane/heptanes 4:6-1:0). Two fractions were obtained: 38.7 g of tert-butyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate as a yellow solid, and a less pure fraction (26.1 g) that was purified by recrystallization from methanol to yield tert-butyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate. Both fractions were combined (17.0 g, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20]C)[CH:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.B(Br)(Br)Br>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]2[NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)=[C:4]([OH:20])[CH:3]=1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1cc(Br)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2cc(Br)cc(O)c21

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 800 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 348 mg of 5-amino-quinolin-2(1H)-one. 16 mg of diastereomer A of 5-{[7-bromo-2-,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one (fraction A) and 79 mg of diastereomer B of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one are obtained by reaction of 800 mg of imine with 7.9 ml of boron tribromide solution (1H in dichloromethane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.CO[C:22]([C:24]1[S:25][C:26]([CH:30](O)[CH2:31][CH3:32])=[C:27]([Cl:29])[CH:28]=1)=[O:23].Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40]>>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:22]([C:24]1[S:25][C:26]([CH:30]([O:8][C:6]2[CH:5]=[C:4]([CH3:9])[C:3]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=3)=[C:2]([CH3:1])[CH:7]=2)[CH2:31][CH3:32])=[C:27]([Cl:29])[CH:28]=1)=[O:23]
Reactant: COC(=O)CCN
Reactant: CCC(O)c1sc(C(=O)OC)cc1Cl
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CCC(Oc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1sc(C(=O)NCCC(=O)OC)cc1Cl

Procedure:
This compound is made by the general method as exemplified in Preparation 94 using 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol and 4-chloro-5-(1-hydroxy-propyl)-thiophene-2-carboxylic acid methyl ester in Step A and 3-amino-propionic acid methyl ester hydrochloride salt in Step C as the starting materials to provide (±)-3-({4-chloro-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.094 g) as a white foam. MS (ES): 552.2 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N+:10]([C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([C:23]2[N:19]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:20]=[CH:21][CH:22]=2)[CH:3]=1)([O-:12])=[O:11]
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ncc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 105.5 %

Procedure:
To a solution of 5-bromo-3-nitropyridine-2-carbonitrile (2.00 g, 8.77 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.68 g, 9.65 mmol) in 10 ml of ethylene glycol dimethyl ether were added bis(triphenylphosphine)palladium(II) chloride (0.31 g; 0.44 mmol) and 9 ml of 2 M sodium carbonate-solution. The reaction mixture was heated at 50° C. for 2 h. Cooled reaction mixture was filtered, the solids were washed with water and dried in vacuum to give 2.77 g (105%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.50-1.66 (m, 3H), 1.81-2.04 (m, 2H), 2.29-2.47 (m, 1H), 3.66-3.79 (m, 1H), 3.97-4.07 (m, 1H), 5.37 (dd, 1H), 6.99 (d, 1H), 7.74 (d, 1H), 8.92 (s, 1H), 9.25 (s, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:21]=[C:20]([CH2:22][N:23]([CH3:42])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH:19]=[CH:18][CH:17]=3)=[O:15])=[C:9]([C:43](=[O:60])[NH:44][C:45]3[CH:49]=[CH:48][N:47]([C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=4)[N:46]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH3:42][N:23]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[C:43](=[O:60])[NH:44][C:45]2[CH:49]=[CH:48][N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:57])([F:58])[F:59])[CH:51]=3)[N:46]=2)[N:21]=1
Reactant: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCOCCOCCOCCC(=O)O)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(2-(2-(2-(((6-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)-phenyl)carbamoyl)pyridin-2-yl)methyl)(methyl)amino)ethoxy)ethoxy)ethoxy)propanoate (210 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (4 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 32.9 mg (13%) of a brown solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.81-8.78(d, J=9.3 Hz, 1H), 8.48-8.47(d, J=2.7 Hz, 1H), 8.33-8.31(d, J=7.5 Hz, 1H), 8.21-8.16(d, J=7.5 Hz, 2H), 7.87-7.86(d, J=2.4 Hz, 1H), 7.79-7.72(m, 2H), 7.64-7.62(d, J=6.9 Hz, 2H), 6.98-6.97(d, J=2.4 Hz, 1H), 4.75(s, 2H), 3.80-3.77(t, J=4.5 Hz, 2H), 3.66-3.47(m, 16H), 3.11-3.09(d, J=6.3 Hz, 3H), 2.49-2.45(d, J=6 Hz, 2H), 1.94-1.75(m, 6H). MS (ES, m/z): 782 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:37]([O:38]C)=[CH:36][CH:35]=[CH:34][C:7]=1[O:8][CH:9]1[CH2:12][N:11]([C:13]([CH3:33])([CH3:32])[CH2:14][CH2:15][C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([NH2:19])=[O:18])[CH2:10]1>ClCCl>[NH3:11].[F:5][C:6]1[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:7]=1[O:8][CH:9]1[CH2:12][N:11]([C:13]([CH3:33])([CH3:32])[CH2:14][CH2:15][C:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([NH2:19])=[O:18])[CH2:10]1
Reactant: COc1cccc(OC2CN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC(Oc2cccc(O)c2F)C1
Product: N
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Boron tribromide (1M in dichloromethane, 1.5 mL, 1.5 mmol) was added to an ice-cooled solution of the product of example 133 (45 mg, 0.094 mmol) in dichloromethane (5 mL) and the mixture was stirred at 0° C. for 45 minutes. The reaction was warmed to room temperature. After 15 min, a further 1.5 mL boron tribromide was added. After 20 minutes, the reaction was quenched with 0.88 ammonia (20 mL) and the solution stirred at room temperature for 18 hours. The organic layer was separated and washed with saturated sodium hydrogen carbonate solution (10 mL) and dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia 100:0:0 to 98:2:0.2 to give the title compound in 100% yield (44 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.[N:40]1([CH2:46][CH:47]=[CH:48][C:49](Cl)=[O:50])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[C:17]([NH:20][C:49](=[O:50])[CH:48]=[CH:47][CH2:46][N:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Cl)C=CCN1CCCCC1
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(C=CCN1CCCCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 2.9 %

Procedure:
N*4*-(3-Chloro-4-fluoro-phenyl)-7-(3-morpholin-4-yl-propoxy)-quinazoline-4,6-diamine (510 mg, 1.18 mmol) and DIPEA (620 μL, 3.55 mmol) were combined in tetrahydrofuran (10 mL) and cooled to 0° C. 4-Piperidin-1-yl-but-2-enoyl chloride (278 mg, 1.48 mmol) was added and the reaction stirred at 0° C. for 2 hours. The mixture was quenched with ethyl acetate, dried with MgSO4 and concentrated. The residue was purified using chromatography on silica eluting with 15%-20% MeOH in CH2Cl2 to yield the desired product (20 mg). 400 MHz 1H NMR (DMSO-d6) δ 8.82 (s, 1H), 8.50 (s, 1H), 8.11 (dd, 1H, J=6.9, 2.6 Hz), 7.77 (m, 1H), 7.40 (t, 1H, J=9.0 Hz), 7.25 (s, 1H), 6.76 (m, 1H), 6.53 (m, 1H), 4.23 (t, 2H, J=6.0 Hz), 3.55 (m, 4H), 3.08 (m, 2H), 2.40 (m, 10H), 1.96 (m, 2H), 1.29 (m, 6H). MS m/z 584 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1(N)NC(C)=C[S:8]1)=[O:6].CC(O[Si](C)(C)C)=N[Si](C)(C)C.C1N=CN([C:31]([N:33]2[CH:37]=[N:36][CH:35]=[CH:34]2)=[O:32])C=1.[CH:38]1([NH:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C1C=CN=CC=1)C>[OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][C:37]([NH:33][C:31]([N:44]([CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]2)=[O:32])=[N:36][C:35]=1[CH3:34])=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CC1=CSC(N)(C(=O)NCCO)N1
Agent: CC(=N[Si](C)(C)C)O[Si](C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1C(=O)NCCO
Reaction time: 12 h

Procedure:
To a mixture of 2-amino-4-methyl-thiazole-carboxylic acid (2-hydroxyethyl)-amide (0.2 g) in dichloromethane was added N,O-bis-(trimethylsilyl)-acetamide (0.2 g) and the mixture stirred for 12 h. CDI (0.16 g) and DMAP (6 mg) was then added and the mixture stirred for 12 h before addition of dicyclohexylamine (0.18 g). After stirring overnight waster was added and the aqueous phase extracted with dichloromethane, concentrated and purified by chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:20]([O:22]C)=[O:21].[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1cnc2c(C)cc(C)cc2c1-c1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2ncc(C(=O)O)c(-c3ccccc3Cl)c2c1
Yield: 96 %

Procedure:
A mixture of methyl 4-(2-chlorophenyl)-6,8-dimehtyl-3-quinolinecarboxylate (0.98 g), potassium hydroxide (0.5 g) and 80% ethanol (10 ml) was refluxed for 15 mins. The mixture was diluted with water and acidified with hydrochloric acid to give 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarboxylic acid as crystals (0.90 g, 96.8%), which was recrystallized from ethanol as colorless prisms. m.p. 234°-235° C.