Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CN(C)C=O>[Si:20]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5]1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Into a 50-mL round-bottom flask was placed benzyl 3-hydroxyazetidine-1-carboxylate (2.15 g, 10.38 mmol, 1.00 equiv), TBSCl (2.34 g, 15.60 mmol, 1.50 equiv), imidazole (1.27 g, 18.68 mmol, 1.80 equiv) and N,N-dimethylformamide (15 mL). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water. The mixture was extracted with 3×40 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of sodium chloride (sat.). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). Purification afforded 3.0 g (90%) of benzyl 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carboxylate (50.3) as a light yellow liquid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[C:17]([CH2:20]C(=O)C)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:6]([C:5]1[CH:4]=[C:3]([CH2:2][CH2:18][C:17](=[O:19])[CH3:20])[CH:16]=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1cccc(C(=O)c2ccccc2)c1
Yield: 39.7 %

Procedure:
A mixture of 3-bromomethylbenzophenone (2.75 g.), acetylacetone (1 g.), potassium carbonate (1.4 g.) and ethanol (50 ml) was refluxed for 2 hours. The solvent was then evaporated and the residue extracted with ether. Distillation of the concentrated extracts gave 4-(m-benzoylphenyl)-2-butanone (1 g.), b.p. 220° C. (4 mm). [An alternative preparation of this compound appears in German Offenlegungsschrift 2243444].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:19])(=[O:18])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH3:20][O:21][CH2:22]Br>ClCCl.C(N(CC)C(C)C)(C)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:19])(=[O:18])[N:11]([CH2:20][O:21][CH3:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COCBr
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCN(c1ccccc1)S(=O)(=O)c1ccsc1C(=O)OC
Temperature: 0 °C

Procedure:
The Sulfonamide of Step One, 3-phenylsulfamoylthiophene-2-carboxylic acid methyl ester, was dissolved in dry dichloromethane and N,N-diisopropyl ethylamine. The resulting mixture was chilled to 0° C. prior to the addition of bromomethyl methyl ether. The reaction mixture was stirred over night at room temperature. The mixture was partitioned between dichloromethane and aqueous HCl (2N). The organic layer will then be washed one time with saturated sodium chloride solution and dried over sodium sulfate, followed by concentration to dryness under reduced pressure to give the desired product, 3-(N-methoxymethyl-N-phenylsulfamoyl)thiophene-2-carboxylic acid methyl ester (3 g, quantitative).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:23])[C:14](=[O:15])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1>ClCCl>[CH3:8][C:9]1([CH3:23])[C:14](=[O:15])[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CNCCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroactic acid (4 mL, 51.92 mmol) was added to a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (2.0588 g, 9.06 mmol) in dichloromethane (12 mL). The reaction was stirred at RT for 2 h and the solution was concentrated to remove the solvent. The residue as the product was directly used in the next step without further purification. m/z 128.
Reaction SMILES: [Na].[SH:2][CH:3]([CH2:6][SH:7])[CH2:4][OH:5].Cl[CH2:9][C:10]([CH2:12]Cl)=[CH2:11]>C(O)C>[OH:5][CH2:4][CH:3]1[CH2:6][S:7][CH2:12][C:10](=[CH2:9])[CH2:11][S:2]1
Reactant: OCC(S)CS
Reactant: C=C(CCl)CCl
Agent: [Na]
Solvent: CCO
Product: C=C1CSCC(CO)SC1
Yield: 92.2 %

Procedure:
Sodium metal (0.77 g) was dissolved in 35 mL of absolute ethanol at room temperature under nitrogen protection. Then 2,3-dimercapto-1-propanol (1.99 g, 1.6 mL, 16 mmoles) was added dropwise. The solution was taken up in a syringe and diluted to 44 mL. Solution 2. 2-(Chloromethyl)-3-chloro-1-propene (2 g, 16 mmoles) was dissolved in 30 mL of absolute ethanol. The solution was taken up into a syringe and diluted to a volume of 44 mL. Solutions 1 and 2 were added simultaneously (via syringe pump using separate teflon feed lines) to a 40 mL of absolute ethanol at room temperature under nitrogen protection over a period of one hour. After the addition was completed, the reaction was refluxed for one hour. The reaction was then worked up by evaporation of the solvent, dilution with water and extraction with ether. The ether extracts were dried and evaporated to give 2.6 g of oil. The oil was chromatographed on Silica gel using ether:hexane (1:3) to give 1.6 g (57%) of clear oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[N:26]1[CH:27]=[CH:28][C:23](/[CH:21]=[CH:22]/[C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Temperature: 100 °C
Yield: 49 %

Procedure:
A solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (2.0 g, 4.98 mmol), 4-vinylpyridine (0.69 mL, 6.47 mmol), diisopropylethylamine (1.74 mL, 9.96 mmol) and DMF (50 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (112 mg, 0.500 mmol) and P(o-tol)3 (457 mg, 1.50 mmol) were added and the reaction heated to 100° C. for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted with EtOAc (3×) and the combined organics washed with water (2×) and brine (2×). The organic layer was dried over MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 97:3 CH2Cl2/MeOH) to give 927 mg, 49% of the title compound which was used without further purification. MS ESI 380.2 [M+H]+, calcd for [C21H25N3O2Si+H]+ 380.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21](O)=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[NH2:34][C@@H:35]([CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[C:20]([CH:24]=2)[C:21]([NH:34][C@@H:35]([CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCS(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(C)(C)OC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A mixture of 5-[(1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy)]-2-(4-fluorophenethyl)benzoic acid (800 mg, 1.79 mmol), tert-butyl (2S)-2-amino-4-(methylsulfonyl)butanoate (L-methionine sulphone tert-butyl ester) (630 mg, 2.68 mmol), and DMAP (870 mg, 7.1 mmol), was treated with EDC.HCl (510 mg, 2.7 mmol) was stirred at ambient temperature for 16 hours. The reaction mixture was washed with aqueous citirc acid (1M, 2×), brine, dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography on silica (40 gm Dynamax column, gradient elution 2-10% methanol/dichloromethane) to give a gum which, when triturated with diethyl ether/iso-hexane, gave the title compound as a cream solid (889 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23](F)[CH:22]=2)[N:3]=1.O.[NH2:31][NH2:32]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:21]2[CH:22]=[C:23]3[C:24]([C:27]([NH2:28])=[N:31][NH:32]3)=[CH:25][CH:26]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CO[C@H](CNS(C)(=O)=O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CO[C@H](CNS(C)(=O)=O)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 26.8 %

Procedure:
A mixture of crude N-({(2S,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)methanesulfonamide (0.25 mmol theoretical) and hydrazine monohydrate (0.24 mL, 4.95 mmol) in 1,4-dioxane (3 mL) was stirred at 100° C. in a sealed tube for 17 hours. The mixture was concentrated in vacuo and the residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were concentrated in vacuo, taken up in EtOAc (25 mL), washed with saturated aqueous NaHCO3 (2×15 mL) and brine (15 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (29 mg) as a pale yellow solid. LC-MS (ES) m/z=433 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.6 Hz, 3H), 2.72-2.88 (m, 1H), 2.96 (s, 3H), 3.09-3.22 (m, 2H), 3.45-3.55 (m, 1H), 3.67 (dd, J=11.4, 2.5 Hz, 1H), 3.79 (d, J=11.1 Hz, 1H), 4.04-4.75 (bs, 2H), 5.39 (s, 2H), 6.14 (s, 2H), 6.56 (s, 1H), 7.23 (t, J=6.1 Hz, 1H), 7.57 (dd, J=8.6, 1.0 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[OH:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:23][CH:24]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:18])[CH:24]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Product: Nc1ncc(-c2cccc(O)c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-hydroxyphenyl-boronic acid pinacol ester gives “A70”; method 1: HPLC/MS: 1.12 min, [M+H]=307.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1.[C:14]([O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:29]#[CH:30])([CH3:17])([CH3:16])[CH3:15].N1CCCCC1>CCOC(C)=O.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>[C:14]([O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:29]#[C:30][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 70 °C

Procedure:
A mixture of 1-bromo-3-(propane-1-sulfonyl)-benzene (Intermediate 5; 493 mg, 1.87 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 500 mg; 1.87 mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg; 0.07 mmol) and piperidine (550 μL; 5.6 mmol) was heated at 70° C. for 18 hours. The reaction mixture was taken up in EtOAc, washed twice with citric acid (0.5 M aqueous solution) and once with brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a crude, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a dark orange sticky solid (640 mg, 76%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:22]=[N:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:17]=[CH:16][N:15]=3)[CH:11]=2)[C:6]([CH3:32])([CH3:31])[CH2:5]1)(=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO.Cl>[CH3:31][C:6]1([CH3:32])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:22]=[N:23][C:24]5[C:29]([CH:30]=4)=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(Nc3nccc(Nc4cnc5ccccc5c4)n3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)CNc2cc(Nc3nccc(Nc4cnc5ccccc5c4)n3)ccc21

Procedure:
A mixture of N2-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-N4-(3-quinolinyl)-2,4-pyrimidinediamine (Example 110, 170 mg, 0.266 mmol) was dissolved in EtOH (6 mL) and 10 drops conc. HCl were added. The mixture was heated to reflux in a sealed tube for 72 h. The crude mixture was poured into EtOAc (125 mL) and sat NaHCO3 (20 mL). The organics were dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified via medium pressure liquid chromatography using linear gradient starting from 0:100 MeOH/CH2Cl2 ending with 10:90 MeOH/CH2Cl2 as the solvent system to yield the desired product as a tan solid. M+H—383; Calc'd for C23H22N6—382.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][C:21]=1[CH2:30][OH:31]>CC#N>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:29]=[C:8]([C:3]3[S:4][C:5]([CH3:7])=[N:6][C:2]=3[CH3:1])[CH:9]=[CH:10][N:28]=2)=[CH:22][C:21]=1[CH2:30][OH:31]
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1ccc(Cl)c(CO)c1
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(Cl)c(CO)c3)n2)s1

Procedure:
By condensation of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-chloro-3-hydroxymethyl-phenyl)-guanidine nitrate. Yellow solid. Mp 245-246° C. Anal. RP-HPLC: tR=14.6 min (10-70% MeCN, purity>95%). 1H-NMR (DMSO-D6) δ: 2.62 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.53 (d, 2H, J=5.5 Hz, CH2), 5.34 (m, 1H, OH), 7.08 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.29 (m, 1H, Ph-H), 7.73 (m, 1H, Ph-H), 7.94 (s, 1H, Ph-H), 8.51 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.78 (s, 1H, NH). MS (ESI+) m/z 347.11 [M+H]+ (C16H15ClN4OS requires 346.84).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH:1]([O:4][C:5]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(OC(C)C)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(OC(C)C)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.61 g portion of 4-isopropoxy-2-methoxybenzoic acid was dissolved in 20 ml of acetic anhydride, 0.38 ml of concentrated nitric acid and a small amount of acetic acid were added, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured on crushed ice, extracted with chloroform and then dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the resulting residue was dissolved in 5 ml of tetrahydrofuran and 5 ml of 1N sodium hydroxide aqueous solution, followed by stirring for 1 hour. The reaction solution was poured into 1N hydrochloric acid aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to give 0.43 g of 4-isopropoxy-2-methoxy-5-nitrobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: O=Cc1nccc(Cl)n1
Reactant: C1COCCN1
Product: Clc1ccnc(CN2CCOCC2)n1

Procedure:
The title compound was prepared according to the general procedure in Example 45 Step 1 using 4-chloropyrimidine-2-carbaldehyde (2 g, 14.03 mmol) and morpholine (1.467 mL, 16.84 mmol) as the starting materials.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:22][CH:21]4[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:2]1=2.FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:22][CH:21]4[CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)CC1CC1c1ccc(OCCc2ccc3c(n2)NCCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)CC1CC1c1ccc(OCCc2ccc3c(n2)NCCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
The product of step 7 (380 mg, 1 mmol) was dissolved in 5 ml methanol and 2.5 ml 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, acidified with 1 ml trifluoroacetic acid, and concentrated. The residue was purified on HPLC using acetonitrile gradient 15-50% in 30 min to yield 210 mg desired product as an yellow oil. FAB-MS:(MH+)=355.H MNR(CDCl3) δ 0.78 (m, 1H), 0.86 (m, 1H), 1.21 (m, 1H), 1.70 (m, 1H), 2.35 (m, 2H), 3.12 (t, 2H), 3.63 (t, 2H), 4.22 (t, 2H), 4.26 (t, 2H), 6.65 (d, 1H), 6.79 (d, 2H), 7.0 (d, 2H), 7.6 (d, 1H). Anal Calcd. for C20H22N2O4 plus 1 CF3COOH and 0.2H2O: C, 55.98; H, 5.00; N, 5.93. Found: 55.90; H, 5.28; N, 5.24.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3.00 g (13.6 mmol) 4-iodophenol, 1.60 mL (15.0 mmol) 1-bromo-2-methylpropane and 7.50 g (54.5 mmol) K2CO3 are dissolved in 30 mL DMF and stirred at 80° C. for 4 h. Afterwards the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with diluted aq. NaOH (2×) and water (2×), dried over MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccccc3F)n2)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of compound 133 (0.3 g, 0.785 mmol), 2-fluorophenol (0.106 g, 0.942 mmol) and potassium carbonate (541 mg, 3.93 mmol) in dimethylformamide (3 mL) was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E28 as a pale yellow solid (0.2 g, 56%). mp 98-100° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 29.79 min, 99.82% purity; MS (CI): m/z 458 (M+H, 100).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CCCCCCN(CC)c1ccccc1)c1ccccc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
50.8 g of N-ethyl aniline together with 48.8 g of 1,6-dibromohexane and 25.2 g of sodium carbonate were dissolved in 500 ml of toluene. The mixture was stirred while refluxed at 115° C. Reflux was continued overnight. The precipitate was filtered and stirred in 1.25 l of ethyl acetate. The ethyl acetate phase was washed with 500 ml of water and 20 ml of acetic acid. The filtrate and the ethyl acetate phase were washed with a saturated sodium chloride solution and dried on sodium sulfate. The reaction product was isolated by concentration under reduced pressure. 45.4 g of N,N'-diethyl-N,N'-diphenyl-1,6-diaminohexane were obtained (yield: 70%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.Cl[C:28]([O:30][C@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)=[O:29].C(N(CC)CC)C>CN(C=O)C>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:28](=[O:29])[O:30][C@H:31]3[CH2:35][CH2:34][O:33][CH2:32]3)[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Yield: 64.9 %

Procedure:
To a solution of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (175 mg, 0.5 mmol) in DMF at 0° C. were added (S)-tetrahydrofuran-3-yl chloroformate (75 mg, 0.5 mmol) and triethylamine (137 μL, 1.0 mmol) simultaneously. Ten to fifteen minutes after addition, the reaction was complete, and it was quenched with water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 98% CH2Cl2/2% MeOH gave (S)-tetrahydrofuran-3-yl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (150 mg, 54%). LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).