Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:13]=2[C:14]([O:16]C)=[O:15])[N:4]=1.[OH-].[Na+].O>C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:13]=2[C:14]([OH:16])=[O:15])[N:6]=1
Reactant: COC(=O)c1c(F)cccc1Oc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1

Procedure:
To a solution in ethanol (10 ml) of methyl 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoate (3.0 g), an equimolar amount of an aqueous sodium hydroxide solution (30 ml) was added, and the mixture was reacted at room temperature for 12 hours under stirring. The reaction mixture was poured into water, and extracted with ethyl ether, and non-reacted starting materials were removed. Then, the aqueous phase was acidified with a 10% hydrochloric acid aqueous solution. The aqueous solution was then extracted with ethyl ether. The extract was washed with water and dried, and then the solvent was distilled off under reduced pressure to obtain the above identified compound as a white crystal (1.5 g). (Melting point: 133°-134° C.).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]#[C:13][CH3:14])[CH:10]=2)[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:18].C(O)(C(F)(F)F)=O>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]#[C:13][CH3:14])[CH:10]=2)[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: CC#Cc1cnc2c(c1)c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Product: CC#Cc1cnc2c(c1)c(O)c(C(=O)NCC(=O)O)c(=O)n2C

Procedure:
The title compound was prepared similarly to the procedure described for Example 1 (g) by treatment of tert-butyl 2-(4-hydroxy-1-methyl-2-oxo-6-(prop-1-ynyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 83 (a)) with TFA. MS (ESI, pos. ion) m/z: 315 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm: 12.98 (s, 1 H), 10.41 (t, J=5.4 Hz, 1 H), 8.83 (d, J=2.2 Hz, 1 H), 8.34 (d, J=2.0 Hz, 1 H), 4.14 (d, J=5.6 Hz, 2 H), 3.67 (s, 3 H), 2.12 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:22])[N:4]=1.CN1C=CN=C1.[F:29][CH:30]([F:35])[S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[F:29][CH:30]([F:35])[S:31]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:22])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1nc(OC)nc(C2C(=O)Nc3c(OC)cccc32)n1
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3c(OC)cccc32)n1
Temperature: -15 °C
Reaction time: 48 h

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-7-methoxy-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.47 g) are introduced as initial charge in 8 ml of dichloromethane and cooled to −15° C. with nitrogen. With stirring, difluoromethanesulfonyl chloride (0.62 g) is added dropwise in two portions and the mixture is heated to 10° C. in 2.5 hours. It is cooled to 0° C., 1-methyl-1H-imidazole (0.24 g) and difluoromethanesulfonyl chloride (0.35 g) are added, and the mixture is warmed to room temperature over the course of 3 hours, after-stirred for 4 hours and left to stand for 48 hours. For work-up, water is added and the mixture is stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 91% (0.52 g, 39% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: Cl.[CH:2]1([NH2:9])[CH2:7][CH:6]=[CH:5][CH2:4][CH:3]1[NH2:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[C:21](=[O:24])([O-])[O-:22].[K+].[K+]>O.C(#N)C>[CH2:14]([O:22][C:21](=[O:24])[NH:8][C@H:3]1[C@@H:2]([NH:9][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH:6]=[CH:5][CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CC=CCC1N
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@H]1CC=CC[C@H]1NC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Cyclohexene-1,2-diamine hydrochloride (4.0 g) was dissolved in a solvent mixture of water (20 mL) and acetonitrile (20 mL), and to the solution were added benzyl chloroformate (7.66 mL) and potassium carbonate (14.9 g), followed by stirring at room temperature for 3 days. The reaction mixture was poured into water, and the thus-obtained mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride), to thereby give the title compound (8.22 g).
Reaction SMILES: [C:1]([CH:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(O)=[O:2].C(=O)(O)[O-].[Na+]>C1COCC1>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH:4]([CH2:1][OH:2])[CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: COC(=O)c1ccc(CCC(Cc2ccc(C#N)cc2)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(CO)Cc2ccc(C#N)cc2)cc1
Temperature: -5 °C
Reaction time: 4 h

Procedure:
47.43 ml (47.73 mmol) of a 1 M borane-THF complex solution are added dropwise to a solution of 8 g (23.71 mmol) of methyl 4-[3-carboxy-4-(4-cyanophenyl)butyl]benzoate in 200 ml of THF at −10° C. After warming to −5° C., the mixture is stirred at this temperature for a further 4 hours. After reaction is complete, the reaction mixture is mixed with saturated sodium bicarbonate solution, and the solvent is concentrated to dryness. The residue is taken up in dichloromethane, dried over sodium sulfate and again freed of solvent. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 1:10). 5.8 g (98% purity, 74% of theory) of a colorless solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8]C(=O)OC(C)(C)C)[O:5][CH:6]=1.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[O:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)co1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(Br)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl [(4-bromo-2-furyl)methyl]carbamate (15.3 g, 55.4 mmol) in dichloromethane (86 mL) at 0° C. was treated with trifluoroacetic acid (43 mL) over 15 minutes. The reaction mixture warmed to room temperature over 30 minutes. The solvent was removed in vacuo and chased with toluene (3×50 mL). The product was lyophilized for 18 hours to give the desired product as a brown solid (13.0 g, 81%). LCMS calculated for C5H4BrO (M+H2)+: m/z=158.9, 160.9. 1H NMR (400 MHz, DMSO-d6): δ 8.34 (br s, 3H), 8.01 (s, 1H), 6.70 (s, 1H), 4.08 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[C@@H:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:26]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[C@@H:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:12]([OH:26])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)=O
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@H](C=O)OCc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Yield: 96 %

Procedure:
Following the general procedure for the oxidation of aldehydes to carboxylic acids of Description 13, (3R)-2,2-dimethyl-4-oxo-3-(phenylmethoxy)butyl (3-chloropropyl)sulfonate (11b) (10.0 g, 27.5 mmol) dissolved in 200 mL of acetone was reacted with 13.7 mL of Jones-reagent (2.0 M in water). After work-up, 10.0 g (96% yield) of the title compound (11) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=1.11 (s, 3H), 1.13 (s, 3H), 2.27-2.34 (m, 2H), 3.26-3.29 (m, 2H), 3.65-3.68 (m, 2H), 3.91 (s, 1H), 4.04 (d, J=9.6 Hz, 1H), 4.21 (d, J=9.6 Hz, 1H), 4.50 (d, J=10.8 Hz, 1H), 4.69 (d, J=10.8 Hz, 1H), 7.33-7.38 (m, 5H) ppm. 1H NMR (400 MHz, DMSO-d6): δ=0.97 (s, 3H), 1.01 (s, 3H), 2.07-2.16 (m, 2H), 3.41-3.46 (m, 2H), 3.69-3.73 (m, 2H), 3.76 (s, 1H), 3.99 (d, J=9.6 Hz, 1H), 4.14 (d, J=9.2 Hz, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.53 (d, J=11.2 Hz, 1H), 7.27-7.37 (m, 5H), 12.05 (v. br., s, 1H) ppm. MS (ESI) m/z 379.12 (M+H)+, 401.02 (M+Na)+, 376.9 (M−H)−. The analytical data was consistent with the proposed structure.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[C:9]([NH:14][C:15](=[O:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)=[N+]=[N-].[C:25]1([P:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[CH:6][CH:5]=[C:4]2[N:1]=[P:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [N-]=[N+]=Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c(N=P(c3ccccc3)(c3ccccc3)c3ccccc3)ccnc12)c1c(Cl)cccc1Cl
Temperature: 45 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a suspension of 4-azido-8-(2,6-dichlorobenzoylamino)quinoline (518 mg) in ethyl acetate (5 ml) was added triphenylphosphine (383 mg), and the mixture was stirred for 3 hours at 45° C. The resulting precipitates were collected by filtration, and the residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-[(triphenylphosphoranylidene)amino]quinoline (846 mg) as white crystal.
Reaction SMILES: C(C1C=CC([S:9]([Cl:12])(=[O:11])=[O:10])=CC=1OCC)#N.[Cl:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([N+]([O-])=O)=[CH:19][C:18]=1[O:27][CH3:28]>>[Cl:16][C:17]1[C:18]([O:27][CH3:28])=[CH:19][C:20]([S:9]([Cl:12])(=[O:11])=[O:10])=[C:21]([F:23])[CH:22]=1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Product: COc1cc(S(=O)(=O)Cl)c(F)cc1Cl

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with 1-chloro-5-fluoro-2-methoxy-4-nitro-benzene.
Reaction SMILES: [O:1]=[PH:2]1[O:9][C:8]2[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[CH2:6][C:5]2[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:4]=2[O:3]1.Cl[P:35]1[O:42][C:41]2[C:43]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:44][C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:46][C:40]=2[CH2:39][C:38]2[CH:55]=[C:56]([C:63]([CH3:66])([CH3:65])[CH3:64])[CH:57]=[C:58]([C:59]([CH3:62])([CH3:61])[CH3:60])[C:37]=2[O:36]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]([C:12]1[CH:11]=[C:10]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:8]2[O:9][P:2]([O:1][P:35]3[O:42][C:41]4[C:43]([C:51]([CH3:52])([CH3:53])[CH3:54])=[CH:44][C:45]([C:47]([CH3:50])([CH3:48])[CH3:49])=[CH:46][C:40]=4[CH2:39][C:38]4[CH:55]=[C:56]([C:63]([CH3:66])([CH3:65])[CH3:64])[CH:57]=[C:58]([C:59]([CH3:62])([CH3:61])[CH3:60])[C:37]=4[O:36]3)[O:3][C:4]3[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:22][C:5]=3[CH2:6][C:7]=2[CH:13]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[PH](=O)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(OP1Oc3c(cc(C(C)(C)C)cc3C(C)(C)C)Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3O1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2.0 g (4.3 mmol) of the compound of Example 5 in 150 mL of toluene is added 2.1 g (4.3 mmol) of the compound of Example 4 and 3.0 mL (22 mmol) of triethylamine at ambient temperature. The reaction mixture is stirred at room temperature for 14 hours. The solvent is removed under vacuum and the residue is recrystallized twice from acetonitrile to give the title compound as a white solid melting at 249°-252° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][CH2:27][CH:28]([OH:30])[CH3:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][CH2:27][CH:28]([OH:30])[CH3:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)CS
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CC(O)CSCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 58 %

Procedure:
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 1-mercapto-2-propanol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 58% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:13]2[N:14]=[C:15]3[C:21]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:20][N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:16]3=[N:17][CH:18]=2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:36][S:37][CH2:38][CH2:39]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:25][C:23]([CH3:26])([CH3:24])[C:22]([C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:4]3[CH:5]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:7]=[C:2]([O:1][CH2:39][CH2:38][S:37][CH3:36])[CH:3]=3)[N:14]=2)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:20]=1)=[O:27]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(O)cc(N4CCCC4)c3)nc12
Reactant: CSCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCCC2)c1
Reaction time: 2 h

Procedure:
A flask was charged with 1-[2-(3-hydroxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (140 mg, 0.28 mmol), 2-methylsulfanyl-ethanol (reagent A, 0.03 ml, 0.34 mmol), triphenylphosphine (reagent B, 89 mg, 0.34 mmol). THF (1.5 ml) was added and the mixture cooled (ice bath) under nitrogen atmosphere. Diisopropyl azodicarboxylate (reagent C, 0.07 ml, 0.34 mmol) was added via syringe and the material was warmed to ambient. After 1 hour a further 1.2 equivalents each of reagents A, B and C were added. After 2 hours repeat. The mixture was stirred overnight. The crude was loaded onto 2 preparative TLC plates eluting with 20% EtOAc in hexanes. The product band was collected providing 2,2-dimethyl-1-[2-[3-(2-methylsulfanyl-ethoxy)-5-pyrrolidin-1-yl-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one, 82 mg as a yellow viscous oil.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:32])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:24]=[N:23][C:22]3[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:20][C:19]([Cl:31])=[N:18][C:17]=3[CH:16]=2)[CH:10]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:1]([O:4][CH2:5][O:6][C:7](=[O:32])[N:8]([C:40](=[O:42])[CH3:41])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:24]=[N:23][C:22]3[C:21]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[N:20][C:19]([Cl:31])=[N:18][C:17]=3[CH:16]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCOC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCOC(=O)N(C(C)=O)c1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To a 100 mL round bottom flask, (((3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carbamoyl)oxy)methyl acetate (1.0 g, 0.0022 mol), triethylamine (0.6 mL, 0.0044 mol) N,N-dimethylpyridin-4-amine (0.0054 g, 0.000044 mol) and DCM (25 mL) were added. To the same flask was added acetic anhydride (2.67 g, 0.0264 mol). The reaction was continued at room temperature for 18 hour. Additional acetic anhydride (1.63 g, 0.0161 mol) was then added to the reaction mixture. The reaction was further continued at room temperature for 24 hours. The reaction mixture was diluted with DCM. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to provide the title compound (0.97 g, 83%). 1H NMR (400 MHz, DMSO-d6): δ 9.14 (d, J=2.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.53 (dd, J′=7.6 Hz, J″=0.8 Hz, 1H), 5.66 (s, 2H), 4.65-3.97 (br s, 4H), 3.80 (t, J=4.8 Hz, 4H), 2.55 (s, 3H), 2.03 (s, 3H). LC-MS (ESI): Calculated mass: 499.13; Observed mass [M+H]+: 499.8 (RT: 1.52 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24]Cl)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[Na+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CCl)CC1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline (0.15 g) (starting material for Example 17) and sodium iodide (0.02 g) in morpholine (5 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated under vacuum and the residue dissolved in methylene chloride/methanol. This was adsorbed onto silica and purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the title product were combined and evaporated under vacuum. The residue was triturated with diethylether, filtered and dried under vacuum to give the title product as a beige crystalline solid (0.105 g); 1H NMR Spectrum: (DMSO d6 and CD3COOD) 1.57-1.80 (m, 2H), 1.91-2.12 (m, 2H), 2.40-2.51 (m, 4H), 3.14-3.48 (m, 4H), 3.52-3.61 (m, 4H), 3.81-3.90 (m, 2H), 3.94 (s, 3H), 4.76 (m, 1H), 7.20-7.30 (m, 2H), 7.42-7.54 (m, 2H), 7.85 (s, 1H), 8.36 (s, 1H); Mass Spectrum: (M+H)+ 530.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.Cl.[CH3:16]O>>[OH:10][C:9]1[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][C:1]([O:14][CH3:16])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: CO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: Cl
Product: COC(=O)CCc1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 ml of 10% hydrogen chloride-methanol was added to 1.94 g (10 mmol) of ferulic acid and the mixture was stirred at room temperature for one day. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with water, and dried (MgSO4). The solvent was distilled off. The resulting residue was dissolved in 25 ml of methanol. 0.5 g of 10% palladium-carbon was added thereto and the solution was stirred overnight under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1 (v/v)) to obtain 1.86 g (8.85 mmol) of methyl 3-(4-hydroxy-3-methoxyphenyl)propionate as a colorless oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[N:8]([CH2:9][OH:10])[C:6](=[O:7])[N:5](CO)[C:3]1=[O:4].C=O>>[CH3:1][C:2]1([CH3:13])[N:8]([CH2:9][OH:10])[C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: CC1(C)C(=O)N(CO)C(=O)N1CO
Agent: C=O
Product: CC1(C)C(=O)NC(=O)N1CO

Procedure:
DMDMH is a formaldehyde donor which is the diformylated product of DMH and formaldehyde. MDMH is first formed as an intermediate. MDMH, itself, is a formaldehyde scavenger containing about 19% by weight of bound, but available, formaldehyde. Subsequent reaction of MDMH with formaldehyde yields DMDMH which theoretically contains 31.9% of bound but available, formaldehyde.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[F:6][C@@H:7]([CH3:11])[C:8](O)=O.O=P(Cl)(Cl)Cl>O1CCOCC1>[F:6][C@H:7]([C:11]1[S:4][C:3]([NH2:5])=[N:2][N:1]=1)[CH3:8]
Reactant: C[C@H](F)C(=O)O
Reactant: NNC(N)=S
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@H](F)c1nnc(N)s1
Temperature: 0 °C
Yield: 70.4 %

Procedure:
A 350 mL sealable pressure vessel was charged with thiosemicarbazide (11.17 g, 122.5 mmol) and dry dioxane (100 mL), and the mixture was cooled at 0° C. under an N2 atmosphere. To this rapidly stirring mixture was slowly added a solution of (S)-2-fluoropropanoic acid (9.40 g, 102.1 mmol, from Fritz-Langhals, E., Tetrahedron Asymmetry, 981 (1994)) in dioxane (10 mL). To the resulting mixture was added POCl3 (11.22 mL, 122.5 mmol) dropwise, then the cooling bath was removed and the thick white slurry was stirred at room temperature for 1 h. The vessel was then sealed and the mixture was heated at 90-95° C. (oil bath temperature) for 5 h. The cooled mixture was stirred at room temperature for 14 h (Note: this was for convenience only and is optional) and then the supernatant (two-phase mixture) was decanted and concentrated under reduced pressure. The lower phase was slowly poured into ice water (250 mL) and then the concentrate was also added. This mixture was rapidly stirred until it was essentially a homogeneous (turbid) solution, and then it was basified to pH 9-9.5 using 40% aqueous NaOH. The resulting slurry was filtered and the filter-cake was washed with water (Note: LC of this beige solid showed that it contained only a trace of the desired product, so it was not further investigated). The combined filtrate was then extracted with EtOAc (×3) and the organic phase was dried (Na2SO4) and evaporated to give a cream solid (10.58 g, 70%) which was the essentially pure product according to LC and LCMS. This material was used as such without further purification. An analytical sample was purified by flash chromatography [Isco/0-20% (MeOH—NH4OH, 9:1)-DCM] to give a white solid. LC (Method B): 0.608 min. MS (ESI) calcd. for C4H6FN3S m/z: 147.03. found: 148.05 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.38 (s, 2H), 5.82 (dq, J=6.4, 48.0 Hz, 1H), 1.65 (dd, J=6.4, 24.0 Hz, 3H). Chiral LC: S:R=95:5.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)=[N:1]2
Reactant: O=Cc1ccncc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccncc3)nc2c1
Yield: 63 %

Procedure:
5,7-Dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-pyridine carboxaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 5,7-Dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one (142 mg, 63%) was isolated as a pale brown solid and then converted to the corresponding hydrochloride (yellow solid). Selected data: MS (m/z): 284.06; MP 294-295° C. (hydrochloride).