Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10](OC)=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].N#N>O1CCCC1>[OH:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cccc2[nH]ccc12
Temperature: 0 °C

Procedure:
A solution of 25 g of methyl 4-indolecarboxylate (1) in 200 ml of tetrahydrofuran is added to a suspension of LiAlH4 in 100 ml of tetrahydrofuran under a protective-gas atmosphere (N2) at such a rate that the temperature of the reaction mixture does not exceed 40° C. When the addition is complete, the reaction mixture is stirred at room temperature (25° C.) for approximately two further hours until the methyl 4-indolecarboxylate has reacted completely. The reaction mixture is subsequently hydrolysed by addition of ice-water (about 100 ml), and the hydrolysate is filtered through a bed of kieselguhr. After the tetrahydrofuran has been removed by distillation, the aqueous phase obtained is extracted with ethyl acetate. The organic phase obtained is dried over magnesium sulfate and evaporated, giving 16.0 g (76% of theory) of a pale-beige crystalline residue of 4-hydroxymethylindole (2).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[C:8]([F:17])[CH:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:7]=[C:8]([F:17])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[C:10]([F:12])[C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: CC(=O)Nc1c(F)cc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
30.7 g (487 mmol) of concentrated nitric acid were added dropwise at 0-5° C. to a solution of 100 g (487 mmol) of N-(4-chloro-2,6-difluorophenyl)acetamide in 500 ml of concentrated sulfuric acid. After the reaction mixture had been stirred for one hour at 0-5° C., it was stirred into ice-water. The resulting solid was separated off, washed twice with water and dried. Yield: 81.3 g (72%);
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl.N1C=CC=CC=1>C(OCC)C>[C:1]([O:6][Si:8]([CH3:11])([CH3:10])[CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: C/C=C/C(=O)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: C/C=C/C(=O)O[Si](C)(C)C
Temperature: 38 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
To a single-neck reaction flask (250 mL) were added of crotonic acid (10.750 g, 0.125 mol), anhydrous ethyl ether (125 mL) and trimethyl chlorosilane (19 mL, 0.150 mol). The mixture was stirred for 5 min. Pyridine (12 mL, 0.150 mol) was dropwise added into the resulting mixture under stirring at the temperature of 35° C. After the addition finished, the mixture was warmed up to the temperature of 38° C. and stirred under relux for 3 hr. The white solid was filtered in vacuo. Ethyl ether was evaporated under atmospheric pressure. The resultant was distilled under reduced pressure to collect the fraction under 10 mmHg at the temperature of 46° C.-48° C. to give (E)-trimethylsilyl 2-butenoate as a colorless liquid (12.242 g). Yield: 62.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:27][CH2:26]3)[CH:19]=2)=[N:14][CH:13]=1)=[O:11].[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[S:16][C:15]([NH:17][C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]3)[CH:19]=2)=[N:14][CH:13]=1)=[O:11]
Reactant: CCOC(=O)CN1CCN(c2cc(Nc3ncc(C(=O)Nc4c(C)cccc4Cl)s3)nc(C)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CC(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A mixture of ethyl 2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)acetate (4) (0.21 g, 0.40 mmol) in 10 mL of MeOH was added 1.0 N NaOH (2.4 mL, 2.4 mmol) at rt. The mixture was stirred at rt for 1 h to become a clear solution. The HPLC indicated the reaction was complete with a single peak with Rt 2.417 min. The solvents in the solution were reduced to a small volume. The remaining liquid was treated with H2O (10 mL). The aqueous solution was washed with CH2Cl2 (2×10 mL) and then adjusted to pH 6-7 with 1 N HCl (2.4 mL) to result in white precipitation. The solid was collected on a filter, washed with water to give 0.18 g of 2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2-methylpyrimidin-4-yl)piperazin-1-yl)acetic acid (IV) (90% yield). HPLC>99% pure. LC/MS (ES+) 502/504 (M+H, 100), HRMS calcd for C22H24ClN7O3S 502.1428, found 502.1413.1H NMR (DMSO-d6) δ 11.49 (br s, 1H), 9.89 (s, 1H), 8.23 (s, 1H), 7.41(dd, J=7.5, 1.6 Hz, 1H), 7.28 (m, 2H), 6.07 (s, 1H), 3.55 (s, 4H0, 3.19 (s, 2H), 2.61 (t, J=4.7 Hz, 4H), 2.42 (s, 3H), 2.24 (s, 3H). Anal. Calcd for C22H24ClN7O3S 0.85H2O: C, 51.08; H, 5.01; Cl, 6.85; N, 18.95; S, 6.20; H2O, 2.96%. Found: C, 51.23; H, 4.97; Cl, 7.08; N, 19.09; S, 5.92; H2O, 2.94%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:31](=[O:32])[CH2:30][C:27]3[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[CH:29][CH:28]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 86A and 2-[4-(methylsulfonyl)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.95-8.02 (m, 2H), 7.90-7.94 (m, 2H), 7.72-7.75 (m, 1H), 7.65-7.68 (m, 2H), 7.61-7.66 (m, 4H), 3.86 (s, 2H), 3.20 (s, 3H); MS (ESI−) M/Z 466 (M−H)−.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27](O)([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O.O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:24])([F:23])[F:25])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([Cl:33])([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCCc1ccc(-n2c(C(C)(C)O)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCc1ccc(-n2c(C(C)(C)Cl)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Yield: 87.4 %

Procedure:
To a solution of 2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (300 mg, 0.68 mmol) in dichloromethane (15 ml) was added thionyl chloride (0.07 ml, 1.02 mmol) and the reaction mixture was refluxed overnight. The reaction mixture was poured into water (10 ml) and the mixture was extracted with dichloromethane (30 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). The solvent was removed to give 273 mg (87%) of the title compound as white amorphous.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2I)[CH2:3][CH2:2]1.[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:37]>>[CH:1]1([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:37])[N:18]([CH3:17])[CH:27]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ccc(CCC2CC2)c(I)c1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2CCC2CC2)c2ccccc2c1=O

Procedure:
The title compound of Example 315, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 315, step 4 to give the title compound. 1H NMR (CD3OD, 400 MHz): δ 8.67 (d, J=8.0 Hz, 1H), 8.21 (dd, J1=2.0 Hz, J2=6.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.92-7.86 (m, 2H), 7.82-7.79 (m, 1H), 7.61 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 3.91 (s, 3H), 3.38 (s, 3H), 2.94-2.89 (m, 1H), 2.83-2.77 (m, 1H), 1.64-1.55 (m, 2H), 0.75-0.71 (m, 1H), 0.51-0.47 (m, 2H), 0.01-0.00 (m, 2H). LCMS: 382 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].CC(O)=O.C[N:35](C)C=O>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[N:35]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:20]=2)=[CH:24][CH:25]=1
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc(F)c(F)c2)cc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(4-chlorophenyl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (0.80 g), and AcOH (1.0 mL) in dimethylformamide (20 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA, and lyophilized to give 2-[6-(4-chlorophenyl)-4-(3,4-difluoro-phenyl)-pyridin-2-yl]-phenol; mp 146-148° C.; 1H NMR (DMSO-d6) d 6.75 (m, 1H), 7.00 (m, 2H), 7.35 (m, 2H), 7.57 (m, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.95 (d, J=8.6 Hz, 1H), 8.18 (d, J=8.6 Hz, 2H), 8.32 (m, 2H), 14.00 (s, 1H); IR (KBr) 1606 cm−1; MS [M+1] m/z=394. Anal. calcd for C23H14ClF2NO: C, 70.15; H, 3.58; N, 3.50; Found: C, 69.98; H, 3.51; N, 1.80.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1.C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3nc(C(C)C)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)ethanol (1.7 g, 6.08 mmol), methyl 2-(4-hydroxyphenyl)acetate (1.5 g, 9.1 mmol) and triphenylphosphine (2.4 g, 9.1 mmol) were dissolved in THF (30 ml). The mixture was stirred at RT under N2 for 5 min and disisopropyl azodicarboxylate (1.78 ml, 9.1 mmol) was added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with water, dried and evaporated. The crude material was purified by silica gel column (100 g SNAP, 5-25% EtOAc in hexane) to afford the desired product. LC/MS (m/z): 428 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].[H][H]>CN(C=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CC#Cc1cnccn1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cnccn1
Yield: 65.9 %

Procedure:
N-[3-(2-Pyrazinyl)-2-propynyl]phthalimide (780 mg, 2.96 mmol) was dissolved in DMF (30 mL) followed by addition of 10% palladium on carbon (500 mg, 50% water), and then the mixture was stirred in a hydrogen atmosphere at room temperature for 5.5 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to give N-[3-(2-pyrazinyl)propyl]phthalimide (521 mg; yield 66%).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([NH2:45])=[N:15][CH:16]=[N:17][C:18]=2[N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[N:26]([CH2:38][CH2:39]OS(C)(=O)=O)[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=4)[N:29]=3)[CH2:21][CH2:20]2)[CH:10]=[N:9]1)=O)(C)(C)C.[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C1COCC1>[CH:46]1([NH:49][CH2:39][CH2:38][N:26]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=3)[N:29]=[C:25]2[CH:22]2[CH2:23][CH2:24][N:19]([C:18]3[N:17]=[CH:16][N:15]=[C:14]([NH2:45])[C:13]=3[C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)[CH2:20][CH2:21]2)[CH2:48][CH2:47]1
Reactant: NC1CC1
Reactant: Cc1cc(-c2cn(CCOS(C)(=O)=O)c(C3CCN(c4ncnc(N)c4-c4cnn(C(=O)OC(C)(C)C)c4)CC3)n2)ccc1F
Solvent: C1CCOC1
Product: Cc1cc(-c2cn(CCNC3CC3)c(C3CCN(c4ncnc(N)c4-c4cn[nH]c4)CC3)n2)ccc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-(4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-pyrazole-1-carboxylic acid tert-butyl ester (100.00 mg; 0.16 mmol; 1.00 eq.) in seal tube was added THF 2 ml and cyclopropylamine (0.70 ml; 9.81 mmol; 62.84 eq.), stirred at 50° C. for overnight.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:9]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10]1>O1CCOCC1.C(OCC)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=C1CCCC(=O)O1
Reactant: CCN1CCNCC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCN1CCN(C(=O)CCCC(=O)O)CC1
Reaction time: 19 h
Yield: 65 %

Procedure:
1.5 g of 1-ethylpiperazine and 1.5 g of glutaric anhydride in solution in 5 cm3 of dioxane are added, under argon, to 10 cm3 of dioxane. The stirring is continued at 25° C. for 19 hours. The solvents are evaporated under reduced pressure (2.7 kPa) to give a brown oil which is stirred in ethyl ether. The solid obtained is filtered, rinsed with diethyl ether and then dried at 20° C. (90 Pa) to give 1.95 g of 5-(4-ethylpiperazin-1-yl)-5-oxopentanoic acid in the form of a hygroscopic pink solid which is used as it is.
Reaction SMILES: [NH4+].[Cl-].Cl.[CH:4]1([CH2:7][N:8]2[CH2:25][CH2:24][C@:15]34[C:16]5[C:17]6[O:23][C@H:14]3[C:13](=[O:26])[CH2:12][CH2:11][C@@:10]4([O:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:9]2[CH2:22][C:21]=5[CH:20]=[CH:19][CH:18]=6)[CH2:6][CH2:5]1>CO.[Zn]>[CH:4]1([CH2:7][N:8]2[CH2:25][CH2:24][C@@:15]34[C:16]5[C:17]([OH:23])=[CH:18][CH:19]=[CH:20][C:21]=5[CH2:22][C@@H:9]2[C@:10]3([O:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:11][CH2:12][C:13](=[O:26])[CH2:14]4)[CH2:5][CH2:6]1
Reactant: O=C1CC[C@@]2(OCCCc3ccccc3)[C@H]3Cc4cccc5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: O=C1CC[C@@]2(OCCCc3ccccc3)[C@H]3Cc4cccc(O)c4[C@@]2(CCN3CC2CC2)C1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
NH4Cl (0.72 g, 13.46 mmol) was added to a reflux boiling solution of 54 (1.2 g, 2.71 mmol) in 50 ml MeOH under stirring. 0.88 g (13.46 mmol) activated zinc powder was added in small portions to this mixture. This mixture was stirred under reflux for 80 min., then cooled to room temperature and filtered off from the inorganic residue. The inorganic residue was washed with hot methanol and the filtrate evaporated down. 50 ml H2O was added to the evaporation residue which was then alkalised with conc. NH4OH. This mixture was extracted with CH2Cl2 (3×80 ml), the combined organic phases washed with saturated NaCl solution (5×100 ml), dried over Na2SO4 and evaporated down. 1.20 g (99%) of 17-(cyclopropylmethyl)-4-hydroxy-14β-[(3-phenylpropyl)oxy]morphinan-6-one (55) was obtained as a yellowish oil which was used for the next reaction step without further purification. For analytical purposes 0.08 g of the oil was dissolved in ether and after the addition of etherial HCl 0.059 g of 0.17-(cyclopropylmethyl)-4-hydroxy-14β-[(3-phenylpropyl)oxy]morphinan-6-one hydrochloride (55.HCl) was isolated as a colourless powder. Fp. >170° C. (decomposition); MS (CI): m/z 446 (M++1); IR (KBr): 1709 (C═O) cm−1; 1H-NMR (DMSO-d6): δ 9.82 (s, 1H, C4-OH), 8.43 (s, wide, 1H, +N17-H), 7.30-7.20 (m, 5 arom. H, C14-O(CH2)3Ph), 7.03 (t, J=8.0 Hz, 1 arom. H, C2-H), 6.66 (m, 2 arom. H), 4.40 (ps-d, C9-H), 1.09 (m, 1H, N17-CH2CH(CH2)2), 0.70-0.67 (m, 2H, N17-CH2CH(CH2)2), 0.52-0.40 (m, 2H, N17-CH2CH(CH2)2).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[ClH:2].[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:19]=1[NH:20][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc(N)c(F)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(C)cc3F)c2cc1OC
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (130 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), and 2-fluoro-4-methylaniline (63 mg, 0.5 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature, the precipitated solid was collected by filtration, washed with isopropanol and ether and dried to give 4-(2-fluoro-4-methylanilino)-6,7-dimethoxyquinazoline hydrochloride (87 mg, 50%) as an off-white solid.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][N:12]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][CH:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:31][CH2:30]2)=[CH:25][C:24]=1[F:40])[C:13]([C:15]1[C:16](Cl)=[N:17][CH:18]=[N:19][C:20]=1[Cl:21])=[O:14])(C(C)(C)C)(C)C>O1CCOCC1.CO>[Cl:21][C:20]1[C:15]2[C:13](=[O:14])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:30][CH2:31][CH:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:33][CH2:34]4)=[CH:25][C:24]=3[F:40])[CH2:11][CH2:10][O:9][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COC(=O)CC1CCC(c2ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c3c(Cl)ncnc3Cl)c(F)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CC1CCC(c2ccc(N3CCOc4ncnc(Cl)c4C3=O)c(F)c2)CC1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
The title compound of Preparation 4 was prepared as follows. 4M HCl in dioxane (0.5 mL) was added to a solution of methyl 2-(4-(4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine-5-carboxamido)-3-fluorophenyl)cyclohexyl)acetate (30 mg, 0.05 mmol) in methanol (1 mL). The mixture was stirred at 23° C. for 30 minutes. The reaction mixture was concentrated to remove solvent. The residue was dissolved in acetonitrile (1 mL) and NEt3 (0.05 mL) was added to it. The reaction mixture was stirred at 80° C. for 18 hours. EtOAc (15 mL) and water (15 mL) were added to reaction mixture. The organic layer was separated and dried over MgSO4 and concentrated. The crude material was purified by a 4 g silica gel column eluted with 30-50% EtOAc in heptane to give methyl 2-(4-(4-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)-3-fluorophenyl)cyclohexyl)acetate a colorless oil (20 mg). m/z=448.4 (M+1).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1.C(#N)C.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
18.47 grams of (S)-1-hexadecyl-sn-glycerol and 19 grams of triphenylchloromethane were dissolved in a mixture of 250 ml dry THF and 58 ml dry acetonitrile. 17 ml of triethylamine was added and the reaction mixture was refluxed for 17 hours. The reaction mixture was cooled to room temperature, poured on ice (20 grams) and triethylamine (5 ml), transferred to a separatory funnel and extracted with diethyl ether. The organic phase was washed consecutively with 200 ml water, twice with 200 ml dilute (1.5%) sulfuric acid, 200 ml water, 200 ml saturated aqueous sodium bicarbonate, and again with 200 ml water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 41.79 grams of crude product as a residue. This residue was dissolved in 300 ml ethyl acetate and cooled at −20° C. overnight. The mixture was centrifuged (3,500 rotations per minute) at −10° C., and the mother liquid was poured of. The obtained solid melted and was dissolved in hexane and refrigerated (5±3° C.) overnight. Filtration of the precipitate yielded 18.97 grams of pure (R)-1-hexadecyl-3-trityl-sn-glycerol as an off-white solid.
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:12][C:13]([F:25])([F:24])[C:14]1[S:15][CH:16]=[C:17]([C:19](OCC)=[O:20])[N:18]=1>O.C(OCC)(=O)C>[F:25][C:13]([F:12])([F:24])[C:14]1[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=1
Reactant: CCOC(=O)c1csc(C(F)(F)F)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1csc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
To anhydrous ether (40 ml) was added lithium aluminium hydride (0.33 g). To this mixture was added dropwise an anhydrous ether (20 ml) solution of ethyl 2-trifluoromethyl-4-thiazole carboxylate (2 g). The mixture was stirred for 3 hours at room temperature. To the reaction mixture was added dropwise water (20 ml) under cooling with ice to decompose excess amount of the reducing agent. To the resultant reaction mixture were added ethyl acetate (50 ml) and water (25 ml), which was subjected to extraction with ethyl acetate. The organic layer was washed with water (25 ml) and a saturated aqueous solution of sodium chloride (25 ml) successively, followed by drying over magnesium sulfate. The solvent was distilled off, and the residue was subjected to a silica gel chromatography (2.5×30 cm), eluting with ethyl acetate-hexane (3:1). The desired fraction was concentrated to give 2-trifluoromethyl-4-hydroxymethylthiazole (1.1 g) as a pale yellow oily product.