Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:36])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:35])[C:18]([O:26]C(C3C=CC=CC=3)=O)=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].N(C)C.[C:40]1([CH2:46][NH2:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>C(O)C>[CH2:46]([NH:47][C:21]([C:19]1[N:20]=[C:9]2[C:8]3([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:36])[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]3)[CH2:11][N:10]2[C:17](=[O:35])[C:18]=1[OH:26])=[O:23])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Agent: CNC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccccc2)c(O)c1=O
Temperature: 50 °C
Reaction time: 0.12 h
Yield: 37.5 %

Procedure:
To a mixture of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (20 mg, 0.040 mmol) in ethanol (2 mL) was added 2M Me2NH (0.040 mL, 0.081 mmol) and the mixture heated at 50° C. for 1 h (mixture became clear after 5-10 min at 50° C. and then precepitate formed). Phenylmethanamine (0.022 mL, 0.201 mmol) followed by triethylamine (0.028 mL, 0.201 mmol) were then added and the mixture heated at 90° C. for 18 h. After work-up the crude product was purified by preparative HPLC to afford the title compound (7 mg, 0.015 mmol, 38% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 12.04 (1 H, s), 8.53 (1 H, brs), 8.29 (1 H, s), 7.35-7.39 (2 H, m), 7.28-7.34 (2 H, m), 7.24-7.27 (1 H, m), 4.57 (2 H, d, J=6.27 Hz), 4.14 (2 H, d, J=4.02 Hz), 3.26 (3 H, s), 2.87 (3 H, s), 2.44-2.58 (3 H, m), 2.01-2.10 (2 H, m), 1.86-1.99 (2 H, m), 1.64-1.75 (2 H, m). LCMS (M+H)=454.73. HPLC purity: >95%.
Reaction SMILES: [Mg].[Si:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1.C(OC)(C)(C)C>[O:9]([C:10]1[CH:15]=[CH:14][C:13]([B:17]([OH:20])[OH:18])=[CH:12][CH:11]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
Magnesium turnings (0.53 g, 22 mmol) and 20 mL of THF were placed into a two-necked flask. Next, tert-butyldimethylsilyloxyphenyl bromide (5.64 g, 19.6 mmol) was added and the mixture was heated under reflux for 2 h before it was cooled to room temperature. The brown mixture was added to a solution of trimethyl borate (2.43 g, 24 mmol) in 5 mL of THF through a dropping funnel at −78° C. and allowed to warm to room temperature overnight. After hydrolysis with 90 mL of ca. 0.1 M hydrochloric acid followed by standard work-up with methyl tert-butyl ether, the brown residue was washed with 20 mL of cold hexane, and the resulting white product (3.86 g, 78%) was dried in vacuo. Mp: 175° C. (1H NMR (300 MHZ, CDCl3): δ0.25 (s, 6H); 1.01 (s, 9H); 6.95 (d, J=8.5 Hz, 2H); 8.11 (d, J 8.5 Hz, 2H). 13C NMR (75 MHZ, CDCl3): δ−4.3; 18.1; 25.7; 119.8; 137.5; 159.8. Reference: Bolm, C.; Derrien, N.; Seger, A. Synlett 1996, 387.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:42])=[C:11]([CH:39]=[CH:40][CH:41]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:42])=[C:11]([CH:39]=[CH:40][CH:41]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonylpiperidin-3-yloxy)-7-methoxyquinazoline (0.67 g) in methylene chloride (15 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated under vacuum and the residue dissolved in methylene chloride. The methylene chloride solution was washed with a saturated solution of sodium bicarbonate, water, brine, dried over MgSO4 and evaporated to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline (0.28 g); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Br)cc1

Procedure:
A solution of 4-bromophenylacetic acid (10.0 g, 46.5 mmol), in methanol (125 mL) and sulfuric acid (5 mL) was heated at reflux overnight. The reaction mixture was concentrated and partitioned between ethyl ether and saturated aqueous sodium bicarbonate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The organic layer was filtered and evaporated to an oil to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][C@H:5]([C:25]1[S:26][C:27]([C:30]2[C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[N:32](S(C3C=CC=CC=3)(=O)=O)[CH:31]=2)=[CH:28][CH:29]=1)[NH:6][C:7]([C:9]1[C:10](=[O:24])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)=[O:8].C(Cl)Cl>C[O-].[Na+].CO>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[CH2:15][N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]([NH:6][C@@H:5]([C:25]2[S:26][C:27]([C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:4][C:3]([OH:48])=[O:2])=[O:8])[C:10]1=[O:24]
Reactant: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1

Procedure:
(R)-3-[5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-3-{[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-propionic acid methyl ester (0.050 g, 0.000072 mol;) was dissolved in 0.5 M of Sodium methoxide in methanol (3 mL) and Methylene chloride (3 g, 0.04 mol;). The reaction was heated at 75 C for 1 hour. LC-MS showed the disappearance of starting material and the appearance of product at 1.25 535.55. Some methyl ester and acid were seen but by the time it was injected on gilson only acid was present. The reaction was concentrated and dissolved in DMSO and methanol 1:1 for purification by Gilson Preparative HPLC. Pure fractions were combined and concentrated. ES (+) MS m/e=535.55; NMR (400 MHz, DMSO-d6) δ ppm 2.98 (d, 2H, J=7 Hz), 5.22 (s, 2H,), 5.66 (m, 1H), 6.66 (t, 1H, J=8 Hz), 7.03 (d, 1H, J=3 Hz), 7.14-7.20 (m, 2H), 7.22 (d, 1H, J=4 Hz), 7.38-7.49 (m, 2H), 7.81 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.27 (d, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 99.9 %

Procedure:
Using general procedure A, 4-methoxyphenylamine (246 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (612 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:16])[N:7]2[C:12]=1[C:11]1[S:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8]2.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>CN(C)C=O>[O:16]=[C:6]1[N:7]2[NH:8][CH2:9][C:10]3[CH:15]=[CH:14][S:13][C:11]=3[C:12]2=[C:3]([CH2:2][O:1][C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH:4]=[C:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1NCc1ccsc1-2
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2)N1CCOCC1
Temperature: 0 °C

Procedure:
2.62 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazin-7-one are dissolved in 80 ml of N,N-dimethylformamide and cooled to 3° in an ice-bath. 440 mg of 55 percent sodium hydride (NaH) dispersion are added portionwise thereto and the mixture is stirred for an additional hour after the last portion has been added. A solution of 1.5 g of N-chlorocarbonylmorpholine in 3 ml of N,N-dimethylformamide is now added dropwise thereto. The reaction mixture is left to stir at about 5° for an additional 45 minutes and poured into 800 ml of ice-water, whereby the crude product crystallizes out. After washing with water and drying, the crude product is purified by chromatography on silica gel and recrystallization. There is obtained (4,5-dihydro-7-oxo-8-phenyl-7H-pyrido[1,2-b]-thieno[2,3-d]pyridazin-10-yl)methyl-4-morpholinecarboxylate of m.p. 207°-210° (acetonitrile).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.C(O)C>[C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 4.3 h
Yield: 62.8 %

Procedure:
The ester from Step 1 (0.24 g, 0.64 mmol) was dissolved in THF (2 mL) and ethanol (2 mL), treated with 2.5 N sodium hydroxide (1.5 mL, 3.8 mmol), and stirred at room temperature for 4.3 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl yielding a solid. The solid was collected by filtration and was recrystallized from ethanol-water to yield a white solid (0.14 g, 64%): mp 269.8–270.8° C. 1H NMR (acetone-d6/300 MHz) 8.04 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.88 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.79 (m, 2H), 7.68 (m, 1H), 7.57 (m, 1H), 7.23 (d, 1H, J=8.6 Hz), 5.98 (q, 1H, J=7.0 Hz). FABLRMS m/z 347 (M−H). ESHRMS m/z 347.0560 (M−H, Calc'd 347.0531). Anal. Calc'd for Cl18H11F3O4: C, 62.08; H, 3.18. Found: C, 61.48; H, 3.22.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.CCCCCC>C(OCC)(=O)C>[NH2:5][C:4]1[CH:3]=[C:2]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Nc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(Nc2cccc(N)c2)cc1
Yield: 42.9 %

Procedure:
Following the general procedure, 3-bromoaniline (56 μL, 0.5 mmol) was coupled with ethyl 4-aminobenzoate (125 mg, 0.75 mmol) with the reaction temperature of 80° C. and the reaction time of 17 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 55 mg (43%) of the title compound as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:28][N:29]=[C:30]=[O:31]>ClCCl>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([CH:15]1[CH2:14][CH2:13][N:12]([CH2:11][CH:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:30]([NH:29][CH3:28])=[O:31])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:17][CH2:16]1)[CH:19]=[CH:20]2
Reactant: CN=C=O
Reactant: Nc1ccc2c(c1)C(CN1CCC(n3ccc4cc(Cl)ccc43)CC1)CC2
Solvent: ClCCl
Product: CNC(=O)Nc1ccc2c(c1)C(CN1CCC(n3ccc4cc(Cl)ccc43)CC1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[1-(6-aminoindan-1-ylmethyl)piperidin-4-yl]-5-chloro-1H-indole, 10h (0.9 g) in dichloromethane (10 mL) was added methylisocyanate (0.2 mL). The mixture was stirred at room temperature for 16 hours. Dichloromethane was evaporated. Upon addition of ethyl acetate the title compound 19a crystallized. The crystalline product was filtered off and dried overnight at 80° C. in vacua. Yield 0.6 g. mp: 193-195° C. 1H NMR (DMSO-d6): δ 1.70-1.85 (m, 1H); 1.90-2.35 (m, 7H); 2.35-2.85 (m, 4H); 2.65 (d, 3H); 3.05-3.15 (m, 2H); 3.25 (quin, 1H); 4.35-4.45 (m, 1H); 5.95 (dt, 1H); 6.45 (d, 1H); 7.00-7.20 (m, 3H); 7.50-7.65 (m, 4H); 8.35 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.B.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CC(Cc1ccc(Cl)nc1)C(=O)O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a stirred solution of 3-(6-chloropyridin-3-yl)-2-methylpropanoic acid (6.5 g, 32.6 mmol) in THF (75 mL) cooled in an ice-water bath was added a solution of 1 M borane in THF (48 mL, 48 mmol) in a rapid dropwise fashion. The mixture was stirred at room temperature for 4 h. Water (25 mL) was added carefully followed by 2 N NaOH solution. The two phases were separated and the aqueous phase washed with ether (100 mL). The organic phases were combined, dried over anhydrous MgSO4, filtered, and concentrated to give 4.2 g of the product as a nearly colorless oil in 69% crude yield. [M+H]+=186, 188; IR: 3414 (OH)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].Br[CH2:26][C:27]#[CH:28]>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH2:28][C:27]#[CH:26])=[O:5]
Reactant: Cn1c2c(c(=O)n(-c3cc(C(=O)[O-])c(Cl)cc3F)c1=O)CCC2
Reactant: C#CCBr
Agent: [Na+]
Product: C#CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl

Procedure:
using sodium 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and 3-bromo-1-propyne there is obtained 2-propynyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 193°-195° C.,
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([O:33]CC)=[O:32])=[N:22]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([CH2:30][C:31]([OH:33])=[O:32])=[N:22]2)=[CH:16][CH:15]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)nc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)nc2)c2ccccc12
Yield: 47.9 %

Procedure:
Ethyl 2-[1-[[6-(2-naphthamido)pyridin-3-yl]methyl]-1H-indazol-3-yl]acetate (154 mg, 0.33 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (70 mg, 1.67 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 69 mg, at a yield of 47.7%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:15])[F:16])[C:3]=1[C:17]([N:43]1[CH2:42][CH2:41][N:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:46])([F:47])[F:32])[CH:35]=2)[CH2:45][CH2:44]1)=[O:19]
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 66.8 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a gel-like required compound (593 mg, 1.23 mmol, 67%) was obtained.
Reaction SMILES: C[O-].[Na+].[CH2:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C([O:15][CH2:16][CH:17]1[O:19][CH2:18]1)CCC.ClCl>CO.CCOCC>[CH2:4]([O:10][CH2:18][CH:17]([CH2:16][OH:15])[OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCC1CO1
Reactant: CCCCCCO
Agent: C[O-]
Agent: ClCl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCOCC(O)CO
Temperature: 155 °C

Procedure:
4.7g of a solution containing 22.7% sodium methylate in methanol is added to 61.2g of dehydrated n-hexanol. The methanol is eliminated by heating the mixture to 155°C. After cooling the mixture to 130°C, 39g of tertio-butyl-glycidyl-ether is introduced gradually over a two hour and 50 minute period. This ether has a boiling point of 87°-88°C under 88 mm of mercury and a purity of 95% as determined by measurement of the epoxide function. The secondary products which it contains are chlorinate derivatives having a chlorine content of 0.58%. The reaction is completed by heating the mixture at reflux for one hour.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CCl)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
Chloroacetyl chloride (135 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-(piperidin-4-yloxy)-7-methoxyquinazoline di-hydrochloride (500 mg) (Starting material for Example 16) and diisopropylethylamine (368 mg) in methylene chloride (15 ml) that was cooled at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was adsorbed onto silica and the residue purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the expected product were combined and were re-purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 96/4). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline as a crystalline solid (0.33 g); 1H NMR Spectrum: (DMSO d6) 1.60-1.83 (m, 2H), 1.94-2.10 (m, 2H), 3.36-3.46 (m, 2H), 3.67-3.86 (m, 2H), 3.94 (s, 3H), 4.40 (s, 2H), 4.77 (m, 1H), 7.22 (s, 1H), 7.27 (t, 1H), 7.46-7.55 (m, 2H), 7.89 (s, 1H), 8.38 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [F:1][C:2]1C=CC=CC=1[C@]12COC[C@H]1CSC(NC(=O)C1C=CC=CC=1)=N2.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[N:37][CH:38]=1.O>CN(C)C=O>[F:1][CH2:2][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[N:37][CH:38]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)COC[C@H]2CS1)c1ccccc1
Reactant: COC(=O)c1cnc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCF)cn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
Fluoromethyl toluene-4-sulfonate (Journal of Labelled Compounds & Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (130 mg) in N,N-dimethylformamide (2.0 mL). The reaction solution was stirred at 70° C. for five hours and 30 minutes and then cooled to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6](=[O:60])[NH:7][C@H:8]([C:12]([N:14]1[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16][C@H:15]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[C:36]([Cl:38])[C:35]([NH:39][C:40]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][C@H:49]5[CH3:54])=[CH:46][CH:47]=4)=[O:41])=[CH:34][C:33]=3[O:55][C:56]([F:59])([F:58])[F:57])=[CH:28][CH:27]=2)[N:25]=1)=[O:13])[CH:9]([CH3:11])[CH3:10].C(N(CC)C(C)C)(C)C.[CH3:70][C:71](C)([CH3:75])[C:72](Cl)=O>CC(N(C)C)=O>[CH3:4][O:5][C:6](=[O:60])[NH:7][C@H:8]([C:12]([N:14]1[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16][C@H:15]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[C:36]([Cl:38])[C:35]([NH:39][C:40]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][N:51]([C:71]([CH3:75])([CH3:72])[CH3:70])[CH2:50][C@H:49]5[CH3:54])=[CH:46][CH:47]=4)=[O:41])=[CH:34][C:33]=3[O:55][C:56]([F:59])([F:58])[F:57])=[CH:28][CH:27]=2)[N:25]=1)=[O:13])[CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of ((S)-1-{(2S,4S)-2-[4-(5′-chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-4-methoxy-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester tri-HCl (10 mg, 0.01 mmol; Preparation 28) in DMA (1 mL) was added N,N-diisopropylethylamine (9.44 μL, 0.05 mmol) followed by 2,2-dimethylpropanoyl chloride (1.31 mg, 0.01 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (7 mg, 51% yield) (m/z): [M+H]+ calcd for C44H52ClF3N8O7 897.36. found 897.8.