Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:6]([NH:8][C@H:9]([C:14](OC)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:3][CH2:4][CH3:5].[NH3:25]>CO>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:25])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH2:3][CH2:4][CH3:5]
Reactant: N
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC
Solvent: CO
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O
Reaction time: 8 h
Yield: 91 %

Procedure:
5.0 g (14.5 mmoles) of BOC-Nva-Leu-OMe are dissolved in 50 ml of methanol, and gaseous ammonia is introduced into the solution for 0.5 hours under ice cooling. The solution is allowed to stand at room temperature overnight, then cooled again, saturated with gaseous ammonia, and evaporated after 4 hours of standing. The crystalline residue is recrystallized from a mixture of ethyl acetate and ether. 4.37 g (91%) of BOC-Nva-Leu-NH2 are obtained; m.p.: 158°-159° C., Rf2 =0.60, [α]D25 =-48.7° (c=1%, in methanol).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[CH3:14][C:15]1[C:16]([NH2:25])=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[N:20][CH:19]=[CH:18]2.N>CC(C)=O.C(O)C>[CH3:14][C:15]1[C:16]([NH:25][C:2]([NH2:3])=[S:1])=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[N:20][CH:19]=[CH:18]2
Reactant: Cc1ccc2cnccc2c1N
Reactant: N#C[S-]
Agent: N
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Solvent: CCO
Product: Cc1ccc2cnccc2c1NC(N)=S
Yield: 94.4 %

Procedure:
1.7 g of ammonium thiocyanate are dissolved in 30 ml of acetone, 2.6 ml of benzoyl chloride are then added and the reaction mixture is heated at reflux for 15 minutes. 2.7 g of 6-methyl-5-isoquinolylamine (Compound 28), dissolved in 20 ml of acetone, are added. The reaction mixture is heated for 30 minutes and then evaporated to dryness. The residue is taken up in water and the remaining precipitate is filtered off. The compound thus obtained is deprotected with 10 ml of a 30% ammonia solution and 20 ml of ethanol at reflux for 2 hours. Evaporation is carried out to dryness and the residue is triturated in a 75/25 (v/v) ethyl acetate/hexane mixture, to obtain 3.5 g of a white powder. 1H NMR (CDCl3): 2.38 (s, 3H, --CH3), 3.36 (s, 2H, --NH2), 6.58 (s, 1H, --NH--), 7.47-7.60 (m, 2H, H7, H4), 7.98 (m, 1H, H8), 8.50 (m, 1H, H3), 9.26 (s, 1H, H1) .
Reaction SMILES: N1C(C2C=CC([C:12]3[C:21](C)=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=4)[N:13]=3)=CC=2)=NN=N1.[F:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1B1OC(C)(C)C(C)(C)O1)[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[N:13]=1)[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3n2)c(F)c1
Temperature: 120 °C
Yield: 47.7 %

Procedure:
A mixture of 2-chloro-6-methoxyquinoline (Intermediate 1) (300 mg, 1.55 mmol), methyl 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Intermediate 10) (415 mg, 1.48 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol) and sodium carbonate (320 mg, 3.0 mmol) in 1,4-dioxane/water (6 mL/1 mL) was heated to 120° C. under microwave irradiation for 4 h. The precipitate was filtered and washed with EA. The combined filtrate was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EA=30/1) to give the product (220 mg, 46%) as white solid. MS (ESI): m/z 312.2 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][C:20]=1[O:27][CH2:28][CH3:29])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])=[CH:21][C:20]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1ccc(CBr)cc1OCC
Product: CCCc1c(OCc2ccc(C(=O)OCC)c(OCC)c2)ccc(C(C)=O)c1O

Procedure:
1-(2,4-dihydroxy-3-propylphenyl)ethanone was allowed to react with 4-(bromomethyl)-2-ethoxybenzoic acid ethyl ester according to the procedure of Example 69 and the product was purified by HPLC to give 4-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-2-ethoxybenzoic acid ethyl ester, the title compound, m.p. 92°-94° in 83% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][C:36]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[S:37])=[O:34])=[CH:29][CH:28]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (82 mg, yield 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH2:28])=[CH:27][C:22]=2[O:21][CH2:20]1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:28][C:26]1[CH:25]=[CH:24][C:23]2[O:19][CH2:20][O:21][C:22]=2[CH:27]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Product: COC(=O)C(=CNc1ccc2c(c1)OCO2)C(=O)c1ccc(C)c(C)c1

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1, from crude 2-(3,4-dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester (4.03 g, 16.3 mmol) and benzo[1,3]dioxol-5-ylamine (2.45 g, 17.9 mmol). Yield: 3.14 g of a yellow crystalline solid: LC-MSD, m/z for C20H20NO5 [M+H]+=354.4; HPLC retention time: 2.8 min.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11]([S:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH2:11]([S:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CCSc1cccc(B(O)O)c1
Product: CCSc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 70.7 %

Procedure:
The title compound (900 mg) was prepared from 4-bromo-2,6-difluoroaniline (1 g, 4.8 mmol) and 3-(ethylthio)phenylboronic acid (1.13 g, 6.24 mmol) as a colourless liquid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Cl)[N:11]=1>[H-].[Na+].CN(C)C=O>[CH2:1]([O:8][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(OCc2ccccc2)n1
Yield: 60.4 %

Procedure:
Following the procedure of Example 4a) above, benzyl alcohol (5 g; 46 mmols) reacted with sodium hydride (1.19 g), was refluxed for 1 hour with 2,6-dichloropyridine (6.9 g; 46 mmols) using sodium hydride and dry dimethylformamide as solvent. 2-Benzyloxy-6-chloropyridine (6.1 g; 60%) was obtained as a colorless oil following solvent extraction with chloroform/water (500 ml; 50/50), purification and chromatographic separation of the product from the organic layer, identified by elemental analysis and mass spectrum.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13](OCC)(=O)[CH:14]=[O:15]>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]=[C:14]([OH:15])[CH:13]=[N:12]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CCOC(=O)C=O
Solvent: CCO
Product: CC(C)(C)c1ccc2nc(O)cnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.4 %

Procedure:
To a solution of 2 g (12.18 mmol) 4-tert-butyl-1,2-diaminobenzene in 20 mL ethanol under argon at room temperature, was added 3.139 mL (15.83 mmol) ethyl glyoxalate (50% in toluene). The reaction mixture was stirred at room temperature for 4 h. The resulting suspension was filtered and washed with ethanol. The powder was dried to provide 257 mg (10.4%) of the title compound as a white solid. MS(m/e): 201.0 (M−H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.Cl[CH2:6][C:7]1[N:16]=[C:15]([OH:17])[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=1>>[CH3:1][N:2]([CH2:6][C:7]1[N:16]=[C:15]([OH:17])[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=1)[CH3:3]
Reactant: CNC
Reactant: COc1ccc2c(O)nc(CCl)nc2c1
Agent: Cl
Product: COc1ccc2c(O)nc(CN(C)C)nc2c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
To a solution of dimethylamine (2M solution in tetrahydrofuran, 40.0 mL, 80.0 mmol) was added 2-(chloromethyl)-7-(methyloxy)quinazolin-4-ol hydrochloride (7.5 g, 29 mmol) and the reaction mixture was stirred for 90 minutes at 50° C. After cooling it to room temperature the reaction mixture was concentrated and the residue was partitioned between water (100 mL) and ethyl acetate (250 mL). The organic layer was separated and washed with water (100 mL), saturated sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to give 2-[(dimethylamino)methyl]-7-(methyloxy)quinazolin-4-ol (6.6 g, 97%). MS (EI) for C12H15N3O2: 234 (MH+).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[C:13]([O:16][C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19]([OH:21])=[O:20])(=[O:15])[CH3:14].[ClH:26].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[ClH:26].[C:13]([O:16][C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19]([OH:21])=[O:20])(=[O:15])[CH3:14]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: CC(=O)Oc1ccccc1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC(N)O
Reaction time: 2 h

Procedure:
The Boc-aminopropanol-acetylsalicylic acid obtained above (0.814 mmol) was dissolved in dichloromethane (1 ml), and 4 N hydrochloric acid/ethyl acetate (3 ml) was added thereto under ice-cooling, followed by stirring for 2 hours. After confirming disappearance of Boc-aminopropanol-acetylsalicylic acid by TLC, diethyl ether was added thereto. The thus formed precipitate was centrifuged, and the supernatant was subjected to decantation. The thus obtained precipitate was dried under reduced pressure to give 213.9 mg (yield 96%) of the titled compound. The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>>[F:22][C:16]([F:23])([C:15]([F:25])([F:24])[F:14])[C:17](=[O:18])[CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)=[O:3]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(CC(=O)C(F)(F)C(F)(F)F)c1ccc2ccccc2c1

Procedure:
The compound was synthesized according to example 1 using 2-acetylnaphthalene and ethyl pentafluoropropionate as starting materials. The product was crystallized from petroleum ether. 1H NMR (CDCl3): 6.79 (s, 1 H); 7.57-7.67 (m, 2H); 7.90 (bd, 1 H); 7.94-7.95 (m, 2H); 7.99 (bd, 1H); 8.53 (s, 1 H). IR (film): 1602 (C═O); 1201 (C—F).
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCC2CCCCC2)C(=O)O)COc2ccccc21
Reaction time: 3 h
Yield: 84.9 %

Procedure:
In 10 ml of ethanol is dissolved 1.5 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 49, and 1N sodium hydroxide solution is added dropwise over a period of 15 minutes. After stirring for 3 hours, the solution is diluted with water (200 ml) and extracted with ethyl ether (100 ml). The aqueous layer is acidified slightly with 1N hydrochloric acid to deposit crystals. This product is collected by filtration and dried to give 1.2 g of tert-butyl 3(S)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as colorless needles, melting at 180°-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[N:6][C:7]=1[CH3:8].[ClH:24]>C(Cl)Cl>[ClH:1].[ClH:24].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncc(CNC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Agent: Cl
Solvent: ClCCl
Product: Cc1ncc(CNC2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 206.5 %

Procedure:
A solution of 1,1-dimethylethyl 4-{[(5-chloro-6-methyl-3-pyridinyl)methyl]amino}-1-piperidinecarboxylate (65.58 g, 193 mmol) in DCM (800 ml) at 0° C. was treated with HCl (4M solution in 1,4-dioxane, 386 ml, 1544 mmol) and stirred at room temperature overnight. The resulting white suspension was filtered, washed with DCM and hexane and dried to obtain N-[(5-chloro-6-methyl-3-pyridinyl)methyl]-4-piperidinamine dihydrochloride (62.3 g) as a white solid. The crude product was dissolved in DCM/MeOH 5% (800 ml) and 2N NaOH (500 ml) was added until pH 13.8. Organic phase was extracted and aqueous phase was extracted again with DCM/MeOH 10% (650 ml×2). Combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated under vacuum to give N-[(5-chloro-6-methyl-3-pyridinyl)methyl]-4-piperidinamine (44.82 g, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25]4)=[N:22][CH:23]=2)=[CH:3][C:2]([C:43]2[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 80.2 %

Procedure:
Following general procedure M, tert-butyl (1-(5-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (98 mg, 0.173 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.275 mmol) to afford the desired product (90 mg, 80%) as a brown solid. ESI MS m/z 647 [C34H35Cl2N5O4+H]+
Reaction SMILES: CO[CH2:3][CH2:4][O:5][CH2:6][CH2:7]OC.C(Cl)C.C[O-].[Na+].OC1C=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CO>[CH2:4]([O:5][C:6]1[CH:7]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH3:3]
Reactant: Nc1ccc(O)cc1
Reactant: COCCOCCOC
Agent: CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(N)cc1
Reaction time: 6 h
Yield: 72.1 %

Procedure:
In accordance with the process of Example 2, 150 ml of diethyleneglycol dimethyl ether, 19.3 g (0.3 mole) of ethyl chloride, 42.2 g (0.22 mole) of sodium methylate in 28% methanol solution and 21.8 g (0.2 mole) of p-hydroxyaniline were charged in the autoclave and the reaction was carried out at 80° C. for 6 hours with stirring to obtain 19.7 g of p-ethoxyaniline having a boiling point of 135° to 136° C./24 mmHg. (yield: 72.1%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.Cl[C:17]1[C:18]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1>CN(C)C=O>[CH3:27][N:26]1[C:18]2[C:17]([NH:6][C@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])=[N:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24]([CH3:28])=[N:25]1
Reactant: Cc1nc(Cl)c2c(n1)c(C)nn2C
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Nc1nc(C)nc2c(C)nn(C)c12
Reaction time: 0.25 h

Procedure:
D-alanine methyl ester hydrochloride (6 g, 0.043 mol) is dissolved in 30 ml of cold (5° C.) dimethylformamide and 7 ml (0.05 mol) of triethylamine is added dropwise. After stirring 15 minutes, 6 g of triethylamine hydrochloride is removed by filtering. To the filtrate is added 7 g (0.035 mol) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo-[4,3-d]pyrimidine and another 6 ml of triethylamine. The mixture is stirred at 50°-55° C. for 60 hours and evaporated in vacuo. The residue is dissolved in 100 ml of methylene dichloride, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to give 7.6 g of slightly impure (R)-2-[1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]aminopropionic acid, methyl ester, mp 68°-70° C. from ether as a dihydrate.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:4]2[CH2:3][C:2]([CH3:20])([CH3:1])[O:7][CH2:6][C:5]=2[C:8]([O:10][CH3:11])=[O:9])=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)C1=C(c2ccc(Cl)cc2)CC(C)(C)OC1

Procedure:
To a solution of EXAMPLE 15B (2.88 g), 4-chlorophenylboronic acid (1.88 g) and Pd(Ph3P)4 (0.578 g) in toluene (40 mL) and ethanol (10 mL) was added 2N Na2CO3 (10 mL). The mixture was stirred at reflux overnight. The mixture was diluted ether (300 mL) and washed with water, brine and dried over Na2SO4. After evaporation of solvent, the residue was loaded on a column and eluted with 3% ethyl acetate in hexane to give the product.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 2-bromo-3-methylpyridine
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]#[C:21][CH3:22])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH:5]([CH3:7])[CH3:6]
Reactant: ClCCN1CCOCC1
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Agent: Cl
Product: CC#CCOc1ccc(S(=O)(=O)N(CCN2CCOCC2)C(C(=O)OC)C(C)C)cc1
Yield: 90.5 %

Procedure:
According to the procedure of Example 21, 0.419 g (1.236 mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid methyl ester and 0.408 g (2.20 mmol) of 4-(2-chloroethyl)morpholine hydrochloride provided 0.506 g of 2-[(4-but-2-ynyloxy-benzenesulfonyl)-(2-morpholin-4-yl-ethyl)-amino]-3-methyl-butyric acid methyl ester as a colorless oil. Electrospray Mass Spec 453.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.CCN(C(C)C)C(C)C>C(O)CCC.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[N:26][NH:27]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc5[nH]ncc45)nc(Cl)nc32)cc1
Temperature: 90 °C
Yield: 93.4 %

Procedure:
To a solution of 2,4-dichloro-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.68 g, 2 mmol) in nBuOH (5 ml) was added 4-aminoindazole (0.293 g, 2.2 mmol) and DIPEA (0.534 mL, 3 mmol) at room temperature. After heating at 90° C. for 15 h, it was diluted with EtOAc, the organic layer was washed with 1N HCl, Sat NaHCO3, brine, dried and concentrated to give crude 2-chloro-N-(1H-indazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.82 g).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](C2C=CC=C(F)C=2)[C:8]([C:18]([O-:20])=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].[OH2:23]>>[C:1]([C:5]1[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][O:23][CH2:1][CH2:5]2)[C:8]([C:18]([OH:20])=[O:19])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O
Reactant: CC(C)(C)c1ncc(C(=O)[O-])c(-c2cccc(F)c2)n1
Agent: [Li]O
Product: CC(C)(C)c1ncc(C(=O)O)c(N2CCOCC2)n1
Yield: 194.8 %

Procedure:
Using a procedure to Example B40, 2-tert-butyl-4-(3-fluorophenyl)pyrimidine-5-carboxylate (0.27 g, 0.89 mmol) was treated with LiOH—H2O (86 mg, 3.57 mmol) to afford 2-tert-butyl-4-morpholinopyrimidine-5-carboxylic acid (0.23 g, 92% yield). MS (ESI) m/z: 275.0 (M+H+).