Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:9][C:10]3[CH:19]=[CH:18][CH:13]=[CH:12][CH:11]=3)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Temperature: 110 °C
Yield: 190 %

Procedure:
7-Benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.6 g, 4.7 mmol), (prepared as described for the starting material in Example 1), was then added and the reaction mixture heated at 110° C. for 2 hours. The mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were then washed with 2M sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-6-methoxy-4-phenoxyquinazoline (1.6 g, 95%) as a yellowish solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 150 mg (0.37 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL THF and 0.82 mL 1M 4-chlorophenylmagnesium bromide. Yield: 73 mg of a white solid. LC-MSD, m/z for C22H14BrClN2O2 [M+H]+=453.0, 455.0; HPLC retention time: 2.6 min.
Reaction SMILES: C([O:8][C:9]1[CH:16]2[CH:12]([CH2:13][CH:14]([CH:17]=O)[CH2:15]2)[C:11](=[O:19])[C:10]=1[C:20]1[C:25]([CH2:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:21]=1[CH2:29][CH3:30])C1C=CC=CC=1.[CH:31](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:32]([CH3:34])=[O:33]>ClC(Cl)Cl>[CH2:26]([C:25]1[CH:24]=[C:23]([CH3:28])[CH:22]=[C:21]([CH2:29][CH3:30])[C:20]=1[CH:10]1[C:9](=[O:8])[CH:16]2[CH:12]([CH2:13][CH:14]([CH2:17][CH2:31][C:32](=[O:33])[CH3:34])[CH2:15]2)[C:11]1=[O:19])[CH3:27]
Reactant: CCc1cc(C)cc(CC)c1C1=C(OCc2ccccc2)C2CC(C=O)CC2C1=O
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(CCC(C)=O)CC2C1=O

Procedure:
1.87 g (4.65 mmol) of 6-(benzyloxy)-5-(2,6-diethyl-4-methylphenyl)-4-oxo-1,2,3,3a,4,6a-hexahydropentalene-2-carbaldehyde (compound I-a-2) and 1.63 g (5.11 mmol) of acetonylidenetriphenylphosphorane in 40 ml of trichloromethane are stirred at room temperature for 12 h. The solvent is then removed, and the residue is purified chromatographically on silica gel (mobile phase ethyl acetate/hexane 1:5). This gives 1.37 g (66%) of 3-benzyloxy-2-(2,6-diethyl-4-methylphenyl)-5-(3-oxobut-1-enyl)-4,5,6,6a-tetrahydro-3aH-pentalen-1-one as a colourless oil.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5].CN(C=O)C.[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH2:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)CCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-β-Ala-Ile-Ala-Leu (SEQ ID NO:37), (24.34 g, 0.04 mol) is added into a round bottom flask with DMF (350 mL) and a magnetic stirrer. After the tetrapeptide is dissolved, benzyl bromide (4.76 mL, 0.04 mol), followed by cesium carbonate (13.04 g, 0.04 mol), is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then, the reaction mixture is slowly poured into a flask with 450 mL of iced water. A large amount of white solid precipitates out which is collected by suction filtration. The product is washed with water (2×200 mL) and placed in a vacuum desiccator.
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:10])=O)C.C(Cl)(Cl)[Cl:33].CO>Cl.C(O)(=O)C>[ClH:33].[NH2:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])=[O:10]
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
A solution of the phenylmethyl ester product from part (a) (13.65 g., 32 mmole) in 1.5N hydrogen chloride gas in acetic acid solution (90 ml.) is stirred for 90 minutes at room temperature, and then the solvent is evaporated in vacuo. The residue is triturated in ether and the resulting white precipitate is collected to give 11.45 g. of crude product as a powdery white solid; m.p. 169°-175°. TLC (silica gel; chloroform:methanol:acetic acid, 6:1:1) Rf =0.52. One recrystallization from acetonitrile gives an analytical sample of 3-[[(S)-2-amino-1-oxo-3-phenylpropyl]amino]propanoic acid, phenylmethyl ester, hydrochloride as white needles; m.p. 170.5°-175°.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][O:15]C(=O)C)=[CH:9][C:8]=2[N+:19]([O-:21])=[O:20])=[O:4].O.[OH-].[Li+]>O1CCCC1.CO.O>[OH:15][CH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([N+:19]([O-:21])=[O:20])[CH:9]=1)[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2
Reactant: COC(=O)c1cc2cc(COC(C)=O)cc([N+](=O)[O-])c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cc(CO)cc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
5-Acetoxymethyl-7-nitro-1H-indole-2-carboxylic acid methyl ester (3.5 g, 12.0 mmol) prepared in Step B was dissolved in a solvent mixture of tetrahydrofuran, methanol and water (1:1:1, 100 mL). Lithium hydroxide hydrate (1.5 g, 35.9 mmol) was added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, methanol and tetrahydrofuran were removed by distillation under reduced pressure. 1N hydrochloric acid was added to the residue. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography to give the title compound (2.3 g, Yield 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1Cc2ccc(F)cc2N1

Procedure:
119 g 4-fluoro-2-nitrophenylacetic acid are hydrogenated in 600 ml acetic acid with the addition of 20 g palladium on activated charcoal (10%) under 50 psi of hydrogen pressure. The catalyst is suction filtered, the solvent distilled off. The crude product is stirred with 500 ml petroleum ether, suction filtered, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([CH:11]=[CH:12][O:13]C)=[C:4]2[CH:3]=1.Cl.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([CH2:11][CH:12]=[O:13])=[C:4]2[CH:3]=1
Reactant: COC=Cc1c(-c2ccc(OC)cc2)nn2ccc(Br)cc12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nn3ccc(Br)cc3c2CC=O)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 5-bromo-2-(4-methoxyphenyl)-3-(2-methoxyvinyl)pyrazolo[1,5-a]pyridine (160 mg, 0.45 mmol) in THF (7.3 ml) was added a 4N HCl solution in water (2.45 ml, 9.8 mmol). Heated to 50° C. and stirred for 4 h at which time monitoring the reaction by LC indicated all starting material had converted to the title compound. The solution was cooled to 20° C. and a saturated solution of sodium bicarbonate (10 mL) and ethyl acetate (15 mL) were added The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness to afford a residue that was purified by automated ISCO chromatography (ethyl acetate/dichloromethane; 7/93). The title compound was obtained as a tan solid (43 mg, 28%). LCMS m/z 345.0, 347.0 (M+H)+, ret. time=2.02, 2.12 min. Peak at 2.01 is hydrate of the aldehyde LCMS m/z 363.1, 365.1 (M+H)+ and peak at 2.12 is methyl hemiacetal of the aldehyde LCMS m/z 377.1, 379.1 (M+H)+ both formed under LCMS conditions.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][CH2:10][O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13]>C(O)CCC>[F:8][C:7]1[C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][CH2:10][CH3:9])=[O:13])[CH2:19][CH2:18]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: Fc1cccnc1Cl
Solvent: CCCCO
Product: CCOC(=O)N1CCN(c2ncccc2F)CC1

Procedure:
A solution of 2-chloro-3-fluoropyridine (650 mg, 5.06 mmol) and ethyl N-piperazinocarboxylate (1.61 g, 10.2 mmol) in 60 ml of n-butanol is stirred at reflux under nitrogen for 18 hours. After concentrating to dryness under reduced pressure, the residue is dissolved in a mixture of ethyl acetate and water. The ethyl acetate extract is washed again with water, dried over anhydrous sodium sulfate, filtered and concentrated. The N-carbethoxy derivative of 1-(3-fluoro-2-pyridinyl)piperazine is further purified by chromatography over silica gel 60 (230-400 mesh).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][CH3:26])[C:21](Cl)=[O:22])(=[O:17])[CH3:16].C(SCC(CSC)C(O)=O)(=O)C.S(Cl)(Cl)=O>O>[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][CH3:26])[C:21]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:22])(=[O:17])[CH3:16]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CSCC(CSC(C)=O)C(=O)Cl
Agent: CSCC(CSC(C)=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of L-proline (1.44 g.) and sodium carbonate (2.7 g.) in water (25 ml.) in an ice bath, 3-(acetylthio)-2-(methylthiomethyl)propanoic acid chloride (prepared from the acid of Example 15 with thionyl chloride) (3.6 g.) is added, and the mixture is vigorously stirred at room temperature for two hours. After extraction with ethyl acetate, the aqueous layer is acidified and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to give 1-[3-(acetylthio)-2-(methylthiomethyl)propanoyl]-L-proline.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21](Br)[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl.[CH3:34][NH2:35].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21]([NH:35][CH3:34])[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CN
Reactant: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(Br)cc3c2cnn3-c2ccc(F)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CNc1cc(C(=O)NCc2ccc(S(=O)(=O)NC)cc2)c2cnn(-c3ccc(F)cc3)c2c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide (0.05 g, 0.1 mmol), methylamine hydrochloride (0.01 g, 0.2 mmol), palladium(II) acetate di-t-butylbiphenylphosphine (0.005 g, 0.01 mmol) and sodium t-butoxide (0.03 g, 0.25 mmol) was charged in a sealed tube with dioxane (5 mL). The tube was capped, degassed with argon for 5 minutes and warmed at 90° C. for 2 hours. The reaction was cooled to room temperature and filtered through diatomaceous earth, and diluted with water (5 mL) and ethyl acetate (20 mL). The organic layer was separated and washed with brine (10 mL), dried over sodium sulfate, and concentrated. The residue was purified by reversed-phase HPLC eluting with a gradient of 5-100% CH3CN in water. The desired fractions were combined and diluted with saturated aqueous NaHCO3 (20 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([NH:30][CH3:31])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([N:30]([CH3:31])[C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)=[CH:28][CH:27]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N(C)c2ccc(Cl)cc2)n1
Yield: 14 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloro-N-methylaniline in analogy to example 1c. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a colorless solid in 14% yield.
Reaction SMILES: C1(C[O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[C:22]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:23]
Reactant: CCOC(=O)/C=C\c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(O)c(C(=O)Nc2cccnc2)c1
Reaction time: 5 h

Procedure:
To a suspension of ethyl (2Z)-3-{4-[(phenylmethyl)oxy]-3-[(3-pyridinylamino)carbonyl]phenyl}-2-propenoate (may be prepared as described in Example 68; 160 mg, 0.40 mmol) in methanol (10 ml) was added Pd/C (20 mg). The mixture was put under a hydrogen atmosphere for 5 hours. The catalyst was removed by filtration through Celite and the solvent removed in vacuo to yield the title compound as a pale yellow solid. 119 mg.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[N:15]2[C:16]3[C:11]([CH:12]=[CH:13][C:14]2=[O:17])=[CH:10][CH:9]=[C:8]([F:18])[C:7]=3[C@H:6]1[NH:19][CH2:20][CH2:21][CH2:22][C@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:30]=[CH:31][C:32]3[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=3[CH:39]=2)[CH2:24]1)=[O:4].[ClH:40]>O1CCOCC1>[ClH:40].[F:18][C:8]1[C:7]2[C@@H:6]([NH:19][CH2:20][CH2:21][CH2:22][C@H:23]3[O:27][C:26](=[O:28])[N:25]([C:29]4[CH:30]=[CH:31][C:32]5[S:37][CH2:36][C:35](=[O:38])[NH:34][C:33]=5[CH:39]=4)[CH2:24]3)[C@H:5]([C:3]([OH:4])=[O:2])[N:15]3[C:16]=2[C:11]([CH:12]=[CH:13][C:14]3=[O:17])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H]1[C@H](NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c2c(F)ccc3ccc(=O)n1c23
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CSc2ccc(N3C[C@@H](CCCN[C@@H]4c5c(F)ccc6ccc(=O)n(c56)[C@H]4C(=O)O)OC3=O)cc2N1
Temperature: 50 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
A solution of the compound of Example 181 (20 mg) in dioxane (1 mL) was treated with aq. HCl (37%; 0.142 mL) and stirred at 50° C. for 3 h. The solution was concentrated under reduced pressure and the residue was suspended in EA/MeOH (4:1), filtered, washed with TBME and dried in HV, affording a gray solid (6 mg; 29% yield).
Reaction SMILES: CCl.[C:3]([O:6][CH:7]=[CH2:8])(=[O:5])[CH3:4]>C(O)(=O)C>[C:3]([O:6][CH:7]([O:6][C:3](=[O:5])[CH3:4])[CH3:8])(=[O:5])[CH3:4]
Reactant: C=COC(C)=O
Agent: CCl
Solvent: CC(=O)O
Product: CC(=O)OC(C)OC(C)=O
Reaction time: 6 h
Yield: 43978.1 %

Procedure:
The procedure of Example 9 was repeated except that 10 g of methyl chloride was used in place of methyl iodide and the reaction was effected for 6 hours. GC analysis showed that 0.116 g of vinyl acetate, and 43.3 g of ethylidene diacetate were formed with considerable amount of acetic acid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1.C([O-])(=[O:25])C.[Cs+].CN(C=O)C>O>[OH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc(O)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (5.00 g), cesium acetate (7.23 g) and DMF (40 mL) was stirred at 0° C. for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([NH:4][S:5]([NH:8][C:9]1[C:14]([C:15]([O:17]C)=O)=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:7])=[O:6])[CH2:2][CH3:3].[OH-].[Na+]>O>[CH2:1]([N:4]1[S:5](=[O:7])(=[O:6])[NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]1=[O:17])[CH2:2][CH3:3]
Reactant: CCCNS(=O)(=O)Nc1ncccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1C(=O)c2cccnc2NS1(=O)=O

Procedure:
Methyl 2-(((n-propylamino)sulfonyl)amino)- 3-pyridinecarboxylate (15.7 grams; 0.057 mole), 95 ml of water and 10.5 ml of 50 percent aqueous sodium hydroxide were mixed and the resulting reaction mixture stirred for about one and one-fourth hours at ambient temperatures. The reaction mixture was extracted with two - 50 ml portions of methylene chloride and one - 50 ml portion of ether to remove impurities. The aqueous layer was separated from the organic layer and acidified to a pH of about 4.5 with concentrated hydrochloric acid. The solution was filtered and the filtrate to a pH of about 1. The resulting product precipitate was recovered by filtration, dissolved in acetone and the solution filtered and dried with magnesium sulfate. The mixture was again filtered and the filtrate reduced in vacuo to obtain the title compound as a yellow powder having a melting point of 208° C-210° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:34])[C:13]2[CH:18]=[N:17][C:16](S(C)(=O)=O)=[N:15][C:14]=2[N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH:24]=1)=[O:10])[CH3:7]>>[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:34])[C:13]2[CH:18]=[N:17][C:16]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:14]=2[N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH:24]=1)=[O:10])[CH3:7]
Reactant: COCCN
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCOC)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared from 2-methoxy-ethylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 1, Step E, 10 mg, 0.022 mmol). 7 mg of 8-indan-5-yl-2-(2-methoxy-ethylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.25 (s, 1H), 8.47 (s, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.14 (d, J=7.8 Hz, 1H), 5.99 (br, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.45-3.35 (m, 2H), 3.29 (s, 3H), 3.00 (m, 4H), 2.18 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:40][N:41]([CH3:46])[CH2:42][C:43](Cl)=[O:44]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([C:43](=[O:44])[CH2:42][N:41]([CH3:46])[CH3:40])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CC(=O)Cl
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide and 2-(dimethylamino)acetyl chloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.25 (m, 1 H) 1.33-1.46 (m, 3 H) 1.48-1.65 (m, 3 H) 1.72-1.90 (m, 6 H) 2.35 (s, 6 H) 2.72 (t, J=12.2 Hz, 1 H) 2.72 (t, 1 H) 3.10 (t, J=11.8 Hz, 1 H) 3.31 (s, 3 H) 3.47 (d, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.5 Hz, 2 H) 3.97-4.12 (m, 2 H) 4.35 (d, 1 H) 4.46 (br. s., 1 H) 7.47 (dd, J=8.4, 1.6 Hz, 1 H) 7.50 (d, J=1.7 Hz, 1 H) 7.91 (s, 1 H) 8.19 (d, J=8.1 Hz, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.3 Hz, 1 H). Melting point: 190-191° C. [M+H] calc'd for C31H42F2N8O4 629; found 629.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]1[C:11](=[O:12])O[C:8](=[O:9])[CH2:7]1)=[O:4].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17]>O1CCCC1>[CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:7][C:8](=[O:9])[N:17]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:20]=[C:19]([Cl:21])[CH:18]=2)[C:11]1=[O:12])=[O:4]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)N[C@H]1CC(=O)OC1=O
Solvent: C1CCOC1
Product: COC(=O)NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
12.9 g of N-methoxycarbonylaspartic anhydride are dissolved in 100 ml of tetrahydrofurane, and to this solution is added a solution of 12 g of 3,5-dichloroaniline in 50 ml of tetrahydrofurane. The reaction solution is stirred for 4 hours at 50° C. and then evaporated to dryness in vacuo. The residue is dissolved in 80 ml of acetic anhydride and then 2.5 g of sodium acetate are added and the solution is stirred for 11/2 hours at 80° C. After cooling to room temperature, the reaction mixture is poured into water and stirred vigorously for 1/2 hour. The mixture is extracted with ethyl acetate and the extracts are washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over sodium sulfate, filtered and concentrated. Recrystallisation of the residue affords colourless crystals of the above compound with a melting point of 136°-138° C.