Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:30])[C:10]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[CH2:23]([N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:10]1[N:9]([CH3:30])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnn(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)cnn2C)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 0.799 g (1.862 mmol) of the product of Example 7 in 20 mL of methanol/THF (1:1) was added 9.3 mL of 1N sodium hydroxide solution and the resulting mixture was heated to reflux for 18 h. The reaction was then cooled to room temperature and the organics were removed in vacuo. The resulting mixture was acidified with 10% HCl and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 0.697 g (93%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec: 402 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.[CH2:23]([NH2:25])[CH3:24]>C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:3]=[C:2]([CH2:24][CH2:23][NH2:25])[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=3)[N:5]=2)=[CH:17][CH:18]=1
Reactant: CCN
Reactant: FC(F)(F)c1ccc2c(Cl)nc(-c3ccc(Cl)cc3)nc2c1
Solvent: C1CCOC1
Product: NCCc1nc(-c2ccc(Cl)cc2)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-2-(4-chloro-phenyl)-7-trifluoromethylquinazoline (52.0 g, 0.15 mol) in THF (400 mL) at 0° C. was added dropwise a solution of ethylamine (0.45 mol, 230 mL, 2 M in THF. The ice-bath was then removed and the reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure then partitioned between ethyl acetate (400 mL) and water (400 mL) removing any undissolved solid by vacuum filtration. The filtrate was concentrated to approximately 200 mL and the resultant precipitate was removed by vacuum filtration. The filtrate was again concentrated to approximately 100 mL volume and the resultant precipitate was removed by vacuum filtration. Finally the filtrate was cooled to 0° C. upon which [2-(4-chloro-phenyl)-7-trifluoromethyl-quinazolin-4-yl]ethylamine precipitated from solution. The precipitate (30 g) was isolated by vacuum filtration and dried under vacuum (10 mbar, 50° C.). A second amount of the precipitate of equal purity (19.6 g) was obtained following concentration of the filtrate to approximately 50 mL volume, cooling to 0° C., filtration and drying under vacuum. Combined yield=49.6 g, 93%; LC-MS: 2.9 min, 352 (M+); 1H NMR (DMSO-d6): δ 1.38 (t, 1 H, J=7 Hz), 3.77-3.85 (m, 2 H), 7.46 (d, 2 H, J=8.7 Hz), 7.64 (dd, 1 H, J=8.3, 1.8 Hz), 7.72-7.78 (br s, 1 H), 8.09 (s, 1 H), 8.17 (d, 1 H, J=8.3 Hz), 8.59 (d, 2 H, J=8.7 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:69][C:70]1[S:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:69][C:70]2[S:71][CH:72]=[CH:73][N:74]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3nccs3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 2-aminothiazole (9.01 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.5 mg, 58%). LC-MS m/z 590 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=3[CH3:26])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cc(Cl)ccc1C(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methyl-4-chlorobenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(2-methyl- 4-chlorobenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(Cl)Cl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:15](=[O:17])[CH3:16])[CH:3]=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.9 %

Procedure:
To a solution of 3-amino-5-bromopyridine (1.0 g, 5.78 mmol) and pyridine (1.3 mL, 12.9 mmol) in DCM (5 mL) is added acetic anhydride (0.6 mL, 6.358 mmol) dropwise. The mixture is stirred at room temperature for 17 h. The mixture is concentrated and the resulting crude product is purified by normal phase using 0-75% EtOAc in heptane as the gradient to afford N-(5-bromo-pyridin-3-yl)-acetamide (1.18 g, 95% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][C:19]1[CH:20]=[C:21]2[C:27]([C:28]3[N:33]=[C:32](S(C)=O)[C:31]([F:37])=[CH:30][N:29]=3)=[CH:26][N:25]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:22]2=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]2[C:27]([C:28]3[N:33]=[C:32]([NH:1][CH2:2][CH:3]4[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]4[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:31]([F:37])=[CH:30][N:29]=3)=[CH:26][N:25]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:22]2=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CN
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NCC4CC(F)(F)CCN4C(=O)OC(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
To a solution of tert-butyl 2-(aminomethyl)-4,4-difluoro-piperidine-1-carboxylate, 13i, (0.10 g, 0.41 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.18 g, 0.38 mmol) in THF (2 mL) was added iPr2NEt (0.20 mL, 1.15 mmol). The reaction mixture was heated in microwave at 130° C. for 15 minutes. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes) to afford the desired product, 13j.
Reaction SMILES: [ClH:1].NC(=O)[C@@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1[CH:10]=CC=C[CH:6]=1.[CH3:34]C(C)(C)CN>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][CH2:4][C:5]([CH3:10])([CH3:34])[CH3:6])=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Reactant: CC(C)(C)CN
Agent: Cl
Product: CC(C)(C)CNC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Yield: 31.6 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with 2,2-dimethylpropan-1-amine (Aldrich, 12 mg, 0.2 mmol) in a manner similar to that which is described in Step C of Example 1 to give N1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N3-neopentylmalonamide, hydrochloride salt (13 mg, 32% yield). 1H NMR (DMSO-d6) δ 13.34 (s, 1H), 10.69 (s, 1H), 8.08 (m, 1H), 7.96 (d, 1H, J=7.0 Hz), 7.87 (m, 3H), 7.44 (m, 2H), 6.70 (m, 1H), 6.13 (d, 1H, J=2.0 Hz), 3.34 (s, 2H), 2.91 (d, 2H, J=6.5 Hz), 0.84 (s, 9H); MS(ESI+) m/z 375.32 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[CH3:13][O:14][CH2:15][CH2:16]O.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:16][CH2:15][O:14][CH3:13])=[O:4]
Reactant: COCCO
Reactant: CC(C)CC(O)C(F)(F)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 72.5 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 25 g of 2-methoxyethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 8 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into ice water and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining 23.9 g (yield 73%) of crude 2-methoxyethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH:5]=[CH2:6])[CH3:2].[C:10]1([CH:17]=CC=[C:13](O)[CH:12]=1)[OH:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.S(=O)(=O)(O)O>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][C:9]2[CH:13]=[CH:12][C:10]([OH:11])=[CH:17][C:8]=2[O:7]1)[CH3:2]
Reactant: Oc1cccc(O)c1
Reactant: C=CC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC1CCc2ccc(O)cc2O1
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A solution of 1.6 g of acrolein diethylacetal in 4 ml of ethanol was added dropwise under cooling to a solution composed of 1.1 g of resorcinol, 0.05 g of conc. sulfuric acid and 6 ml of ethanol. While maintaining the temperature at less than 10° C., the mixture was stirred for 2 hours. The reaction mixture was neutralized with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography to give 1.2 g (yield 63%) of the desired product as a colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=O)[CH:8]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29].C(N(CC)CC)C>C1COCC1>[F:26][C:27]([F:31])([F:30])[CH2:28][NH:29][C:10](=[O:12])[CH:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCC(F)(F)F
Reactant: CCCCCCC(C(=O)O)n1cnc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCC(C(=O)NCC(F)(F)F)n1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
2-(4-Nitro-1H-imidazol-1-yl)octanoic acid (7.8 mmoles,2.0 g) was treated with 25 ml oxalyl chloride, concentrated and added to a solution of trifluoroethylamine hydrochloride (7.8 mmoles, 1.06 g) and triethylamine (2 ml) in 50 ml THF. After stirring at room temperature for 16 hours, the mixture was added to ice, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel to yield 0.6 g of N-(2,2,2-trifluoro)ethyl-2-(4-nitro-1H-imidazol-1-yl)octanoamide. (MS).
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][CH2:19][C:20]([N:9]2[CH2:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: c1ccc(C2CNC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.6 %

Procedure:
A solution of 3-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 4-phenyl-1-(3-phenylazetidin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 467 mg of colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[N:4][C:5]([F:13])=[C:6]([F:12])[C:7]=1[CH2:8]C(O)=O.[Br:15]Br>ClC1C=CC=CC=1.[Hg]=O>[Br:15][CH2:8][C:7]1[C:6]([F:12])=[C:5]([F:13])[N:4]=[C:3]([F:14])[C:2]=1[Cl:1]
Reactant: O=C(O)Cc1c(F)c(F)nc(F)c1Cl
Reactant: BrBr
Agent: O=[Hg]
Solvent: Clc1ccccc1
Product: Fc1nc(F)c(Cl)c(CBr)c1F
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a 1 L 3-neck flask equipped with addition funnel, was placed chlorobenzene (150 ml). (3-Chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid (19.57 g, 86.77 mmol) and mercury oxide (20 g, 92.34 mmol) were added in this order. The mixture was heated up to 140˜150° C. in an oil bath. Bromine (5.4 ml, 105 mmol) in chlorobenzene (90 ml) was then added dropwise through the addition funnel for 3 hr. After the addition of bromine solution, the reaction mixture was refluxed for further 1 hr. and cooled to room temperature. The mixture was filtered through celite pad and the pad was washed with chlorobenzene. The combined filterate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:15)) to give 17 g (75%) of 4-bromomethyl-3-chloro-2,5,6-trifluoro-pyridine as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:46][C:45]5[CH:44]=[CH:43][C:42]([CH2:41][N:38]6[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]6)=[CH:48][CH:47]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
In a dry round bottom flask, 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (89.4 mg, 0.2 mmol), 4-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride (66.7 mg, 0.24 mmol) were dissolved in dry N,N-dimethylformamide (3.0 mL). Then added diisopropylethylamine (107 μL, 0.6 mmol) and finally HATU (114 mg, 0.3 mmol) to the reaction, continued at room temperature for 2 hours. After completion, purified the product using reverse phase HPLC using water-acetonitrile solvent system. Pure fractions were mixed and evaporated to a minimal amount then basified with sat.NaHCO3 solution and extracted into EtOAc ((2×100 mL), combined organic layer was washed with sat. brine solution, dried over Na2SO4 and evaporated to get the pure product 72 mg (57% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.80 (m, 6 H) 1.97 (br. s., 2 H) 2.15 (s, 3 H) 2.34 (br. s., 8 H) 3.42 (s, 2 H) 3.93 (s, 3 H) 4.07 (t, J=12 Hz, 2 H) 4.80 (t, J=8.21 Hz, 1 H) 7.26 (d, J=8.59 Hz, 2 H) 7.51-7.67 (m, 2 H) 7.70 (m, J=8.59 Hz, 2 H) 8.05 (s, 1 H) 8.29 (s, 1 H) 8.37 (d, J=8.34 Hz, 1 H) 10.09 (s, 1 H). [M+H] calc'd for C33H40F2N8O3, 635; found 635.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].O>O1CCCC1>[CH3:1][NH:2][S:12]([C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylamine (2 M in tetrahydrofuran) (24 mL, 47.5 mmol) was added to an ambient temperature solution of p-nitrobenzenesulfonyl chloride (3.5 g, 15.8 mmol) in tetrahydrofuran (30 mL). After stirring at ambient temperature for 30 min, the reaction mixture was poured into water and extracted with ethyl aceate. The organic phase was dried (magnesium sulfate) and concentrated to afford N-methyl-4-nitrobenzenesulfonamide which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]([CH2:26][CH3:27])[C:14]([CH3:28])=[N:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]([CH2:26][CH3:27])[CH:14]([CH3:28])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1c2cc(OC)c(OC)cc2C(c2ccc(OC)c(OC)c2)=NNC1C

Procedure:
To a solution of 3.82 g (0.01 mole) of 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine in 38 ml of glacial acetic acid a solution of 3 g of sodium borohydride in 10 ml of water is dropped within 2 hours at 3° to 8° C., under stirring. Then the reaction mixture is stirred further for 5 hours at 20° to 25° C. and evaporated in vacuo. The residue (18 g) is dissolved in 30 ml of water, and 10 ml of a 40% sodium hydroxide solution are added. The product separated in soft form crystallizes after cooling. Yield: 3.1 g. The product shrinks from 75° C. The pure compound can be obtained by proceeding as described in Example 2. Yield: 2.29 g. M.p.: 120° to 122° C. Molecular formula: C22H28N2O4.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:24]>>[Br:14][C:15]1[C:16]([OH:24])=[C:17]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Product: O=c1cc(N2CCN(Cc3cc(Cl)cc(Br)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3-Bromo-5-chloro-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-bromo-5-chlorosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.62-2.66 (m, 4H), 3.48-3.66 (m, 4H), 3.72 (s, 2H), 5.40 (s, 1H), 6.93-6.94 (m, 1H), 7.44-7.45 (m, 1H), 7.86 (s, 1H), 12.85 (br s, 1H). Mass spectrum (ES) MH+=401.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1>O.C(O)(=O)C>[OH:3][N:1]=[C:15]([C:14](=[O:21])[CH2:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH3:5])[CH:7]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)CCc1cccc(C)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(C)c1
Reaction time: 1 h

Procedure:
Sodium nitrite (32 g) in water (60 ml) was added dropwise over 1 hour to a stirred solution of the product from example 13 step (i) (99.4 g) in acetic acid (200 ml) at a rate such that the internal temperature did not rise above 30° C. The solution was allowed to stir a further 1 hour before adding water (500 ml). After stirring for a further 24 h the reaction mixture was extracted with diethyl ether (×4). The combined ether extracts were washed with saturated sodium bicarbonate solution, and finally water before collecting the organic layer and drying over magnesium sulphate. The solution was filtered and the solvent evaporated under reduced pressure to leave the subtitle product.
Reaction SMILES: [CH3:1][C:2]1O[CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8]CC1C=CC=CC=1.Cl.[CH3:18][NH2:19].[OH-].[Na+].Cl>O.C(O)C>[OH:8][C:7]1[C:6](=[O:16])[CH:5]=[CH:4][N:19]([CH3:18])[C:2]=1[CH3:1]
Reactant: CN
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(O)c(=O)ccn1C
Reaction time: 12 h
Yield: 31.4 %

Procedure:
2-methyl-3-(benzyloxy)-4-pyranone (10.4 g) was dissolved in water (80 mL) and ethanol (80 mL). Methylamine hydrochloride (4.9 g) was dissolved in water (50 mL) and sodium hydroxide was added (2.9 g). This solution was added to the solution of 2-methyl-3-(benzyloxy)-4-pyranone, followed by the addition of 2N sodium hydroxide (4.0 mL). This solution was placed under conditions of reflux for 18 hours. After this time, the pH of the solution was set to 1.1 with hydrochloric acid, and the solution was concentrated. Water was added (80 mL), and the sample was washed with diethyl ether. The resulting precipitate was dissolved in ethanol, and the pH was set to 7.8 with 10N sodium hydroxide. The solution was extracted three times with methylene chloride, and these aliquots were combined and dried over sodium sulfate. After decanting, the solvent was removed by rotary evaporation, resulting in an orange oil. This oil was dissolved in ethanol and hydrochloric acid, and the solvent was removed by rotary evaporation, resulting in a yellow solid. This solid was recrystallized from ethanol and diethyl ether resulting in a white powder. This solid was dissolved in ethanol (70 mL) and water (5 mL) and 5% palladium on charcoal catalyst (0.26 g) was added. The resulting mixture was placed under 1 atm. of hydrogen for 12 hours. Following filtration, the solvent was removed by rotary evaporation resulting in a white solid. This was recrystallized from ethanol and diethyl ether, resulting in a white powder (2.1 g). Proton NMR (D20): 7.79 (d, 1H), 6.89 (d, 1H), 3.79 (s, 3H). 2.38 (s, 3H).