Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:44])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:41]=3)=[C:18]([O:42][CH3:43])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:44])=[CH:17][C:18]=4[O:42][CH3:43])=[N:41][C:27]2=3)[CH2:40][CH2:39][CH2:38]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 820.6 %

Procedure:
A mixture of 0.095 g (0.22 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.066 g (0.33 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.078 g of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester. A mixture of 0.078 g (0.013 mmole) of 4-[4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester 1 mL of trifluoroacetic acid and 5 mL of dichloromethane was stirred for 1 hour and then concentrated under reduced pressure. The residue was taken up in 30 mL of ethyl acetate, washed twice with 30 mL of saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether, to give 0.055 g of 4-(9-cyclobutyl-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 (I-5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:14][N:15](C)[CH2:16]CCN=C=NCC.ClCCl.CNC>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([CH:10]=1)[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=Cc1ccc(Br)cc1C(=O)O
Agent: CNC
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
A 100 mL round-bottom flask was charged with 5-bromo-2-formylbenzoic acid (350 mg, 1.53 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (355 mg, 1.85 mmol, 1.20 equiv), 1-hydroxybenzotrizole (315 mg, 2.33 mmol, 1.50 equiv), dichloromethane (10 mL). The resulting solution was stirred for 15 min at room temperature. Dimethylamine (208 mg, 4.61 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (20 mL), extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (50/50) to provide 86.0 mg (22% yield) of 5-bromo-2-formyl-N,N-dimethylbenzamide as light yellow oil. LCMS (ESI, m/z): 256 [M+H]+.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH2:5]=[C:6]([CH2:9]O)[CH2:7][OH:8].O>CCCCCC>[CH2:2]([CH:1]1[O:8][CH2:7][C:6](=[CH2:5])[CH2:9][O:4]1)[CH3:3]
Reactant: C=C(CO)CO
Reactant: CCC=O
Solvent: O
Solvent: CCCCCC
Product: C=C1COC(CC)OC1
Yield: 73.2 %

Procedure:
A mixture of 16.3 g of propionaldehyde and 20.2 g of 2-methylene-1,3-propanediol in 1200 ml of hexane containing 0.1 g p-toluenesulfonic acid was stirred thoroughly and the mixture was heated under reflux for two hours while 5.3 g of by-product water was collected in a Dean-Stark trap. The mixture was cooled, concentrated by evaporation under reduced pressure to 50 ml and then treated with 200 ml of ether. The ethereal solution was washed with 75 ml of ten percent sodium carbonate and two 75-ml portions of water, after which it was dried over MgSO4 and concentrated to an oil. Distillation of the oil gave 21.5 g of 2-ethyl-5-methylene-1,3-dioxane, b.p. 68° C/41 mm Hg.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([F:25])[CH:13]=1>C1(C)C(C)=CC=CC=1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]([F:25])[CH:13]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Reactant: Clc1nc2ccccc2o1
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(Cl)c(Nc2nc3ccccc3o2)cc1F
Temperature: 25 °C
Yield: 74 %

Procedure:
In xylene (4 ml), 2-chlorobenzoxazole (278 μl, 2.43 mmol) and ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (512 mg, 2.21 mmol) were heated under reflux for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, ethyl (4-(2-benzoxazolyl)amino-5-chloro-2-fluorophenyl)acetate (570 mg, 74%) was obtained as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].Cl[C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:13]2[N:12]=1>C1C=CC=CC=1>[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][O:8][C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[C:27]([CH3:29])[CH:28]=[C:13]2[N:12]=1
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCn1ncc2c1ncc1c(OCCCN(C)C)nc3cc(C)nn3c12

Procedure:
To a suspension of 3.6 g of sodium hydride in 100 ml of dry benzene 15.3 g of 3-(dimethylamino)propanol are added and the mixture is refluxed for 6 hours. After this time, 28.6 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine are added in small portions with stirring. The solution is refluxed for 10 hours, and then the solvent is distilled off. The residue is treated with water, filtered off and recrystallized from ethyl acetate, yield 25 g (71%); m.p. 62°-64°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]#[N:17])[CH:5]=[CH:6][CH:7]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:16]([C:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH:3]=2)[NH:13][C:12](=[O:14])[NH:11][C:10]=1[CH3:15])#[N:17]
Reactant: CC1=C(C#N)C(c2cccc(Br)c2)NC(=O)N1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2cccc(-c3ccncc3)c2)NC(=O)N1
Temperature: 95 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-(2H)-pyrimidine (1.62 g, 5.5 mmol), pyridine-4-boronic acid (0.75 g, 6.1 mmol), potassium carbonate (2.28 g, 16.5 mmol) and DMF (10 mL) was flushed with nitrogen gas several times before [1,1′-bis(diphenylphsophino)ferrocene]dichloropalladium (50 mg) was introduced. The reaction mixture was heated at 95° C. under nitrogen for 64 h, cooled to room temperature and filtered through Celite. The filtrate was diluted with MeOH and stirred with AG 50W-X2 Resin for 10 min. The resin was collected by vacuum filtration, washed with MeOH and then eluted with 2 M NH3 in MeOH. This NH3-MeOH solution was concentrated in vacuo to give 5-cyano-3,6-dihydro-4-methyl-2-oxo-6-(3-(4-pyridyl)phenyl)-(2H)-pyrimidine as a brown solid (1.6 1 g; 32%): 1H NMR (DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 8.66 (d, 2H, J=2.2 Hz), 7.88 (s, 1H), 7.77 (d, 1H, J=7.9 Hz), 7.69 (m, 3H), 7.57 (m, 1H), 7.41 (d, 1H, J=7.9 Hz), 5.22 (s, 1H), 2.03 (d, 3H, J=2.2 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([CH3:9])=[N:6][C:7]=1Cl.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][SH:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[Br:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([CH3:9])=[N:6][C:7]=1[S:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: Cc1ccc(CS)cc1
Reactant: Cc1nc(Cl)c(Br)c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(CSc2nc(C)n(C)c(=O)c2Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
In 10 ml of methanol were dissolved 0.59 g of 5-bromo-6-chloro-2,3-dimethyl-4(3H)-pyrimidinone and 0.35 g of 4-methylbenzyl mercaptan and then 0.25 g of sodium carbonate was added thereto. The resulting mixture was stirred for 3 hours at room temperature. The solution thus obtained was poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. Solvent was distilled off therefrom under reduced pressure to give an oil. The oil thus obtained was purified by means of column chromatography (on silica gel, eluting with benzene) to give 0.72 g of the intended product.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[CH:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]([CH3:23])[CH3:22])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[F:36][C:37]([F:51])([F:50])[C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:41]Br>C1COCC1>[F:36][C:37]([F:50])([F:51])[C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[CH2:41][N:8]([C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=1)[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[CH:20]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C(c1ccc(C(F)(F)F)cc1CNc1cnc(Br)cn1)N1CCOCC1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Br)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.07 h
Yield: 80.3 %

Procedure:
To a flask charged with (5-Bromo-pyrazin-2-yl)-[2-(2-methyl-1-morpholin-4-yl-propyl)-5-trifluoromethyl-benzyl]-amine (94 mg, 0.198 mmol) was added THF (2 mL) followed by potassium t-butoxide (28 mg, 0.249 mmol). After 4 minutes, 3,5-bis(trifluoromethyl)benzyl bromide (0.05 mL; 0.272 mol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and diluted with ethyl acetate. The mixture was washed with 2N HCl. The aqueous layer was basified with 1N NaOH and extracted with ethyl acetate (2×). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel) (eluting with 10-40% ethyl acetate in hexanes) to afford the title compound (111 mg, 0.159 mmol).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(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>[CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2CC1CC1
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: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2CC1CC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (94.0 mg, 0.299 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (104 mg, 0.314 mmol), Na2CO3 (79.0 mg, 0.745 mmol) and Pd(PPh3)4 (21 mg, 0.018 mmol) in DMF (7.5 mL)/water (1.5 mL). The crude material was purified by an SCX column (2 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→1% MeOH in CH2Cl2 (15-34)→2% MeOH in CH2Cl2 (35-56)], yielding the title compound as an off-white yellow solid. 1H NMR (CDCl3, 400 MHz): δ=0.44-0.50 (m, 2H), 0.63-0.71 (m, 2H), 1.29-1.39 (m, 1H), 4.15 (d, J=7.2 Hz, 2H), 5.20 (brs, 2H), 7.29 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.8 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): S=4.05 (2C, −), 11.31 (+), 48.99 (−), 100.98 (Cquart), 115.67 (Cquart), 118.96 (+), 123.30 (+), 125.94 (Cquart), 127.46 (+), 127.55 (2C, +), 128.23 (+), 128.47 (+), 128.87 (2C, +), 129.50 (+), 136.50 (Cquart), 136.55 (+), 139.45 (Cquart), 148.52 (Cquart), 150.97 (Cquart), 152.04 (+), 156.99 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (100) [MH+], 338.2 (22) [MH+—C4H6]. HPLC: tR=2.9 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[H-].[Na+].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7](=[O:12])[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(=O)N2CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of 5-methoxyindoline-2,3-dione (0.5 g, 2.82 mmol) in dry DMF (7 ml), under nitrogen atmosphere, was cooled to 0° C., and sodium hydride (60% w/w dispersion in mineral oil, 0.135 g, 3.39 mmol) was added portionwise. The mixture was stirred at 0° C. for 1 hour, and tert-butyl 2-bromoacetate (0.458 ml, 3.10 mmol) was added dropwise. The reaction was then stirred at room temperature overnight. The solvent was evaporated, ethyl acetate was added, and the mixture was washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (ethyl acetate:petroleum ether=8:2) to afford tert-butyl 2-(5-methoxy-2,3-dioxoindolin-1-yl)acetate (0.650 g, 2.231 mmol, 79% yield). MS/ESI+ 235.8 [MH-tert-Bu]+.
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:29])[CH2:9][CH2:10][C@@H:11]([CH2:27][OH:28])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH:1]1([O:7][C:8](=[O:29])[CH2:9][CH2:10][C@@H:11]([CH2:27][O:28][S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[N:14]2[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@H](CO)CCC(=O)OC2CCCCC2)COC1(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC2CCCCC2)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 97.8 %

Procedure:
The (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-2-(hydroxymethyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (4.97 g, 12.0 mmol, 1.0 equiv), DMAP (1.47 mg, 12.0 mmol, 1.0 equiv) and tosyl chloride (9.2 g, 48.2 mmol, 4.0 equiv) were dissolved in pyridine (100 mL) and the solution stirred for 18 hr. The pyridine was removed in vacuo and the residue taken up in EtOAc/0.5 M HCl. The layers were separated, and the organic layer washed with 10% K2CO3, brine, dried over Na2SO4, filtered and evaporated. The tosylate was purified by flash chromatography on silica, (12 g), eluting with 0-29% EtOAc in hexanes. This afforded 6.66 g (98% yield) of (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate as a white solid. MS ESI +ve m/z 590 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18](O)[C:17]3[C:12](=[C:13]([CH3:21])[C:14]([OH:20])=[CH:15][CH:16]=3)[O:11][C:10]=2[CH3:22])=[CH:5][CH:4]=1.O.[NH2:24][NH2:25]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:17]3[CH:16]=[CH:15][C:14]([OH:20])=[C:13]([CH3:21])[C:12]=3[OH:11])=[N:24][NH:25][C:10]=2[CH3:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=C(C)Oc3c(ccc(O)c3C)C2O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(-c3ccc(O)c(C)c3O)n[nH]c2C)cc1

Procedure:
3-(4-Methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol (1 eq) was taken up in a 1:1 solution of EtOH:Hydrazine hydrate and heated under microwave conditions (120° C., 300 sec). The solution was concentrated in vacuo, residue quenched with cold water, extracted with ethyl acetate and purified by flash chromatography (1% MeOH-DCM). The yellow oil was then triturated with ether:hexane to give 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-benzene-1,3-diol as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12.[H-].[Na+].[CH3:39]I>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH3:39])[N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12
Reactant: CI
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3cc[nH]n3)ncc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (30 mg, 0.06 mmol) in DMF (1 mL) was treated with sodium hydride (60% in oil, 31.2 mg, 0.78 mmol) and stirred at room temperature for 5 min. Methyl iodide (56 uL, 0.9 mmol)was added and the mixture was stirred at rt for 1 h. Reaction was quenched with H2O and concentrated under reduced pressure. The residue was dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a white solid (20 mg, 67%). 1H NMR (500 MHz, DMSO-D6) δ ppm 3.15 (s, 2 H) 3.32 (s, 2 H) 3.47 (s, 2 H) 3.71 (s, 2 H) 4.05 (s, 3 H) 6.92 (s, 1 H) 7.58-7.65 (m, 3 H) 7.69 (s, 2 H) 7.91 (s, 1 H) 8.30 (d, J=12.83 Hz, 2 H) 12.30 (s, 1 H). LCMS: m/e 501 (M+H)+, ret time 1.37 min (method 3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.C(N(CC)CC)C.Cl.[CH3:23][NH:24][O:25][CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([N:24]([O:25][CH3:26])[CH3:23])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2cc(Br)ccc2n1
Yield: 91.4 %

Procedure:
A DMF (1 ml) solution of 6-bromoquinoline-2-carboxylic acid (4000 mg, 15.9 mmol, US2005165049A1), triethylamine (6.64 ml, 47.6 mmol), N,O-dimethylhydroxyamine hydrochloride (1860 mg, 19.0 mmol) and HBTU (6620 mg, 17.5 mmol) was treated in the procedure described in Example 1, Step G. The crude residue was applied to a silica gel column and eluted with hexane/ethyl acetate (4:1) to furnish the title compound (4.29 g, 92% yield) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 3.47 (3H, s), 3.80 (3H, s), 7.68-7.80 (1H, brs), 7.81-7.85 (1H, m), 8.00-8.06 (2H, m), 8.17 (1H, d, J=8.1 Hz). MS (ESI): m/z 295, 297 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25]CC)=[O:24])=[C:16]4[S:21][CH:20]([CH3:22])[N:17]43)=[CH:12][C:11]=2[Cl:29])[CH2:6][CH2:5]1)(=O)C.Cl.O.N>C(O)C>[Cl:29][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[N:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)[N:17]1[CH:20]([CH3:22])[S:21][C:16]1=[C:15]([C:23]([OH:25])=[O:24])[C:14]2=[O:28]
Reactant: CCOC(=O)c1c2n(c3cc(N4CCN(C(C)=O)CC4)c(Cl)cc3c1=O)C(C)S2
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(Cl)c(N4CCNCC4)cc3n21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 610 mg of ethyl 7-(4-acetyl-1-piperazinyl)-6-chloro-1-methyl-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate, 12 ml of 5% hydrochloric acid and 3 ml of ethanol was heated with stirring on an oil bath of 100°-110° C. for 2 hours. After cooling to about 50° C., this was neutralized with 5% ammonia water. Crystals separated out were collected by filtration, washed with water, dried and recrystallized from N,N-dimethylformamide to give pale yellow crystals, m.p. not lower than 300° C. (decompn).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36](Cl)[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]>>[C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[N:35]=4)=[CH:30][CH:29]=3)[CH:22]=2)[NH:17][CH:16]=1)#[N:14]
Reactant: NCCCCCN1CCOCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCCCN5CCOCC5)n4)cc3)cc12

Procedure:
Using 5-(morpholin-4-yl)-pentylamine (reference example 93b) and and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 538 (M+H)+.