Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([N+:18]([O-])=O)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[NH2:15][C:14]1[CH:16]=[CH:17][C:11]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:12][C:13]=1[NH2:18]
Reactant: Nc1ccc(OCCOc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCOc2ccccc2)cc1N

Procedure:
A mixture of 1.8 g. of 4-(2-phenoxyethoxy)-2-nitroaniline and 0.3 g. of 5% of palladium-on-charcoal catalyst in 200 ml. of methanol is hydrogenated under ambient conditions. After the uptake of hydrogen is complete, the mixture is filtered and 1,2-diamino-4-(2phenoxyethoxy)benzene is isolated from the filtrate by evaporation.
Reaction SMILES: [C:1]([CH:3]1[CH:8]2[CH:4]1[CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7]2)#[N:2].[CH:16]1([CH2:19]Br)[CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[C:1]([C:3]1([CH2:19][CH:16]2[CH2:18][CH2:17]2)[CH:4]2[CH:8]1[CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]2)#[N:2]
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CC2C(C#N)C2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2(C#N)CC1CC1
Reaction time: 18 h

Procedure:
To a solution of 3 (1.68 g, 8.08 mmol) and cyclopropylmethyl bromide (1.31 g, 9.70 mmol) in toluene (25 mL) at 0° C. was added a solution of KHMDS (0.5 M in toluene, 17.8 mL, 8.89 mmol) and stirred for 18 h. The reaction was partially concentrated under vacuum and purified by column chromatography (silica gel) using 0 to 65% EtOAc in hexanes to 4a (minor diastereomer, 290 mg, 14%) and 4b (major diastereomer, 685 mg, 32%) as clear oils; 1H-nmr (400 MHz, CDCl3) δ (minor diastereomer) 3.60 (td, J=12.0, 4.0 Hz, 1H), 3.49 (d, J=12.0 Hz, 1H), 3.41 (d, J=12.0 Hz, 1H), 2.28-2.24 (m, 1H), 1.43 (s, 9H), 1.43-1.28 (m, 2H), 0.94-0.86 (m, 1H), 0.66-0.59 (m, 1H), 0.21 (q, J=6.0 Hz, 1H); LC-MS (214 nM) 3.18 min (>98%), m/z 207.1 [M-tBu]. 1H-nmr (400 MHz, CDCl3) δ (major diastereomer) 3.81 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.0 Hz, 1H), 3.57 (td, J=12.0, 4.0 Hz, 1H), 1.83-1.78 (m, 2H), 1.43 (s, 9H), 1.46-1.40 (m, 2H), 0.92-0.84 (m, 1H), 0.61-0.52 (m, 2H), 0.22-0.16 (m, 2H); LC-MS (214 nM) 3.11 min (>98%), m/z 162.9 [M-Boc], 285.2 [M+Na].
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]([OH:38])=O)[C:9]([CH:11]=[P:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[NH2:39][C:40]1[S:41][C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]([NH:39][C:40]1[S:41][C:42]2[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=2[N:44]=1)=[O:38])[C:9]([CH:11]=[P:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: COc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1OCC(=O)O
Reactant: Nc1nc2ccccc2s1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To dichloromethane (50 ml) are added (3-methoxy-4-carboxymethoxybenzoyl)methylenetriphenylphosphorane (5 g), 2-aminobenzothiazole (1.9 g), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.93 g) and triethylamine (3.3 ml), and the mixture is stirred overnight. After the reaction is complete, the mixture is washed with an aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate to remove the solvent, and further recrystallized from toluene to give [3-methoxy-4-(2-benzothiazolylaminocarbonylmethoxy)benzoyl]methylenetriphenylphosphorane (5.17 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]2[C@:10]3([CH3:21])[C@@H:15]([CH2:16][CH2:17][C:6]=2[CH:5]=1)[C@@:14]([CH2:19][NH2:20])([CH3:18])[CH2:13][CH2:12][CH2:11]3)[CH3:3]>CCOCC>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][C:7]2[C@:10]3([CH3:21])[C@@H:15]([CH2:16][CH2:17][C:6]=2[CH:5]=1)[C@:14]([CH2:19][NH2:20])([CH3:18])[CH2:13][CH2:12][CH2:11]3)[CH3:1]
Reactant: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(CN)CCC[C@]21C
Solvent: CCOCC
Product: CC(C)c1ccc2c(c1)CC[C@H]1[C@@](C)(CN)CCC[C@]21C

Procedure:
dl-5-Benzyloxymethyl-cyclopent-2-enyl-4-hydroxy-1-acetic acid (88.5 g.) in ether (1500 ml.) was slowly treated with dehydroabietylamine (92.4 g.) in ether (500 ml.). The precipitated salt (140 g., [α]DMeOH = + 19°) was collected by filtration and was crystallised from benzene (20 ml./g.) to afford a salt (54 g.), [α]D = + 13° (methanol). Two subsequent crystallisations from benzene (50 ml./g; 2 hours at room temperature) gave the dehydroabiethylamine salt of 1-5α-benzyloxymethyl-4β-hydroxycyclopent-2-enyl-1β-acetic acid (42 g.), [α]DMeoH = + 10°. A suspension of this salt in ether-water (2:1) was treated with 1.2 equivalents of 5% potassium hydroxide and extracted with ether. The aqueous layer was then treated with 8N sulphuric acid to pH 1.5, saturated with ammonium sulphate and extracted with chloroform to yield the pure 1- 5α-benzyloxymethyl-4β-hydroxy-cyclopent-2-enyl-1β-acetic acid, which showed [α]D = -26.5°; [α]365° = - 78° (CHCl3) and [α]D = -5.4°. [α]365° = -13° (MeOH). The mother liquors from the first benzene crystallization were diluted with ether to obtain a benzene-ether ratio of 5:4 and stored for 3 hours at 5°. The precipitated salt (48 g., [α]DMeOH = + 27°) was collected by filtration and recrystallised from benzene-ether (1 g. salt, benzene 20 ml., ether 40 ml.) to yield 44 g. of the dehydroabietylamine salt of d-5β-benzyloxymethyl-4α-hydroxycyclopent-2-enyl-1α-acetic acid, [α]DMeOH = + 28.8°. In a similar way, the 5α-p-methoxybenzyloxymethyl-4β-hydroxy-cyclopent-2-enyl-1β-acetic acid was obtained from the dl-acid.
Reaction SMILES: Br[C:2]1[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1.[BH4-].[Na+]>CO.CS(C)=O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:3]2[C:4]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=3[S:6](=[O:8])(=[O:7])[CH:2]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(Br)=C2Oc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc2c(c1)S(=O)(=O)C=C2Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 2-bromo-3-(4-bromophenoxy)-6-methoxy-benzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol) in MeOH (10 mL) and DMSO (30 mL) was added NaBH4 (0.789 g, 20.85 mmol). The mixture was stirred at room temperature for 3 h after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (2.47 g, 6.73 mmol, 97% yield) as an off white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm=3.85 (s, 3 H), 5.38 (s, 1 H), 7.02-7.08 (m, 3 H), 7.22 (d, J=2.53 Hz, 1 H), 7.47-7.60 (m, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][CH:9]1[CH2:18][O:19][S:21]([CH3:20])(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Hydroxymethyl)-4-(methanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.715 g) was dissolved in pyridine (20 ml), and methanesulfonylchloride (0.6 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Br:17]C(Cl)(Cl)C(Cl)(Cl)Br>O1CCCC1>[Br:17][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccc(Br)n1
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of N-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol) in dry tetrahydrofuran (500 mL) at −78° C. was added dropwise a solution of n-butyllithium (2.5 M in hexane, 105.5 mL, 0.264 mol) while maintaining the temperature below −60° C. A thick solid formed during the addition. Upon completion of the addition the reaction mixture was maintained for an additional 15 minutes, after which time a solution of 1,2-dibromo-tetrachloroethane (90 g, 0.276 mol) in tetrahydrofuran (150 mL) was added dropwise while maintaining the temperature below −70° C. The reaction mixture turned a clear orange; stirring was continued for an additional 15 minutes. The −78° C. bath was removed and the reaction was quenched with water (600 mL). The reaction mixture was extracted with dichloromethane (4×), and the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using dichloromethane/hexane (50:50) as eluent to afford the title product as a clear colorless oil (57.04 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH2:11][C:12](=[CH2:17])[CH2:13][C:14](=[CH2:16])[CH:15]=1)[CH3:2].C1(C)C(S(O[CH2:31][CH:32]2[CH2:36][CH:35]=[CH:34][CH2:33]2)(=O)=O)=CC=CC=1>>[CH:32]1([CH2:31][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:36][CH:35]=[CH:34][CH2:33]1
Reactant: C=C1C=C(C(=O)c2[nH]c(=O)[nH]c(=O)c2CC)CC(=C)C1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CC=CC2)c(=O)[nH]c1=O
Yield: 59.6 %

Procedure:
5-Ethyl-6-(3,5-dimethlylbenzoyl)-2,4-pyrimidinedione and (cyclopent-3-en-1-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound (84 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:18][C:6]2[C:7]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1.[Cl:19][C:20]1[C:21]([N:26]2[CH:30]=[C:29]([CH:31]=O)[C:28]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1.CN1CCOCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:2][C:3]1[S:18][C:6]2[C:7]3([CH2:13][CH2:14][N:15]([CH2:31][C:29]4[C:28]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:27][N:26]([C:21]5[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][N:22]=5)[CH:30]=4)[CH2:16][CH2:17]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Reactant: CCOC(=O)c1nn(-c2ncccc2Cl)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCOC(=O)c1nn(-c2ncccc2Cl)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]hydrochloride (0.35 g, 1.1 mmol) and ethyl 1-(3-chloropyridin-2-yl)-4-formyl-pyrazole-3-carboxylate (0.3 g, 1.0 mmol) in 1,2-dichloroethane (20 mL) is added N-methyl morpholine (0.33 g, 3.2 mmol) and molecular sieves (0.10 g). The reaction mixture is stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.58 g, 2.7 mmol) is added and stirred at room temperature for 16 h. After completion, the reaction mixture is filtered through celite and partitioned between dichloromethane (15 mL) and water (15 mL). The aqueous phase is extracted with dichloromethane (3×30 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography over silica gel eluting with dichloromethane/methanol (98:2) to yield 0.4 g (67%) of ethyl 4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-3-carboxylate. MS (m/z): 543 (M+1).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1CNC(=O)N1
Reactant: Oc1ccccc1
Agent: BrBr
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
4.0 g (40 mmol) of hydantoin, 10 ml of dioxane, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 100° C. for 30 minutes. The reaction mixture was then cooled to a temperature of 0° C. To the reaction mixture was then added 5.7 g (60 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 0° C. for 12 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 5.53 g (yield: 72%) of 5-(p-hydroxy-phenyl)hydantoin. The crystal thus obtained exhibited a melting point of 263° to 265° C. The infrared spectrum, NMR spectrum and Rf value of silica gel thin layer chromatography of the crystal showed a complete conformance to that of a specimen synthesized by the method as disclosed in JP-B-55-22474.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([Br:40])=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([Br:40])=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CN1Cc2c(Br)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Yield: 37.9 %

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (50.0 mg, 0.118 mmol) and 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (34.14 mg, 0.1416 mmol). The reaction mixture was concentrated under reduced pressure to yield a yellow oil which was purified on an ISCO Combiflash system using (DCM/MeOH 100:0→95:5) as eluent to isolate 28.1 mg of the title compound (38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.07 Hz, 6H), 3.09 (s, 3H), 3.18-3.27 (m, 2H), 3.92-4.03 (m, 4H), 4.43 (s, 2H), 7.23-7.33 (m, 8H), 7.55 (br. s., 5H), 7.63 (d, J=8.84 Hz, 4H), 8.50 (s, 4H), 9.95 (s, 4H), 10.54 (br. s., 3H). MS (ES+): m/z 627.95/629.93 (91/100) [MH+]. HPLC: tR=3.72 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=3)=[N:20][N:21]=2)=[O:16])[CH2:12]1)[CH:5]=O.Cl.[CH3:31][C:32]1([OH:36])[CH2:35][NH:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:34]2[CH2:35][C:32]([OH:36])([CH3:31])[CH2:33]2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:14][N:13]([C:15]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:20][N:21]=2)=[O:16])[CH2:12]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4Cl)C3)o2)cc1
Reactant: CC1(O)CNC1
Agent: Cl
Product: CC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)c(Cl)c2)C1
Yield: 31 %

Procedure:
Using a similar protocol as described in Example 70 employing 79A and 3-methylazetidin-3-ol hydrochloride as starting materials afforded 29 mg (31%) of 79 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.51 (s, 3H), 3.04 (d, 2H), 3.28 (d, 2H), 3.57 (s, 2H), 3.89 (s, 3H), 4.41 (m, 1H), 4.65 (m, 1H), 4.80 (m, 1H), 5.10 (m, 2H), 5.30 (s, 1H), 7.01 (d, 2H), 7.13 (s, 1H), 7.36 (s, 1H), 8.09 (d, 2H), MS (APCI+) m/z 485 [M+H]+, LC purity: 88%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH2:28][C:29]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]>ClCCl>[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH2:28][C:29]([N:38]2[CH2:39][CH2:40][N:41]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:42][CH2:43]2)([C:30]([O:32][CH3:33])=[O:31])[C:34]([O:36][CH3:37])=[O:35])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
0.6 ml (4 mmol) of triethylamine and then 0.3 ml (4 mmol) of methanesulfonyl chloride are added to a solution of 1.6 g (4 mmol) of dimethyl 2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate diluted in 30 ml of dichloromethane. The reaction medium is then stirred at ambient temperature for 3 h and then evaporated to dryness. The crude residue is purified by chromatography on silica gel, elution being carried out with a 99/1 dichloromethane/methanol mixture. 1.1 g (58%) of dimethyl 2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiperazin-1-yl)malonate are obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]1[C:23]2[CH:24]=[CH:25][NH:26][C:27](=[O:28])[C:22]=2[C:21]2[C:16](=[CH:17][CH:18]=[N:19][CH:20]=2)[N:15]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1.S([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:13][C:14]1[C:23]2[CH:24]=[CH:25][NH:26][C:27](=[O:28])[C:22]=2[C:21]2[C:16](=[CH:17][CH:18]=[N+:19]([O-:37])[CH:20]=2)[N:15]=1
Reactant: CC(C)(O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)c1cc(Cl)c(Nc2nc3cc[n+]([O-])cc3c3c(=O)[nH]ccc23)c(Cl)c1
Reaction time: 2 h

Procedure:
To a solution of 6-{[2,6-dichloro-4-(1-hydroxy-1-methylethyl)phenyl]amino}pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Example 146, Step 1) (30 mg, 0.07 mmol) in CH2Cl2 (3 mL) at 0° C. was added m-CPBA (40.5 mg, 0.18 mmol, 77% max) and stirred for 2 hr. 10% Sodium sulfite and saturated NaHCO3 were added and stirred for 30 min. The solution was extracted with 3:1 CHCl3/iPrOH, dried with MgSO4, filtered, and concentrated under reduced pressure. Column chromatography (100% CH2Cl2 to 30% MeOH, 70% CH2Cl2) provided the desired product.
Reaction SMILES: [NH:1]([CH2:3][CH:4]([OH:8])[CH:5]([CH3:7])[CH3:6])[NH2:2].[Cl:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([CH2:16][CH2:17][C:18](O)=[O:19])=O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>O>[OH:8][CH:4]([CH:5]([CH3:7])[CH3:6])[CH2:3][N:1]1[C:18](=[O:19])[CH2:17][CH2:16][C:14]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:22][CH:21]=2)=[N:2]1
Reactant: CC(C)C(O)CNN
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C(O)CN1N=C(c2ccc(Cl)cc2)CCC1=O
Yield: 92.1 %

Procedure:
A mixture of 9.5 grams (0.085 mol) of 1-hydrazino-3-methyl-2-butanol, 14.4 grams (0.070 mol) of 3-(p-chlorobenzoyl)-propanoic acid and 100 milliliters of toluene are stirred in a flask equipped with a condenser and Dean-Stark water collecting apparatus at reflux for about 2.0 hours during which 2.8 milliliters of water is collected in the Dean-Stark tube. The toluene solution is washed with 50 milliliters of 2 N sodium hydroxide solution, 25 ml. of 2 N hydrochloric acid and then water. The toluene layer is then dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The solid obtained is crystallized from methylene chloride-petroleum ether to yield 19.0 grams of 2-(2-hydroxy-3-methylbutyl)-6-(p-chlorophenyl)4,5-dihydropyridazine-3(2H)-one, (m.p. 90°-92° C.)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:24]=[C:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:15]
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)CCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2c1c(=O)n(CCCCCC(C)=O)c(=O)n2C
Yield: 162.4 %

Procedure:
2.1 g of 3-methyl-7-propylxanthine, 0.7 g of 1-chloro-heptan-6-one and 1.4 g of potassium carbonate are heated at 120° C. in 15 ml of dimethylformamide for 7.5 hours, while stirring. After the mixture has been concentrated under reduced pressure, the residue is poured into 100 ml of H2O, the mixture is extracted three times with 100 ml of CHCl3 each time, and the combined chloroform extracts are treated with 1 N sodium hydroxide solution and water in succession and dried over sodium sulfate. The concentration residue is chromatographed in a column using silica gel 60 and chloroform/ethanol (9:1) as the mobile phase. After recrystallization from petroleum ether/diisopropyl ether (3:1), 2.45 g (=76.6% yield) of 1-(6-oxoheptyl)-3-methyl-7-propylxanthine of melting point 69-70° C. are obtained.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[C:6]([O:8]CC)=[O:7].[Li+].[OH-]>CO.O>[F:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)N(C)CCF
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCF)C(=O)C(=O)O
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of ethyl 2-((2-fluoroethyl)(methyl)amino)-2-oxoacetate (1.2 g, 7.36 mmol) in methanol/water (30 mL, 1:1) was added LiOH (0.352 g, 14.71 mmol). The solution was stirred for 2 h. The methanol was removed by concentration and concentrated HCl (2 mL) was added. The solvent was removed and the residue dissolved in CH2Cl2 and filtered. The filtrate was concentrated to give the title compound as an off-white crystalline powder (0.615 g, 56% yield). 1H NMR (400 MHz, CDCl3) δ: 4.47-4.89 (2 H, m) 3.67-4.39 (2 H, m) 3.07-3.60 (3 H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11]I.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:9][C:10]([F:14])([F:13])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(O)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(OCC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
To a solution of 3-hydroxytoluene (5.0 g, 46.2 mmol) in N,N-dimethylformamide (50 ml) were added 2,2,2-trifluoro-1-iodoethane (10.7 g, 50.9 mmol) and potassium carbonate (12.8 g, 92.5 mmol) and the mixture was stirred overnight at 80° C. The reaction solution was diluted with water (200 ml) and extracted with diethyl ether (300 ml×2). The extract was washed successively with water and saturated brine, dried-over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-(2,2,2-trifluoroethoxy)toluene (7.60 g, 86%) as a colorless oil.