Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[CH:19][CH:18]=2)[CH2:8][CH2:7][CH2:6]1)=[N+]=[N-]>C(O)C>[NH2:1][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[CH:19][CH:18]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CN=[N+]=[N-])c3ccccc32)cc1
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CN)c3ccccc32)cc1
Reaction time: 6 h
Yield: 47.2 %

Procedure:
5-Azidomethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) is suspended in ethanol (50 ml) and the mixture is subjected to catalytic hydrogenation at room temperature under 3 kg/cm2 for 6 hours by using 10% Pd--C (27 mg). The catalyst is removed by filtration with celite and the filtrate is distilled off and the resulting residue is recrystallized from ethanol to give 5-aminomethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.12 g) as colorless needles, m.p. 233°-235° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>O1CCOCC1>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: Nc1cccc(Cl)c1
Solvent: C1COCCO1
Product: O=Cc1cnn2c(NC3CC3)cc(Nc3cccc(Cl)c3)nc12
Temperature: 120 °C
Yield: 10.6 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (177 mg, 0.75 mmol) in 1,4-dioxane was added 3-chloroaniline (397 μl, 3.75 mmol). The mixture was heated in microwave at 120° C. for 60 minutes. Precipitate was filtered off, and the filtrate was prepared by TLC (1% methanol/dichloromethane) to yield 26 mg (11% yield) of 5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=328)
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@H:8]2[OH:17])[CH2:4][O:3]1.CC(OC(C)=O)=O.C(Cl)Cl.[BH4-].[Na+]>CS(C)=O.O.C(Cl)Cl.CO>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@@H:8]2[OH:17])[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@@H](O)[C@H]2O1
Temperature: 0 °C
Yield: 58 %

Procedure:
1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 260 g (1 mole) was stirred for 24 h in DMSO 2000 ml and Ac2O 500 ml (5 mole) at RT. By that time, TLC (DCM (dichloromethane)/MeOH 95:5) indicated complete reaction of the starting material. The solution was then cooled to 0° C. and sodium borohydride 16 g (0.42 mole) was added portion wise. By that time, TLC (DCM/MeOH 95:5) indicated complete formation of the target compound, approx. 1 h, water 2500 ml was added and the solution was extracted with DCM 3×1000 mL. The combined organic phases was washed with water 2×1000 ml and brine and dried with magnesium sulfate and evaporated to an oil. To the oil was added tert-butyl methylether (300 mL) and extracted with water 2×750 mL. The combined water phases were extracted with dichloroethane 2×400 mL. The combined organic phases was dried with magnesium sulfate and evaporated to an oil. Crystallisations twice from cyclohexane, 500 ml and 300 ml respectively, gave 151 g (58%) of pure 1,2:5,6-di-O-isopropylidene-α-D-allofuranose.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1.C(Cl)Cl.[CH:18]([C@@:21]1([C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:25][C@H:24]([NH2:26])[CH:23]=[CH:22]1)([CH3:20])[CH3:19].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]([C@@:21]1([C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=[CH:37][N:36]=3)[CH2:33][CH2:34]2)=[O:28])[CH2:25][C@H:24]([NH:26][CH:8]2[CH2:7][CH2:6][N:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH:3]2[O:2][CH3:1])[CH:23]=[CH:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)C=C[C@@H](N)C1
Reactant: CCOC(=O)N1CCC(=O)C(OC)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(N[C@@H]2C=C[C@@](C(=O)N3CCN(c4cc(C(F)(F)F)ccn4)CC3)(C(C)C)C2)C(OC)C1
Reaction time: 8 h

Procedure:
The title compound was prepared by taking ethyl 3-methoxy-4-oxopiperidine-1-carboxylate (148 mg, 0.000737 mol) in Methylene chloride (3 mL, 0.04 mol) and adding (1S,4S)-4-isopropyl-4-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopent-2-en-1-amine (0.31 g, 0.00081 mol;), Triethylamine (0.8 mL, 0.006 mol;) and Sodium triacetoxyborohydride (0.312 g, 0.00147 mol). The reaction was stirred overnight. The reaction was quenched with (20 mL) NaOH and extracted with (3×10 mL) CH2Cl2. The organic layers were collected, dried over MgSO4 and concentrated in vacuo. The crude was taken on to the next step as-is (410 mg, 98%). MS calculated for C28H40F3N5O4: (M+H) 568; found 568.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](I)[CH:3]=1.[F:12][CH:13]([F:25])[C@H:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[OH:15].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:12][CH:13]([F:25])[C@H:14]([C:16]1[CH:17]=[CH:18][C:19]([C:4]2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:20][CH:21]=1)[OH:15]
Reactant: OB(O)c1ccc([C@H](O)C(F)F)cc1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc(-c2ccc([C@H](O)C(F)F)cc2)c1
Temperature: 85 °C

Procedure:
A mixture of PdCl2 (dppf)—dichloromethane adduct (40.8 mg, 0.050 mmol), 1-fluoro-3-iodo-5-nitrobenzene (267 mg, 1.00 mmol), {4-[(1S)-2,2-difluoro-1-hydroxyethyl]phenyl}boronic acid (222 mg, 1.10 mmol), sodium carbonate (1.50 mL, 3.00 mmol) and DMF (5 mL) was degassed by sparging with nitrogen and then heated to 85° C. for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with water, and aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to give (1S)-2,2-difluoro-1-(3′-fluoro-5′-nitrobiphenyl-4-yl)ethanol. MS ESI calc'd. for C14H11F3NO3[M+H]+ 298, found 298.
Reaction SMILES: [OH-].[Na+].C([O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH:20]=[C:21]([F:23])[F:22])[CH2:15][CH2:14]1)=[O:12])C1C=CC=CC=1.Cl.O[Li].O>CO.C1COCC1.O>[F:22][C:21]([F:23])=[CH:20][CH2:19][CH:16]1[CH2:17][CH2:18][CH:13]([C:11]([OH:12])=[O:10])[CH2:14][CH2:15]1
Reactant: O=C(OCc1ccccc1)C1CCC(CC=C(F)F)CC1
Agent: Cl
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCC(CC=C(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85028.6 %

Procedure:
A 1 N aqueous NaOH solution (0.084 ml, 0.084 mmol) was added to a solution of 4-(3,3-difluoro-allyl)-cyclohexanecarboxylic acid benzyl ester (trans:cis=4:1) (14.1 mg, 0.0478 mmol) in methanol (1.0 mL). The mixture was stirred at room temperature for 1.5 hours, and then adjusted to pH 6 with a 1 N aqueous HCl solution and concentrated under reduced pressure. The resulting residue was adjusted to pH 3 with dilute hydrochloric acid and extracted with dichloromethane, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was dissolved in THF (0.2 ml)-H2O (0.2 ml), and LiOH.H2O (7.7 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for three hours, and then adjusted to pH 3 with a 1 N aqueous HCl solution and extracted with dichloromethane. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane-ethyl acetate) to give 4-(3,3-difluoro-allyl)-cyclohexanecarboxylic acid (8.3 g, 86%).
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH2:15][O:16][CH3:17])([CH3:14])[CH2:12][NH:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][C:13]1([CH2:15][O:16][CH3:17])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC1(C)CNC(=O)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC1(C)CNCCN1Cc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 130 mg (0.524 mmol) 4-benzyl-5-methoxymethyl-5-methyl-piperazin-2-one in 5 mL THF was cooled with ice and 780 μL (0.780 mmol) 1M lithium aluminum hydride solution in THF was added dropwise under argon atmosphere. The resultant mixture was stirred 3 h under ice-bath cooling and 2.5 h at Rt. Then the mixture was quenched with saturated aqueous Na2SO4 solution, stirred for 1 h, filtered through Celite, washed with EtOAc and concentrated in vacuo.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:25][NH:26][O:27][CH3:28].Cl>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:7](=[O:9])[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCC1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
A solution of 2.0 mL (15.9 mmol) of cyclopentylacetic acid in 80 mL of CH2Cl2 at 0° C. was treated with 3.7 mL (33.6 mmol) of N-methyl-morpholine and 2.2 mL (16.9 mmol) of isobutyl chloroformate. After stirring for 20 min, 1.61 g (16.5 mmol) of N,O-dimethyl-hydroxylamine.HCl was added. The reaction was warmed to rt and stirred for 3 h. The reaction was partitioned between 200 mL of EtOAc and 200 mL 2.0 N HCl. After separating the phases, the organic layer was washed with 200 mL of 1.0 N NaHCO3, dried over Na2SO4 and concentrated. Flash chromatography on silica gel using 4:1 v/v hexanes/EtOAc afforded 2.28 g (83%) of the title compound as a colorless oil. RF: 0.27 (4:1 v/v hexanes/EtOAc). 1H NMR (300 MHz): δ 1.12-1.23 (m, 2H), 1.51-1.89 (m, 6H), 2.28 (m, 1H), 2.44 (d, J=7.5, 2H), 3.18 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].[CH3:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH2:34][CH:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[OH:36])=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[N:26]=2)[CH:23]=1.O>ClCCl>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH2:34][C:35]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[O:36])=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[N:26]=2)[CH:23]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(O)c2cccs2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2cccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a magnetically stirred solution of pyridinium chlorochromate (PCC) (0.90 g, 4.18 mmol), sodium acetate (0.38 g, 4.63 mmol), and 4 Å molecular sieves (0.38 g) in dichloromethane (DCM) (100 mL) at 0° C. under Ar atmosphere was added 2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-1-thiophen-2-yl-ethanol 6c (0.70 g mL, 2.01 mmol). The reaction mixture was stirred for 0.5 h at 0° C., then warmed to room temperature and stirred for 3 h. Water (100 mL) was added, and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic layers were washed with water (2×100 mL), dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel (80:20 dichloromethane/EtOAc, as eluent), which gave the title compound (0.26 g, 36%) as an off white solid. 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 2.39 (s, 3H), 4.61 (s, 2H), 7.07 (m, 2H), 7.25 (d, J=7.7 Hz, 2H), 7.55 (m, 3H), 7.63 (d, J=3.7 Hz, 1H), 7.65 (d, J=5.1 Hz, 1H), 7.77 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 18.6, 21.5, 35.8, 112.9, 117.0, 121.7, 122.2, 127.8, 128.6, 128.6, 129.6, 131.8, 133.2, 134.9, 137.8, 142.8, 144.5, 144.9, 188.2. Mass spectrum m/e 347 (M+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[F:17][C:18]([F:28])([C:24]([F:27])([F:26])[F:25])[CH2:19][CH2:20][C:21](Cl)=[O:22]>C1COCC1>[F:17][C:18]([F:28])([C:24]([F:25])([F:26])[F:27])[CH2:19][CH2:20][C:21](=[O:22])[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(C)=O
Reactant: O=C(Cl)CCC(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a stirred solution of ethyl acetate enolate, prepared from ethyl acetate (4.4 g, 50 mmol) and sodium hexamethyldisilazide (50 mmol) in THF at −70° C., was added neat 4,4,5,5,5-pentafluoropentanoyl chloride (2.1 g, 10 mmol) at −70° C. Cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The mixture was diluted with diethyl ether and quenched with water. The organic layer was separated, washed with aqueous 2 N hydrochloric acid, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified by flash chromatography on-silica gel (hexane ethyl acetate 5:1) to give ethyl 6,6,7,7,7-pentafluoro-3-oxoheptanoate as colorless oil yield: 1.46 g (56%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.S(=O)(=O)(O)O.N>ClC1C=CC=CC=1.CCO>[CH2:1]([N:8]1[CH2:9][CH:10]2[O:16][CH:14]([CH2:13][N:12]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH2:11]2)[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N1CC(O)CN(Cc2ccccc2)CC(O)C1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: Clc1ccccc1
Product: O=S(=O)(c1ccccc1)N1CC2CN(Cc3ccccc3)CC(C1)O2
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
The chlorobenzene solution from step (ii) above was treated at 50° C. with water (6 mL) and then concentrated sulfuric acid (60 mL) was added over 10 min. whilst maintaining the temperature at between 50 and 60° C. The mixture was then heated to 110° C. for 1 hour. The mixture was allowed to cool to 50° C. and EtOH (60 mL) was added in one portion, causing the internal temperature to rise to 67° C. The mixture was basified by the addition of aqueous ammonia (17.5%, 300 mL) with external cooling to keep the internal temperature between 60 and 70° C. Chlorobenzene (600 mL) was added and the mixture was stirred rapidly for 10 minutes. The mixture was allowed to settle and the layers were separated. The upper (chlorobenzene) layer was subjected to reduced pressure (50 mbar) distillation to remove 380 mL of solvent. The mixture was allowed to cool to 50° C. and 480 mL of ethanol was added. The mixture was cooled to 7° C. and the resulting solid was filtered and washed with ethanol (2×50 mL) before drying to constant weight under reduced pressure at 40° C. The product was obtained as an off white solid, 10.25 g (9.0% yield).
Reaction SMILES: [Cl:1][CH:2]([Cl:18])[C:3]1[O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[C:5]=2[N:4]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[NH:24][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[OH-].[Na+].Cl>O.O1CCCC1>[Cl:1][CH:2]([Cl:18])[C:3]([NH:4][C:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](=[O:9])[CH:26]([C:25]([NH:24][C:20]1[S:19][CH:23]=[CH:22][N:21]=1)=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:8]
Reactant: CCOC(=O)CC(=O)Nc1nccs1
Reactant: O=c1oc(C(Cl)Cl)nc2c(C(F)(F)F)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(=O)Nc1nccs1)C(=O)c1cccc(C(F)(F)F)c1NC(=O)C(Cl)Cl
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
At 20° C., 150 g of 2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-4-one, 120 g of ethyl 3-(2-thiazolylamino)-3-oxo-propanoate and 1.5 liters of tetrahydrofuran were mixed together and stirred for 30 minutes and then, while maintaining the temperature at 20° C., 40 g of sodium hydroxide in flakes were added thereto. After stirring the mixture at 20° C. for two hours, it was poured into a mixture of 4.5 liters of water and 150 ml of concentrated hydrochloric acid and the mixture was stirred at 0° to +5° C. for 30 minutes. The crystals formed were separated, rinsed with water and dried to obtain 255 g of ethyl 2-[(2,2-dichloro-1-oxoethyl)-amino]-β-oxo-α-[(2-thiazolylamino)-carbonyl]-3-(trifluoromethyl)-benzene-propanoate melting at 90° C.
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[Na+].[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:22][C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:15]([NH2:30])[N:14]=1)[CH2:9][CH2:10][CH3:11]>C(O)(=O)C>[Br:1][C:18]1[N:19]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[C:20]2[C:16]([N:17]=1)=[C:15]([NH2:30])[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=2
Reactant: CCCCOc1nc(N)c2ncn(Cc3ccc(Cl)nc3)c2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCOc1nc(N)c2nc(Br)n(Cc3ccc(Cl)nc3)c2n1
Yield: 62.1 %

Procedure:
Potassium carbonate (2.85 g, 20.6 mmol) and 2-chloro-5-chloromethylpyridine (3.33 g, 20.6 mmol) were added to the DMF solution (125 ml) of 2-butoxyadenine (2.60 g, 12.5 mmol) obtained in Reference Example 1. The resultant was stirred while heating at 80° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, water (100 ml) was added thereto, and the resultant was neutralized with 1N hydrochloric acid. The precipitated solid was collected by filtration. The resulting solid was dissolved in methylene chloride (100 ml), hexane (150 ml) was added under ice cooling, and the precipitated crystal was collected by filtration. Thus, 2-butoxy-9-(6-chloro-3-pyridylmethyl)adenine was obtained (yield: 3.12 g). Bromine (1.92 ml, 37.5 mmol) was added to an acetic acid suspension (186 ml) comprising sodium acetate (3.05 g, 37.2 mmol) and 2-butoxy-9-(6-chloro-3-pyridylmethyl)adenine (3.1 g, 9.31 mmol) at room temperature, and the resultant was allowed to react for 4 hours. The reaction solution was removed by distillation under reduced pressure, water (200 ml) was added to the residue, and the resultant was neutralized with 5N sodium hydroxide under ice cooling. The precipitated crystal was collected by filtration, and crude crystal was recrystalized with the aid of methanol. The resultant was dried under reduced pressure at 40° C. for 15 hours. Thus, 2.38 g of the title compound was obtained as a white powdery crystal (yield: 62%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][NH:32][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NC)ccc21
Yield: 48.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (75.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), methylamine (2.0 M solution in THF, 1.0 mL), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421.
Reaction SMILES: [N:1]([C:4]1[C:14]([F:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:16])[C:5]=1[CH3:17])=[N+]=[N-].C(OCC)C.O.[OH-].[Na+]>CO>[NH2:1][C:4]1[C:14]([F:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:16])[C:5]=1[CH3:17]
Reactant: CCOC(=O)c1cc(F)c(N=[N+]=[N-])c(C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cc(F)c(N)c(C)c1F
Reaction time: 0.5 h

Procedure:
In 60 ml of methanol was suspended 14.2 g of stannous chloride, and to this suspension was dropwise added a solution of 10.0 g of ethyl 4-azido-2,5-difluoro-3-methylbenzoate in 20 ml of methanol at room temperature over one hour, after which the resulting mixture was stirred at the same temperature for 30 minutes. The methanol was removed by distillation under reduced pressure, and to the residue obtained were added 300 ml of diethyl ether and 100 ml of water, after which the pH was adjusted to 12.5 with 2N aqueous sodium hydroxide solution. The organic layer formed was separated, washed with water and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 8.91 g of yellow, oily ethyl 4-amino-2,5-difluoro-3-methylbenzoate.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH:12]1[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:15][CH:14]([CH:22]([N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:13]1)([OH:11])=[O:10].C(N(CC)CC)C.O>CN(C)C=O>[CH2:1]([O:11][C:9]([CH:12]1[C:16]2([CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:15][CH:14]([CH:22]([N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[NH:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)O)C2(CCOCC2)S1)N1C(=O)c2ccccc2C1=O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCOCC2)S1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
3.3 g (0.019 mole) of benzyl bromide are added all at once to a solution of 4.62 g (0.01 mole) of the alpha isomer of tert-butyl 4-carboxy-alphaphthalimido-8-oxa-1-thia-3-azaspiro[4.5]decane-2-acetate in 50 ml of dimethylformamide, and then, over a period of 20 minutes, 1.32 g (0.013 mole) of triethylamine in 5 ml of dimethylformamide are added. The reaction mixture is gently stirred overnight at ambient temperature. The clear solution thus obtained is poured into a mixture of ice and water and then extracted with benzene. After washing the organic phase with a 5% aqueous solution of sodium hydrogen carbonate and then with water, it is evaporated to dryness. The residue obtained is recrystallized from diethyl ether to give 4.7 g (0.00085 mole) of tert-butyl 4-benzyloxycarbonyl-alpha-phthalimido-8-oxa-1-thia-3-azaspiro[4.5]decane-2-acetate (yield: 85.2% of theory); M.P. 168-169° C. Another synthesis with quantities 10 times larger gave a yield of 93.6% of theory.