Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:11][C:10]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)c(C2OCCO2)c1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(C2OCCO2)c1
Temperature: -60 °C
Yield: 55.1 %

Procedure:
A solution of 2-(2-benzyloxy-5-bromophenyl)-1,3-dioxolane (7.8 g, 23.2 mmol) in freshly distilled THF (160 ml) was cooled to -75° C. with stirring under an argon atmosphere. To this solution was added n-butyl lithium (25.6 ml, 1.6 M in hexane) keeping the temperature below -70° C. The reaction mixture was stirred at -70° C. for 1 hour. The reaction was allowed to warm to -60° C. and added to a cooled (-60° C.) solution of ethyl chloroformate (5.05 g, 46.5 mmol) in freshly distilled THF (70 ml). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl ether (100 ml), washed with ice/water (1×50 ml), saturated aqueous NaHCO3 (1×35 ml), brine (1×35 ml) dried over MgSO4 and evaporated. The product was purified by chromatography (eluant: ethyl ether/hexane) to give 2-(2-benzyloxy-5-ethoxycarbonylphenyl)-1,3-dioxolane as a colourless gum (4.2 g, 55%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][N:5]=[C:6]=[S:7].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][NH:5][C:6](=[S:7])[NH:11][NH2:12]
Reactant: NN
Reactant: COC(CN=C=S)OC
Solvent: CCO
Solvent: O
Product: COC(CNC(=S)NN)OC
Reaction time: 12 h
Yield: 70.4 %

Procedure:
2,2-Dimethoxyethyl isothiocyanate (37.7 g) is added in the course of 1 hour to a solution of hydrazine hydrate (14.35 g) in ethanol (40 cc), whilst stirring at a temperature of between 5 and 9° C. After 12 hours at 4° C., the mixture is concentrated to dryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). The yellow syrup obtained crystallises after seeding. The solid is dissolved in hot methanol (50 cc) and the solution is filtered and diluted with diethyl ether (200 cc). After about ten hours at 4° C., the mixture is filtered and 4-(2,2-dimethoxyethyl)-thiosemicarbazide (32.3 g) is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C(Cl)Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[OH:35])[CH2:30][CH2:29]2)=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([O:35][CH:34]([CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=4)=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)[C:36]2[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:40][CH:41]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)OC(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1
Temperature: 35 °C
Reaction time: 16 h

Procedure:
A 0.06 gram (0.0004 mole) sample of 4-chlorophenylisocyanate was weighed into a two-dram vial, followed in turn by 1.2 mL of methylene chloride, 0.18 gram (0.0004 mole) of {1-[(4-(2-pyridyloxy)phenyl)methyl](4-piperidyl)}[4-(trifluoromethyl)phenyl]methanol, and 0.06 mL of triethylamine. The vial was tightly capped and gently shaken at 35° C. for 16 hours using a vortex mixer. After this time, the methylene chloride was removed under a nitrogen stream to provide a residue. The residue was purified with column chromatography on silica gel using mixtures of acetone and methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.2 gram of Compound 227. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2.[CH:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([CH:17]([CH3:18])[CH2:19][CH3:20])=[CH:22][CH:23]=2)=[O:16])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:12])(=[O:13])[N:6]=2
Reactant: CCC(C)c1ccc(N)cc1
Reactant: CC1=CN2CCS(=O)(=O)N=C2C(C(=O)O)=C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)c1ccc(NC(=O)C2=CC(C)=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylic acid 2,2-dioxide (76 mg) in DMF (3 mL) were added 4-sec-butylaniline (0.069 mL), HOBt (67 mg), and EDCI HCl (84 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (10 ml), and the resulting precipitate was collected by filtration. The obtained solid was recrystallized from DMSO-ethanol to give the title compound (114 mg) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO.S(Cl)([Cl:20])(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([Cl:20])[C:7]=1[OH:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Yield: 60 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-4-hydroxyphenyl)acetate (20 g, 0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol) and the mixture was refluxed. Sulfuryl chloride (6.8 ml 0.846 mol) was slowly added under over a period of 10 min. The reaction mixture was refluxed for a further 5 h. Upon completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layer were washed with 10% NaHCO3 solution and water, dried over Na2SO4, filtered and evaporated under vacuum to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g). 1HNMR (CDCl3): 7.37 (s, 1H); 7.27 (s, 1H); 5.68 (bs, 1H); 4.16 (q, 2H); 3.48 (s, 2H); 1.29 (t, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].CN(C=O)C.Br[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1>C(OCC)(=O)C>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)=[O:19]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Yield: 55.2 %

Procedure:
To 4.19 g cesium carbonate and 1.37 g methyl 1-hydroxy-2-naphthoate in 25 ml abs. DMF was added 1.62 g 2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine and the mixture was reacted for 16 h at 50° C. The reaction was poured unto ice, the resulting precipitate was isolated by filtration, dissolved in ethyl acetate and washed with brine. The organic phase was dried over magnesium sulphate and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to yield 1.31 g of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:23]([OH:25])=O)[CH2:6][S:7][CH2:8][CH:9]=[C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:16])[CH3:11])(=[O:3])[CH3:2].[NH2:26][NH2:27]>ClCCl.C1COCC1>[NH:26]([C:23](=[O:25])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][S:7][CH2:8]/[CH:9]=[C:10](\[CH3:11])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:16])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[NH2:27]
Reactant: NN
Reactant: CC(=O)N[C@@H](CSCC=C(C)CCC=C(C)CCC=C(C)C)C(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)NN
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In 50 mL round bottom flask, N-acetyl-S-farnesyl-L-cysteine (368 mg, 1.0 mmole) was dissolved in dichloromethane (10 mL). N-Cyclohexylcarbodiimide,N′-methyl polystyrene HL (1.7 g, 3.3 mole, from NovabioChem) was added followed by sufficient dichloromethane to swell the resin and keep the reaction mobile and the mixture gently magnetically stirred in 30 minutes. 5 mL of hydrazine in THF (1M) was added to the reaction solution and the reaction mixture was stirred in 3 hours at room temperature. The used resin was removed by filtration and washed with dichloromethane. Evaporation of the filtrate provided crude reaction mixture. The desired product was purified by preparative HPLC (305 mg, 80% yield) to yield Compound I: 1H-NMR (500 MHz, CDCl3): δ 1.60 (s, 6H), 1.67 (s, 6H), 1.70 (S, 3H), 1.92-2.09 (m, 8H), 2.75 (dd, J=7.9, 13.9 Hz, 1H), 2.88 (dd, J=5.7, 13.6 Hz, 1H), 3.20 (d, J=7.9 Hz, 2H), 4.51 (dd, J=7.6, 13.6 Hz, 1H), 5.10 (m, 2H), 5.24 (t, J=7.6 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.0, 16.1, 16.2, 17.6, 17.7, 23.2, 23.4, 23.5, 25.7, 25.8, 26.2, 26.3, 26.5, 26.7, 30.0, 31.8, 31.9, 32.9, 33.2, 39.6, 39.7, 39.9, 51.3, 51.4, 119.6, 120.3, 123.6, 124.2, 131.4, 131.6, 135.5, 135.6, 135.8, 140.2, 140.3, 170.2, 171.1; ES-MS: mass calcd for Chemical Formula: C20H35N3O2S 381.2 (M+). Found (M+Na) m/z 404.3.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:28])[CH2:26][OH:27])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[CH2:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](F)=[CH:35][CH:34]=1)[CH3:30].C(OCC)(=O)C>CC(N(C)C)=O>[OH:27][CH2:26][C@H:25]([CH3:28])[O:24][C:22]1[CH:23]=[C:8]([CH:9]=[C:10]([C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])[CH:21]=1)[O:7][C:36]1[CH:37]=[CH:38][C:33]([C:32]([O:31][CH2:29][CH3:30])=[O:40])=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3cnc(C)cn3)c2)cc1
Temperature: 130 °C
Yield: 3.1 %

Procedure:
Caesium carbonate (8.45 g, 26 mmol) was added to a mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (4 g, 13 mmol) and ethyl-4-fluorobenzoate (2.33 g, 13 mmol) in dimethylacetamide (70 mL) and the stirred mixture heated at 130° C. for 72 hours. The mixture was allowed to reach RT and ethyl acetate (100 mL) added. The mixture was washed with water (5×40 mL), brine (40 mL), dried (MgSO4), filtered, and reduced in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50% ethyl acetate in isohexane, to give the desired compound (0.18 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[CH3:22][O:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:35][CH:34]=2)[CH2:30]1)=[O:15]
Reactant: COc1ccc(CC2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: COc1ccc(CC2CCN(C(=O)c3cnoc3-c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-methoxybenzyl)pyrrolidine oxalate (16.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.1 mg). Calcd for C22H21ClN2O3: 396.1241, found 396.1235.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][S:9]([N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[CH2:34][C:25]4([CH2:33][C:27]5([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH2:26]4)[O:24][C:21]3=[CH:22][N:23]=2)[CH2:14][CH2:13]1)(=[O:11])=[O:10].C(N(CC)CC)C>ClCCl>[CH:5]([O:4][C:2]([N:30]1[CH2:31][CH2:32][C:27]2([CH2:26][C:25]3([O:24][C:21]4=[CH:22][N:23]=[C:18]([C:15]5[CH2:16][CH2:17][N:12]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:13][CH:14]=5)[CH:19]=[C:20]4[CH2:34]3)[CH2:33]2)[CH2:28][CH2:29]1)=[O:3])([CH3:7])[CH3:6]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2
Reaction time: 3 h

Procedure:
Isopropyl chloroformate (1 mol/L in toluene; 0.15 mL) is added to a mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 60 mg), triethylamine (40 μL), and dichloromethane (5 mL) at room temperature. The solution is stirred for 3 h and then concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:4) to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CCO>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([OH:18])[CH2:13][CH2:14][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH2:16][CH2:17]2)=[CH:8][CH:7]=1
Reactant: C=CC#N
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CCO
Product: N#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
Acrylonitrile (2.33 mL, 35.4 mmol, 2.50 equiv) was added at 0° C. to a solution of 4-(4-chlorophenyl)-4-hydroxypiperidine (3.00 g, 14.2 mmol, 1.00 equiv, Aldrich) in EtOH (30 mL) and the resulting solution was stirred for 1.5 hours at room temperature. The solvent was removed to give 3.71 g (99%) of white solid, which was characterized spectroscopically and used without purification for the next reaction.
Reaction SMILES: C[Al](C)C.[O:5]([CH2:23][CH2:24][NH:25][CH3:26])[Si:6]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27]([C:29]1[C:34]2[N:35]=[C:36]([C:38](OCC)=[O:39])[O:37][C:33]=2[C:32]([F:43])=[C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:30]=1[CH3:50])#[N:28].Cl>ClCCl>[O:5]([CH2:23][CH2:24][N:25]([CH3:26])[C:38]([C:36]1[O:37][C:33]2[C:32]([F:43])=[C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]([CH3:50])=[C:29]([C:27]#[N:28])[C:34]=2[N:35]=1)=[O:39])[Si:6]([C:19]([CH3:20])([CH3:21])[CH3:22])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2c1C#N
Reaction time: 0.67 h
Yield: 66.6 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 1.05 ml, 1.54 mmol) was dropwise added at room temperature to a dichloromethane (3 ml) solution of [2-(tert-butyldiphenylsiloxy)ethyl]methylamine (I-123) (483 mg, 1.54 mmol), and stirred for 40 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (250 mg, 771 μmol) was dropwise added and stirred for 16 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with n-hexane/ethyl acetate (3:1, v/v) gave the entitled compound (304 mg, 67%) as an amorphous substance.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-])=O.Cl.[CH2:13]([O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([O:15][C:16](=[O:20])[CH2:17][N:18]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[NH2:1])[CH3:19])[CH3:14]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN(C)Cc1ccccc1N

Procedure:
A mixture of 8.6 g o-nitrobenzyl chloride, 7.6 g sarcosine ethyl ester hydrochloride and 13.8 g K2CO3 was refluxed in 300 ml acetone for 16 hours, whereafter the mixture was filtered and evaporated. The oily residue was partitioned between ether/1N HCl. The aqueous phase was separated and pH was adjusted to 10 with dil. NaOH, whereafter it was extracted with dichloromethane. The organic phase was dried over Na2SO4 and evaporated. This left an oil which was hydrogenated using a standard procedure by means of 5% PD/C to give N-(o-aminobenzyl)sarcosine ethyl ester as an oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([CH:32]([CH3:34])[CH3:33])[CH:26]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:31][C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][C:27]=1[CH:32]([CH3:34])[CH3:33]
Reactant: Cc1ccc(S)c(C(C)C)c1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(SC2=C(O)CC(CCc3ccccc3)(c3ccccc3)OC2=O)c(C(C)C)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 75°-76° C.). 1H NMR (DMSO-d6) δ1.15 (m, 6H), 2.16 (s, 3H), 2.19-2.36 (m, 3H), 2.62 (m, 1H), 3.21 (m, 1H), 3.44 (q, 2H), 5.82 (d, 1H), 6.40 (dd, 1H), 6.95 (d, 1H), 7.10-7.18 (m, 3H), 7.25 (m, 2H), 7.44 (m, 5H).
Reaction SMILES: [N:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]=S.Cl.Cl.[NH2:16][CH2:17][C@@:18]1([OH:25])[C@@H:23]2[CH2:24][N:20]([CH2:21][CH2:22]2)[CH2:19]1>>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([NH:1][C:2]2[O:25][C@@:18]3([C@@H:23]4[CH2:24][N:20]([CH2:21][CH2:22]4)[CH2:19]3)[CH2:17][N:16]=2)[N:5]=1
Reactant: S=C=Nc1cc2ccccc2cn1
Reactant: NC[C@]1(O)CN2CC[C@H]1C2
Agent: Cl
Product: c1ccc2cc(NC3=NC[C@@]4(CN5CC[C@H]4C5)O3)ncc2c1
Yield: 26 %

Procedure:
3-Isothiocyanatoisoquinoline and (3S*,4S*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride were reacted according to the method of EXAMPLE 6, STEP B to afford (3R*,4S*)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine (80 mg, 0.27 mmol, 26% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[F:22][N+]1C=C(C(F)(F)F)C=CC=1S([O-])(=O)=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:22])=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCCCC(CC(=O)OC)c1ccc(OC)cc1OC
Reactant: O=S(=O)([O-])c1ccc(C(F)(F)F)c[n+]1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCCC(CC(=O)OC)c1cc(F)c(OC)cc1OC
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 18 %

Procedure:
A solution of 943 mg (3.20 mmol) of methyl 3-(2,4-dimethoxyphenyl)octanoate [prepared as described in Preparation 32(i)] in 5 ml of 1,2-dichloroethane was added to a suspension of 864 mg (3.53 mmol) of 1-fluoro-5-trifluoromethylpyridinium-2-sulfonate in 10 ml of 1,2-dichloroethane, and the resulting mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium sulfite, and the aqueous mixture was freed from the solvent by evaporation under reduced pressure, after which it was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 20 g of silica gel, using an 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give a mixture containing the title compound. This mixture was further purified by column chromatography through 40 g of silica gel, using a 7:1 by volume mixture of hexane and acetone as the eluent, to give the desired fluoride compound as an oily substance in a 18% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[C:34]([NH:33][S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:21])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-N-tert-butyl-benzenesulfonamide to general procedure II. Pale-yellow solid. MS (ISP) 524.5 [(M+H)+]; mp 238-239° C.
Reaction SMILES: [N+:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:23])=O>C(OCC)(=O)C>[Cl:23][C:9]1[N:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(=O)[nH]c1C(=O)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)nc1C(=O)OCC
Temperature: 80 °C
Yield: 73.9 %

Procedure:
Diethyl 1,6-dihydro-5-nitro-6-oxo-2,3-pyridinedicarboxylate (26.23 g, 0.092 mol) is partially dissolved under N2 atmosphere in 250 mL of phosphorous oxychloride and the mixture is heated to 80° C. for 15 hours. The mixture is cooled and concentratrated and the resulting oil dissolved in ethyl acetate and washed with water, 10% K2CO3 and brine. The organic layer is dried over MgSO4, filtered and the solvent removed to yield a solid which is recrystallized from absolute ethanol/water to give 20.65 g of the product as a brown solid in 73.9% yield, having a melting point of 84.5°-86° C.