Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]([OH:13])=O)[CH2:6]1)(=[O:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:34][O:35][C:36]1[C:41]2[N:42]=[C:43]([NH2:45])[S:44][C:40]=2[C:39]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]([NH:45][C:43]2[S:44][C:40]3[C:39]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[CH:38][CH:37]=[C:36]([O:35][CH3:34])[C:41]=3[N:42]=2)=[O:13])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CC(=O)O[C@@H]1CC[C@H](CC(=O)O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](OC(C)=O)C3)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (rac)-(cis)-3-(acetyloxy)-cyclopentaneacetic acid (770 mg, 4.1 mmol) and N,N-dimethylformamide (0.01 ml, 0.13 mmol) in dichloromethane (10 ml) were added oxalyl chloride (1.4 ml, 17 mmol) and the resulting solution stirred for 18 h at ambient temperature. After evaporation of the volatile components in vacuo, the residue was taken up in toluene (10 ml) and again evaporated to dryness. The obtained acid chloride was then dissolved in dichloromethane (20 ml) and subsequently treated with N-ethyl-diisopropyl amine (2.5 ml, 15 mmol) and 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (960 mg, 3.6 mmol). After stirring for 2 h at ambient temperature and another hour at 50° C., the mixture was cooled to room temperature and treated with saturated aqueous sodium hydrogen carbonate (15 ml) and extracted twice with dichloromethane (20 ml each). After drying over magnesium sulphate and evaporation of the solvents, flash chromatography (silica, eluent dichloromethane/ethyl acetate 85:15) afforded (rac)-(cis)-2-(3-acetoxy-cyclopentyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide as off-white solid. Separation by preparative chiral HPLC (Chiralpack AD, eluent heptane/isopropanol 85:15) afforded the title compound as first eluting isomer. Light yellow solid (4% yield). MS: m/e=434(M+H+), mp 171-172° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCCOC)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:16]>>[CH2:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: OCc1ccccc1Cc1ccccc1
Product: BrCc1ccccc1Cc1ccccc1
Reaction time: 20 h
Yield: 98 %

Procedure:
2-Benzylbenzyl alcohol (commercial) (1 g) was suspended in 48% aqueous hydrobromic acid (10 ml) and stirred vigorously for 20 hours. The resultant suspended solid was extracted twice with hexane and the extracts dried (MgSO4) and evaporated to give 2-benzyl benzylbromide as yellow solid (1.3 g, 98%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[O:26]C(=O)C)[N:9]=1)=[O:7])[CH3:4].C(O)(=O)C>C(O)C.O.C(OCC)C>[CH2:3]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH2:18][CH2:17][CH2:16][C:15]=2[C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[OH:26])[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cccc(C2=C(c3cc(C)ccc3OC(C)=O)CCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(C2=C(c3cc(C)ccc3O)CCC2)n1
Reaction time: 8 h
Yield: 99 %

Procedure:
60% Sodium hydride (2 mg) was added to a solution of 6-[2-(5-methyl-2-acetoxyphenyl)cyclopent-1-enyl]pyridine-2-carboxylic acid ethyl ester in ethanol (5 ml) and left overnight at room temperature then diluted with water/diethyl ether and acidified with acetic acid. The organic phase was washed with saturated sodium bicarbonate solution, dried (magnesium sulphate) and evaporated to give the title compound as a pale yellow gum (271 mg, 99%). LC/MS: Rt 3.3 [MH+] 324.4
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
A mixture of methyl 2-phenyl-benzoxazole-6-carboxylate 25c (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H2O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 25d (0.34 g).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[N:9]=[C:8]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH:7]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(Cl)nc1Cl
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(-c3ccc(Oc4ccccc4)cc3)c(C#N)c(Cl)n2)cc1
Temperature: 100 °C
Yield: 67.7 %

Procedure:
A mixture of 2,6-dichloro-4-(4-phenoxyphenyl)nicotinonitrile (110 mg, 0.322 mmol), 4-methoxyphenylboronic acid (53.9 mg, 0.355 mmol), palladium tetrakis(triphenylphosphine) (16.30 mg, 0.016 mmol) and potassium phosphate tribasic monohydrate (0.484 mL, 0.967 mmol) in N,N-dimethylformamide (3 mL) was heated under nitrogen to 100° C. for 15 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (80 mL), washed with water (15 mL), brine (15 mL), dried (MgSO4), and concentrated. Silica gel chromatography, loading with toluene and eluting with 5-30% ethyl acetate in hexanes, gave 2-chloro-6-(4-methoxyphenyl)-4-(4-phenoxyphenyl)nicotinonitrile as white solid (90 mg, 68% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.94-8.22 (2H, m), 7.69 (1H, s), 7.56-7.65 (2H, m), 7.42 (2H, t, J=7.97 Hz), 7.18-7.26 (1H, m), 7.06-7.19 (4H, m), 7.02 (2H, δ, J=8.80 Hz), 3.90 (3H, s); MS (ES+) m/z: 413 (M+H); LC retention time: 4.423 min (analytical HPLC Method A).
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+].Cl>CO>[CH2:6]([O:5][CH:3]([OH:4])[C:2]([F:12])([F:1])[C:8]([F:10])([F:11])[F:9])[CH3:7]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(O)C(F)(F)C(F)(F)F
Temperature: -60 °C
Reaction time: 1 h

Procedure:
Ethyl 2,2,3,3,3-pentafluoropropionate (10.99 grams, 57.2 mmol) was dissolved in anhydrous methanol (57 ml) and cooled in an argon atmosphere to −60° C. Sodium borohydride (2.16 g, 57.2 mmol) was added in four portions. After the addition was complete, stirring was continued for one hour and the temperature was held below −45° C. The mixture was cooled to −60° C. and 1M hydrochloric acid (172 ml) was added dropwise so that the temperature remained below −45° C. The mixture was slowly warmed to room temperature and extracted with diethylether (3×100 ml). The combined organic phases were washed with water (two times), dried over magnesium sulfate, the solvent was removed under reduced pressure. 9.76 g (50.3 mmol, 88%) were obtained and used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:42])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:42])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([CH:39]([OH:41])[CH3:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)=O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(C)O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65 %

Procedure:
A mixture of 62 mg (0.15 mmol) [(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-carbonyl)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 14) and 3.95 mg (0.105 mmol) sodium borohydride in 2 mL THF/0.2 mL MeOH was stirred at room temperature for 45 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried with Na2SO4, filtered and evaporated to dryness to yield 58 mg (93%) of the title compound as off-white solid. MS m/e: 595.2 [M+H]+.
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH:11](CC2C=CC=CC=2)[OH:12])[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]12>[Pd].CO.C(O)(=O)C>[C:4]1(=[O:20])[N:5]([CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:1](=[O:25])[C:2]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCNCCC(O)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCNCCCO
Reaction time: 3 h
Yield: 84.6 %

Procedure:
N-Phthalimidoethyl(benzyl)-3-amino-1-propanol (4.62 g, 11.95 mmol), Pd/C 10% (1 g) and MeOH:acetic acid (95:5, v/v) (100 mL) was transferred to a 250 mL par hydrogenation flask. The flask was purged and filled with H2 three times and then left under H2 at 55 psi with shaking. The mixture absorbed 20 psi of H2 in 30 minutes. The shaking was stopped and the pressure was raised to 55 psi again. After 3 hrs the pressure was 45 psi so the pressure was increased to 55 psi once more. The reaction was complete as indicated by TLC dichloromethane:MeOH (9:1, v/v) in 4 hours. The reaction mixture was filtered though a bed of celite and the solvent evaporated under vacuo to leave a yellowish oil. The oil was purified by silica gel flash column chromatography using dichloromethane:MeOH (9:1, v/v) as the eluent. The appropriate fractions were combined and concentrated under vacuo to afford 2.51 g (68%) of the title compound as a white solid (m.p. 94-95° C.).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 17.5 °C

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid (0.37 g), dichloromethane (20 ml) and oxalyl chloride (0.26 ml) was stirred at 15-20° C. and then dimethylformamide (3 drops) was added. The mixture was stirred at 15-20° C. for 30 minutes and then warmed at 40° C. for 1 hour. The solvent was removed under reduced pressure to give a solid which was dissolved in dichloromethane (20 ml) and then aniline (0.13 ml) and triethylamine (0.38 ml) were added. The mixture was stirred at ambient temperature under nitrogen for 2 hours and then washed with water, dried, filtered and evaporated to give a solid which was purified by flash column chromatography on silica to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzanilide, m.p. 186-190° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>C1COCC1>[N:38]1([C:35]2[CH:34]=[CH:33][C:32]([NH:31][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:37][CH:36]=2)[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCOCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 120 mg, 0.298 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (64 mg, 0.3591 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 58% yield (0.097 g, 0.1724 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](OCC)OCC)=[CH:4][C:3]=1[F:17].C(=O)(O)O.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25].[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:22]=[N:23][C:24]([NH2:26])=[N:25][CH:9]=2)=[CH:4][C:3]=1[F:17]
Reactant: N=C(N)NN
Reactant: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Agent: O=C(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 110 °C

Procedure:
A mixture of 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (15.2 g, 50 mmol), aminoguanidine bicarbonate (10.2 g, 75 mmol) and potassium hydroxide (6.6 g, 100 mmol) in ethanol (200 mL) and water (4 mL) was refluxed overnight. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with water, brine, and concentrated under reduced pressure. The residue was dissolved in ethanol (50 mL). To the solution was added 0.2N hydrochloric acid (50 mL). The resultant mixture was heated to 110° C. for 8 h, and cooled with an ice-water bath. The precipitate that formed was collected by filtration and washed with isopropanol to give the desired product. (5.5 g, 41%) LCMS: (M+H)=286.8/288.8. 1H-NMR (400 MHz, CDCl3): 8.60 (s, 1H), 7.79 (dd, J=8.6, 2.0 Hz, 1H), 7.68 (dd, J=8.3, 7.0 Hz, 1H), 7.61 (dd, J=8.3, 2.0 Hz, 1H), 5.43 (s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:21]([O:22][CH3:23])=[C:19]([OH:20])[CH:18]=1>>[CH3:23][O:22][C:21]1[CH:24]=[CH:25][C:17]([CH:16]=[O:15])=[CH:18][C:19]=1[O:20][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COc1ccc(C=O)cc1O
Product: COc1ccc(C=O)cc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Reference Example 3, 4-chloromethyl-5-methyl-2-phenyloxazole was allowed to react with isovanilline to yield 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.121-122° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH:22]=[C:21]([CH3:33])[N:20]=3)[CH:18]=2)=[N:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([CH3:33])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:12]4[S:13][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][N:11]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ncc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-2-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.23 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) to yielded the title compound as a light brown solid (0.028 g, 6%). MS (ISP) 467.1 [(M+H)+]; mp 230° C.
Reaction SMILES: Cl.[NH2:2]O.C([O-])(O)=O.[Na+].[F:9][C:10]([F:20])([F:19])[C:11]([CH3:18])([CH3:17])[C:12](=[O:16])[CH2:13][C:14]#[N:15].Cl.[OH-].[Na+]>O.CO>[F:9][C:10]([F:19])([F:20])[C:11]([C:12]1[O:16][N:15]=[C:14]([NH2:2])[CH:13]=1)([CH3:18])[CH3:17]
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(c1cc(N)no1)C(F)(F)F
Temperature: 0 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
To a mixture of hydroxylamine hydrochloride (23.2 g, 336 mmol) in water (300 mL) cooled to 0° C. was added NaHCO3 (30 g, 351 mmol) and pH=7.5 adjusted. Then to the mixture was added a solution of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (30 g, 167.4 mmol) in MeOH (40 mL). The mixture was stirred at 65° C. for 15 h. After cooled, the mixture was acidified with conc. HCl to pH=1 and then refluxed for 2 h. After cooling to rt, the mixture was neutralized by 4 M NaOH to pH=8. The mixture was extracted with EA (300 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=8:1˜3:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.6) were combined and concentrated to yield a red solid of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (19.5 g, 100.5 mmol, 60% yield): 1H NMR (400 MHz, CDCl3) δ 5.79 (s, 1H), 3.96 (s., 2H), 1.53 (s, 6H); ES-LCMS m/z: 195 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:27])[CH2:25][CH3:26]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH3:23])[C:20]([NH:27][CH2:24][CH2:25][CH3:26])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCN
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Solvent: CO
Product: CCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 293 mg (0.9 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) in 3 ml of methanol was mixed with 3 ml of propylamine, whilst ice-cooling, and the mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was triturated with hexane to afford 315 mg of the title compound as white crystals, melting at 115°-116° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21]>>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:3][CH2:4][N:5]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12]
Reactant: Oc1ccccc1Br
Reactant: CC1CCCC(C)(C)N1CCCl
Agent: Cl
Product: CC1CCCC(C)(C)N1CCOc1ccccc1Br

Procedure:
The title compound was prepared from 1-(2-chloroethyl)-2,2,6-trimethylpiperidine hydrochloride and 2-bromophenol in a similar manner to Example 2 (b).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:19])[CH2:18][CH2:17][C:12]2([O:16]CCO2)[CH2:11][CH2:10]1.FC(F)(F)C([O-])=O>CCCCCC.CCOCC>[C:9]12([CH2:10][CH2:11][C:12](=[O:16])[CH2:17][CH2:18]1)[C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][O:19]2
Reactant: OCc1ccccc1C1(O)CCC2(CC1)OCCO2
Agent: O=C([O-])C(F)(F)F
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C1CCC2(CC1)OCc1ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
0.64 g (2.62 mmol) of 8-(2-Hydroxymethyl-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol was added to 80% trifluoroacetate (TFA) 2.5 ml. The mixture was stirred at room temperature for 5 hours. Rotory evaporation of the TFA left thick brown oil. The oil was dissolved in 2.0 ml of EtOAc and washed first with 1N NaOH and then with H2O. The organic layer was dried with MgSO4 and concentrated, leaving a thick yellow oil. Hexane/ether (2:1) was added and the sides of the flask were scratched. A precipitate began to form. 0.23 Grams of 3′H-Spiro[cyclohexane-1,1′-isobenzofuran]-4-one were obtained, 44% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14](=O)[CH2:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([CH3:36])[CH:30]=2)=[CH:27][NH:26][N:25]=1>>[CH3:35][C:33]1[CH:34]=[C:29]([C:28]2[CH:27]=[N:26][N:25]3[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:23][C:24]=23)[CH:30]=[C:31]([CH3:36])[N:32]=1
Reactant: CCOc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(-c4cc(C)nc(C)c4)c3n2)ccc1C(F)(F)F
Yield: 50 %

Procedure:
Reaction of 1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (120 mg, 50%). MS (ISP) 481.4 [(M+H)+]; mp 257° C.