Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(C)(C)O
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCCCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(C)(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (1.25 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.25 mL, 20.5 eq, 1.44 mmol) followed by (3R)-3-amino-2-methyl-pentan-2-ol (22 mg, 2.7 eq, 0.19 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 3.7 mg (14%). 1H-NMR (d-CDCl3, 250 MHz): δ 1.00 (t, 3H, J=7.27 Hz, —NHCH(CH2CH3)C(CH3)2OH), 1.21 & 1.31 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 1.57 (d, 6H, J=6.63 Hz, —CH(CH3)2), 1.69-1.89 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 3.66-3.83 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.59-4.73 (m, 1H, —CH(CH3)2), 4.77-5.00 (m, 2H, —HNCH2-Pyr), 7.26-7.46 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.49-7.69 (m, 1H, Pyr-H), 7.78 (d, 1H, J=7.10 Hz, Pyr-H). FABMS m/z (relative intensity): 384 ([M+H]+, 65), 366 (23), 324 (100), 217 (35), 192 (55). Accurate Mass (M+H): Actual: 384.2512, Measured: 384.2494.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.Cl[C:14]1[CH:15]=[N:16][CH:17]=C(Cl)[C:19]=1C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:32]=[O:33])[N:27]=[N:28][C:29]=1[O:30][CH3:31]>CCCCCC.O1CCCC1>[CH3:4][C:3]1[CH:17]=[N:16][CH:15]=[C:14]([CH3:19])[C:2]=1[CH2:1][CH:32]([C:26]1[N:27]=[N:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=1)[OH:33]
Reactant: [Li]CCCC
Reactant: COc1cc(C=O)nnc1OC
Reactant: Cc1c(Cl)cncc1Cl
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(C(O)Cc2c(C)cncc2C)nnc1OC
Temperature: -70 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.51 mL of a 1.6 M solution in hexane) is added to a solution of diisopropylamine (0.34 mL) in tetrahydrofuran (29 mL) at −10° C. under a nitrogen atmosphere. After 30 minutes the mixture is cooled to −70° C. and a solution of 3,5-dichloro-4-methylpyridine (0.39 g) in tetrahydrofuran (4 mL) is added dropwise. After 30 minutes a solution of 5,6-dimethoxy-pyridazine-3-carboxaldehyde (0.35 g) in tetrahydrofuran (15 mL) is added at −70 to −60° C. and stirring continued at this temperature for 1 hour before cooling is discontinued. After 24 hours the yellow solution is quenched by the addition of aqueous ammonium chloride and the mixture extracted with ethyl acetate. The dried extracts (MgSO4) are evaporated and the residue purified by flash chromatography (ethyl acetate as eluent on silica) to give (±)-2-(3,5-dimethylpyrid-4-yl)-1-(5,6-dimethoxypyridazin-3-yl)ethanol (0.17 g), as a white solid, m.p. 217-8° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]([CH:27]=O)=[CH:17]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(OCC)=O)C.Cl>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:18](/[CH:27]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:17]2)=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3ccccc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
Sodium hydride (60%, oily, 2.13 g) was added to a mixture of 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carbaldehyde (18.00 g), ethyl diethylphosphonoacetate (12.09 g) and N,N-dimethylformamide (150 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and ethyl(E)-3-[1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (20.16 g, yield: 94%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 111–112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[C:24](Cl)(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(OCCN2CCOCC2)ccc1Cl
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCOCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
2-chloro-5-(2-morpholinoethoxy)aniline (1.9 g, 7.4 mmol, 1 eq.) was placed in a mixture of acetone (2.5 mL) and water (3.2 mL) in the presence of K2CO3 (2.1 g, 14.4 mmol, 2 eq.). Cinnamoyl chloride (1.2 g, 7.4 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford N-(2-chloro-5-(2-morpholinoethoxy)phenyl)cinnamamide (1.7 g, 60%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1.[CH:12](=O)[C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1>O.CO>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=2)=[N:8][CH:9]=1
Reactant: NNc1ccc(N)cn1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C=NNc2ccc(N)cn2)cc1OC
Reaction time: 0.8 h

Procedure:
A solution of 5.0 g (0.025 mole) of the compound of Example I in a mixture of 13 ml of H2O and 20 ml of CH3OH was treated rapidly with a solution of 4.7 g (0.027 mole) of veratraldehyde in 40 ml of methanol using mechanical stirring. The reaction mixture was stirred rapidly for 0.8 hr and filtered. The yellow-brown solid was washed with 40 ml of methanol, ether and air dried, m.p. 232°-233°dec. yield: 7.2 g (83%). Recrystallization from methanol raised the melting point to 235°-236°, dec.
Reaction SMILES: I[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.N1CCCCC1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>[Cu]I>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1)([CH3:23])[CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(CN2CCCC2)cc1
Agent: [Cu]I
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(CN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A reaction mixture of 1 g (3.48 mmol) of 1-(4-iodobenzyl)pyrrolidine, 5 mL of piperidine, 105 mg (0.091 mmol) of tetrakistriphenylphosphine palladium, and 10 mg (0.053 mmol) of copper (I) iodide is cooled to 0° C. At this temperature, 0.59 mL (4.18 mmol) of trimethylsilylacetylene is added dropwise and then the cooling bath is removed. It is stirred for 3 hours at ambient temperature, then combined with a saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate (1:1)). Yield: 0.75 g (83.6% of theory); C16H23NSi (M=257.45); calc.: molecular ion peak (M+H)+: 258; found: molecular ion peak (M+H)+: 258.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=Cc1ccccc1F
Product: CC(C)(C)c1ccc(Oc2ccccc2C=O)cc1
Yield: 77 %

Procedure:
Preparation analogous to Example 12a) from 2-fluoro-benzaldehyde and 4-tert-butylphenol. Yield: 77%, yellow oil after high vacuum distillation (93°-100° C., 0.9 mbar); TLC (silica gel; hexane/ethyl acetate=1:1; UV): Rf =0.65; 1H-NMR (CDCl3, 200 MHz): 1.35 (s, 9H); 6.75-7.55 (m, 7H); 7.92 (dd, 1H) MS: 254 (M+), 239.
Reaction SMILES: C(OP([CH:9]([Cl:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=O)OCC)C.C[O-].[Na+].[CH3:21][C:22]1([CH3:30])[C@@H:24]([CH:25]=O)[C@@H:23]1[C:27](=[O:29])[CH3:28].O>O1CCCC1.CO>[CH3:21][C:22]1([CH3:30])[C@@H:23]([C:27](=[O:29])[CH3:28])[C@@H:24]1[CH:25]=[C:9]([Cl:17])[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)[C@H]1[C@H](C=O)C1(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1[C@H](C=C(Cl)c2ccc(Cl)cc2)C1(C)C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 23.7 g (0.08 mol) of α-chloro-(4-chlorobenzyl)-phosphonic acid diethyl ester in 40 ml of tetrahydrofuran was added dropwise to a solution of 17.8 g (0.084 mol) of sodium methylate in methanol and 160 ml of tetrahydrofuran at 0°-10° C. and the mixture was subsequently stirred at 0°-10° C. for 1 hour. 11.2 g (0.08 mol) of trans-3,3-dimethyl-2-acetyl-cyclopropanecarbaldehyde were then added at 10° C. and the reaction mixture was subsequently stirred for 2 hours, without further cooling, and then poured onto 800 ml of water. The aqueous solution was extracted three times with 200 ml of methylene chloride each time and the combined organic phases were dried over sodium sulphate and evaporated in vacuo. 19.7 g (87% of theory) of trans-3,3-dimethyl-2-(2-chloro-2-(4-chlorophenyl)-vinyl)-1-acetyl-cyclopropane were thus obtained as a yellow oil with a boiling point of 120°-128° C./0.1 mm/Hg. ##STR53##
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 68.7 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 2-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.31 g (69%) of 1-benzyl-piperidin-4-yl 2-methoxy-benzoate were obtained as a yellowish oil. MS: me/e=326 (C20H24NO3 +).
Reaction SMILES: [C:1]1(=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[C:11]([F:24])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[C:11]([F:24])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1F
Yield: 92.5 %

Procedure:
The general hydrolysis procedure, described for 195 was followed. Thus, 1,1-dimethylethyl(2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoate (198) (0.380 g, 0.9 mmol) in CH2Cl2 was treated with TFA to afford 0.305 g (92%) of the title compound as an off-white foam. 1H NMR (300 MHz, CD3OD): δ 7.76 (d, J=15.9 Hz, 1H), 7.59 (appt, J=7.8 Hz, 1H), 7.18 (app t, J=7.8 Hz, 1H), 7.04 (br d, J=8.1 Hz, 1H), 6.94 (br d, J=11.7 Hz, 1H), 6.67-6.60(m, 3H), 6.56 (d, J=16.2 Hz, 1H), 2.34 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 365 (M−H)−. Anal. Calcd for C23H23FO3.1.5H2O, C, 70.38; H, 6.63; F, 4.84; Found: C, 69.96; H, 5.95; F, 4.73.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16])=[C:6]=[O:7]>C1(C)C=CC=CC=1>[CH2:13]([NH:14][C:15]([N:3]1[CH2:4][CH:2]1[CH3:1])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:5][C:6]([N:3]1[CH2:4][CH:2]1[CH3:1])=[O:7]
Reactant: CC1CN1
Reactant: O=C=NCCCCCCN=C=O
Solvent: Cc1ccccc1
Product: CC1CN1C(=O)NCCCCCCNC(=O)N1CC1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methyl aziridine (15.05 grams, 0.26 moles) was added drop wise over one hour to a solution of 1,6-diisocyanatohexane (20.00 grams, 0.12 moles, Aldrich) in toluene (40 mL) while cooling in an ice bath. After stirring for a total of 24 hours at room temperature, a potion of the solvent was removed under vacuum to give N,N′-(hexane-1,6-diyl)bis-(2-methylaziridine-1-carboxamide)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:9][C@H:8]2[CH2:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[CH:14]([O:13][C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:24])[C@H:8]([CH2:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:9]1)([CH3:16])[CH3:15]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)O[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Yield: 56.1 %

Procedure:
A mixture of (S)-3-amino-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (0.04 g, 0.128 mMol), triethylamine (71 uL, 0.512 mMol) and 4-chloro-6-(trifluoromethyl)quinazoline (0.035 g, 0.192 mMol) were taken in EtOH and microwaved at 100° C. for 45 min. The reaction mixture was concentrated and chromatographed to yield (S)-1-((1S,2R,4R)-4-isopropoxy-2-(isopropylsulfonyl methyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one as a white solid (0.04 g). MS found: (M+H)+=557.2
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]2[C:9]3[C:25]4[CH2:26]CCC[C:24]=4[S:23][C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]3)[N:13]=2)=[CH:4][CH:3]=1.[Na]>>[CH3:26][C:25]1[C:9]2[C:8]([NH:7][CH2:6][C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=3)=[N:13][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([C:20]([OH:22])=[O:21])[CH2:18][CH2:19]3)=[N:11][C:10]=2[S:23][CH:24]=1
Reactant: O=C(O)C1CCN(c2nc(NCc3ccc(F)cc3)c3c4c(sc3n2)CCCC4)CC1
Agent: [Na]
Product: Cc1csc2nc(N3CCC(C(=O)O)CC3)nc(NCc3ccc(F)cc3)c12

Procedure:
1-[5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-piperidine-4-carboxylic acid, sodium salt, m.p. 279°;
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7]2.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].[Na]>CO.C(OCC)C>[C:22]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:7]2)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2cc(S(=O)(=O)O)ccc12
Agent: [Na]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CO
Product: CC(=O)Nc1cccc2cc(S(=O)(=O)O)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 29.3 g (0.13 mol) of 5-amino-2-naphthalenesulfonic Acid (Compound 72) was added 40 mL of pyridine and 26 mL of acetic anhydride. The resulting suspension was allowed to stir at ambient temperature. After 24 hr, the resulting solution was diluted with 60 mL of methanol. Then, a solution of 3.6 g (0.156 mol) of sodium in 100 mL of methanol was added. After a solid precipitate began to form, 200 mL of diethyl ether was added and the suspension allowed to stir. The solid was collected by vacuum filtration and was washed with diethyl ether. This provided 38.9 g (0.11 mol) of the desired product. The product was identified by 1H NMR and mass spectroscopy and purity was assessed by RP-HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.4 %

Procedure:
To a solution (37 ml) of methyl 4-cyano-3-methoxybenzoate (700 mg, 3.66 mmol) in methanol was added 1M aqueous sodium hydroxide solution (37 ml), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in water, and the mixture was washed with diethyl ether. The aqueous layer was neutralized with 1M hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous MgSO4 and concentrated under reduced pressure to give the title compound (690 mg, ca. 100%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([O:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:21])[CH3:20]
Reactant: O=C(O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
3-Benzyloxy-5-hydroxybenzoic acid (2.16 g) and acetic anhydride (15 mL) were suspended in acetic acid (15 mL), and the resulting mixture was stirred at 120° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1 to 1/0) to give the title compound (1.74 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1.C(O)(=[O:29])C.OO>C(OCC)(=O)C>[CH3:1][S:2]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:6]=[N:5][CH:4]=1)=[O:29]
Reactant: CSc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Reactant: CC(=O)O
Agent: OO
Solvent: CCOC(C)=O
Product: CS(=O)c1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Intermediate 74 (746 mg) obtained in Example 105, Step B was added with acetic acid (1.5 ml) and 30% aqueous hydrogen peroxide (2 ml) and stirred at room temperature for 17 hours. The reaction mixture was added with ethyl acetate (50 ml) and washed three times with saturated aqueous sodium hydrogencarbonate (25 ml for each time), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:acetone=3:1) to obtain the title compound (390 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:33])(=O)=[O:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([Cl:3])(=[O:33])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of thionyl chloride (3.0 mL) and 2 drops of DMF stirring under nitrogen at 0° C. is added the title B compound, 4-(5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy)-benzenesulfonic acid sodium salt (1.1 g, 2.53 mmol) in one portion. The resulting suspension is stirred at 0° C. for 10 min. The ice bath is removed and the suspension is stirred at RT for 3 h. The solution is concentrated and the resulting residue is azeotrophed twice with toluene. The residue is taken up into DCM, filtered and evaporated at reduced pressure to give 4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonic acid chloride as an oil. It is used as such without any additional purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:6]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][CH2:3][C:4]1[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:6]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(COC)cc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1cc2ccccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 95.3 %

Procedure:
Ethyl ester (147) (20 mg, 0.046 mmol) was saponified with 1 N NaOH in THF and EtOH to give 18 mg (93%) of the title compound (148) as an off-white solid. mp 76-79° C. 1H NMR (400 MHz, CDCl3): δ 3.33 (s, 3H), 4.31 (s, 2H), 6.22 (d, J=15.9 Hz, 1H), 6.60 (d, J=8.8 Hz, 2H), 7.15-7.20 (m, 2H), 7.20-7.30 (m, 5H), 7.44 (t, J=7.9 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.95 (s, 1H). LCMS (ESI): m/z 433 (M+Na)+, m/z 409 (M−H)−. HRMS (EI) Calc for C27H22O4: 411.1596 (M+•). Found: 411.1606.