Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([NH:20][C@@H:21]([CH2:27][OH:28])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[C:33]([O:41][C:42]([F:45])([F:44])[F:43])[CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:37]([C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][C:33]=1[O:41][C:42]([F:43])([F:44])[F:45])(=[O:39])=[O:38])[C:6](=[O:11])[C:5]2([NH:20][C@@H:21]([CH2:27][OH:28])[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(N[C@@H](CO)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N[C@@H](CO)C(=O)N(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 0.88 g of the compound obtained in Step 65-3 and 0.649 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, respectively 140 mg (Isomer A, colorless amorphous) and 170 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Example 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1Cl.COC1CCC(OC)O1>CC(O)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-amino-2-chlorobenzoic acid methyl ester (0.46 g) and 2,5-dimethoxytetrahydrofuran (0.33 mL) in AcOH (16 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extract was washed with satd. NaHCO3 and brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 5/1) to yield 0.48 g of 2-chloro-4-1-pyrrolyl)benzoic acid methyl ester. ESMS: m/z 236 (MH−).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>N1C=CC=CC=1>[S:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=[C:2]1[NH:1][C:12](=[O:13])[O:14][CH2:15][CH3:16]
Reactant: Nc1nc2c(s1)CCCC2
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4,5,6,7-tetrahydrobenzothiazole (12.3 grams; 0.08 mol) dissolved in pyridine (50 ml.) was charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. Ethyl chloroformate (12 ml; 0.11 mol) was added dropwise to the reaction mixture with stirring and cooling. After the addition was completed the reaction mixture was allowed to warm to room temperature and stirring was continued for a period of about 1 hour. After this time the reaction mixture was poured into ice water (50 mol.) to form a precipitate. The precipitate was recovered by filtration, washed with water four times dried and recrystallized from ethanol to yield the desired product ethyl N-(4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate; (16.7 grams); melting point 182°-184° C. The structure of the product was verified by infrared and NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([CH3:10])=[N:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH2:32])=[O:31])[CH:28]=3)[CH:23]=[CH:22]2)[CH2:17][CH2:16]1.[H-].[Na+].[CH3:35]I.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7]([CH3:10])=[N:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH:32][CH3:35])=[O:31])[CH:28]=3)[CH:23]=[CH:22]2)[CH2:17][CH2:16]1
Reactant: CI
Reactant: COc1ccc2c(C)noc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c(C)noc45)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
65 mg of 1-(1-(2-(6-methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide obtained in Example 1 was dissolved in 1 ml of N,N-dimethylformamide, and then, 7.2 mg of 60% sodium hydride was added thereto. The reaction solution was stirred at room temperature for 5 minutes, and 11.2 μl of methyl iodide was then added to the reaction solution. After completion of the reaction, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium bicarbonate aqueous solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), so as to obtain 17 mg of the subject compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15](Cl)(=[O:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>CCOC(C)=O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:26])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NCCCCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
tert-Butyl 5-hydroxypentylcarbamate (950 mg, 4.67 mmol) was dissolved in EtOAc, 4-nitrophenyl carbonochloridate (1.130 g, 5.14 mmol) was added, the mixture cooled on an icebath, triethylamine (0.85 mL, 6.07 mmol) was added with stirring and the mixture gradually allowed to reach rt and stirred overnight. The mixture was transferred to a separatory funnel with EtOAc and H2O, and shaken. The organic phase was extracted with 1N HCl, H2O, NAHCO3 (aq., sat.), H2O (twice), brine, dried over Mg2SO4, filtered and concentrated. The residue was purified by chromatography (mixtures of petroleum ether and EtOAc) to afford compound 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:26])C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([OH:26])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7]
Reactant: COC(=O)CCC(C)(C)c1cccc(OC)c1F
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(O)CC(C)(C)c1cccc(OC)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
19.58 g (77 mmol) of 4-(2-fluoro-3-methoxyphenyl)-4-methylpentanoic acid methyl ester is introduced into 245 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. Within one hour, 220.7 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture is then stirred for 45 more minutes at −70° C. 28.3 g (107.79 mmol) of Davis reagent, dissolved in 245 ml of tetrahydrofuran, is now added in drops within 40 minutes. After two hours of stirring at −70° C., 250 ml of saturated ammonium chloride solution is slowly added in drops, and in this case, the batch is brought to room temperature. After extraction with methyl tert-butyl ether, the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed several times on silica gel (mobile solvent ethyl acetate/hexane). 12.14 g (58.3%) of the desired compound is ultimately isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[N:10]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[C:31]([C:32](O)=[O:33])=[C:30]([F:35])[C:29]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:25][C:26]1[C:31]([C:32]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:20]([F:23])([F:21])[F:22])[N:10]=[C:9]3[NH:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:24])([CH3:1])[CH2:7][CH2:6]2)=[O:33])=[C:30]([F:35])[C:29]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:41])([CH3:40])[CH3:42])=[CH:28][CH:27]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC1(C)CCC(Nc2nc(C(F)(F)F)nc3c(N)cccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CCC(Nc2nc(C(F)(F)F)nc3c(NC(=O)c4c(Cl)ccc(CNC(=O)C(C)(C)C)c4F)cccc23)CC1
Yield: 19.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-dimethylcyclohexyl)-2-(trifluoromethyl)quinazoline-4,8-diamine (Intermediate-26, 100 mg, 0.295 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 127 mg, 0.443 mmol), oxalyl chloride (84 mg, 0.66 mmol), DMF (1 drop) and DIPEA (115 mg, 0.89 mmol) in CH2Cl2 (3 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.67-8.65 (d, J=7.2 Hz, 1H), 8.59-8.56 (d, J=8.1 Hz, 1H), 8.22-8.16 (m, 2H), 7.74-7.68 (t, J=8.4 Hz, 1H), 7.45-7.33 (m, 2H), 4.32-4.30 (d, J=5.4 Hz, 2H), 4.14 (m, 1H), 1.76-1.66 (m, 4H), 1.43-1.24 (m, 4H), 1.14 (s, 9H), 0.99 (s, 3H), 0.95 (s, 3H); MS (m/z): 608.38 (M+H)+.
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)/[C:4]([OH:6])=[O:5].[H][H]>>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In an analogous manner to Example 10, 2.5 g (5.74 mmol) of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid were asymmetrically hydrogenated in the presence of 3.22 mg of [Ru(OAc)2((S)-6-MeO-2-naphthyl)-MeOBIPHEP)] (S/C molar ratio 2000) at 40° C. under 15 bar of hydrogen for 24 h to reach 99.6% conversion. Rotary evaporation of the reaction mixture afforded quantitatively (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid of 75.8% ee with 98.5% purity (HPLC area).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: COc1ccccc1B(O)O
Reactant: Brc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccccc1-c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
2-Bromoiodobenzene (640 μL, 5.0 mmol) was added to a suspension of Pd(PPh3)4 (305 mg, 0.26 mmol) in DME (100 mL) at room temperature under argon. After 15 min at room temperature, a solution of 2-methoxyphenylboronic acid (760 mg, 5.0 mmol) in ethanol (2 mL) was added, followed by aqueous Na2CO3 (2.0 M, 5 mL, 10 mmol). The reaction vessel was fitted with a reflux condenser and heated to reflux under argon for 22.5 h. The reaction mixture was then cooled to room temperature and filtered through Celite. The filter cake was washed with ether and water, and the filtrate was concentrated in vacuo. The resulting aqueous residue was diluted with brine and extracted with ether. The ethereal layer was dried (MgSO4), filtered and concentrated. The crude residue was purified by flash chromatography on silica gel to afford 823 mg (63%) of a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].Cl.[NH2:33]O.Cl>CO.CO.O.O.C(OCC)(=O)C>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:9]2)[O:7][NH:33]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(C(F)(F)F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A solution of trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)-piperidine-1-carboxylate (1.8 g, 4.33 mmol) (from example 107, step 1) in MeOH (7 mL) was added to a solution of NaOH (225 mg, 5.63 mmol) in MeOH/H2O (8 mL/0.5 mL) at −30° C. After 10 min hydroxylamine hydrochloride (0.602 g, 8.67 mmol) and NaOH (347 mg, 8.67 mmol) were added in MeOH (7 mL) and H2O (7 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (60 mL) at 80° C. and heated for 30 min. The reaction mixture was dissolved between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Purification using prepLC (pH=3, large column 25-55% MeCN over 20 min) Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.06 g, 63.6%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.49-2.17 (m, 4H), 2.80-3.22 (m, 4H), 3.34-3.76 (m, 3H), 4.07-4.40 (m, 1H), 4.52-4.84 (m, 1H), 5.65 (s, 1H), 7.28-7.54 (m, 4H). MS m/z 385 (M+H)+
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9].C(N(CC)CC)C.O=C1CCC(=O)N1[C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:42]([O-])=[O:43])=[C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])[CH:31]=2)[N:26]([CH2:45][CH:46]([CH3:48])[CH3:47])[N:25]=1>ClCCl.C(OCC)(=O)C>[F:41][C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[C:42]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9])=[O:43])[N:26]([CH2:45][CH:46]([CH3:48])[CH3:47])[N:25]=[CH:24]2
Reactant: CC(C)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Reactant: CN1CC[C@H](N)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCN(C)C3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 120.2 %

Procedure:
(S)-3-Amino-1-methylpyrrolidin-2-one hydrochloride (211 mg, 1.40 mmol) was dissolved in triethylamine (0.195 mL, 1.40 mmol) and dichloromethane (7 mL). To this, 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 651 mg, 0.677 mmol) was added, and the reaction was allowed to stir at ambient temperature for 16 hours. The crude reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 25% acetone/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Id) (360 mg, 58%). Mass spec: 443 (M+1). 1H NMR (CDCl3) δ 8.36 (s, 1H), 8.29 (br, 1H), 7.18 (m, 1H), 7.01 (m, 2H), 6.92 (m, 1H), 4.56 (ddd, 1H), 4.22 (d, 2H), 3.42 (m, 2H), 2.93 (s, 3H), 2.82 (m, 1H), 2.37 (m, 1H), 1.99 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:3]=12.CS(C)=O.[C:21]12([CH2:31][NH2:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.CS(O)(=O)=O.CO>O>[CH2:15]([N:12]1[C:4]2=[N:5][C:6]3[C:11]([C:2]([NH:32][CH2:31][C:21]45[CH2:30][CH:25]6[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]6)[CH2:28]4)[CH2:22]5)=[C:3]2[CH:14]=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:16]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC34CC5CC(CC(C5)C3)C4)c3ccccc3nc21
Temperature: 110 °C
Yield: 18.6 %

Procedure:
A mixture of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]quinoline (1 g), DMSO (3 ml) and adamantylmethylamine (1 g) was heated at 110° C. overnight. The reaction mixture was poured into water, and a precipitate formed which was collected by filtration and dried to afford the product as a free base. The free base was treated with methanesulfonic acid/methanol, the methanol was evaporated and the salt was recrystallized from 2-propanol to afford 290 mg of 1-ethyl-N-(adamantylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.CH3SO3H, m.p. 310° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]1([CH2:12][C@H:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=2)[C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1>O.CO>[CH:7]1([CH2:12][C@H:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([CH3:24])=[O:2])[CH:18]=2)[C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1cccc([C@@H](CC2CCCC2)C(=O)O)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1cccc([C@@H](CC2CCCC2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of sodium periodate (1.07 g, 4.98 mmol) in water (10 mL) was added a solution of (R)-3-cyclopentyl-2-(3-methylsulfanyl-phenyl)-propionic acid (700 mg, 2.65 mmol) in methanol (15 mL) and the reaction was stirred at 25° C. for 1 h. The reaction mixture was filtered through a pad of celite and the solids were washed with methanol and chloroform. The filtrate was concentrated and azeotroped with benzene to remove any traces of water to yield (R)-3-cyclopentyl-2-(3-methylsulfinyl-phenyl)-propionic acid as a white solid which was then dissolved into methanol (20 mL). To this stirred solution was slowly added potassium permanganate (630 mg, 3.98 mmol) in water (6 mL) and the reaction stirred at 25° C. for 1 h. The reaction mixture was filtered through a pad of celite and the solids washed with methanol. Concentrate the filtrate to yield (R)-3-cyclopentyl-2-(3-methylsulfonyl-phenyl)-propionic acid (705 mg, 90%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([C:23]2[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][C:24]=2[CH3:32])[CH:19]=[N:20][C:21]=1[Cl:22]>N1C=CC=CC=1>[Cl:22][C:21]1[N:20]=[CH:19][C:18]([C:23]2[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][C:24]=2[CH3:32])=[CH:17][C:16]=1[NH:15][S:11]([C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:13])=[O:12]
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3sc(NC(C)=O)nc3C)cnc2Cl)c(OC)c1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2,4-Dimethoxyphenylsulfonyl chloride (J. Med. Chem., 1977, 20, 1235; 376 mg) was added to a stirred solution of N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (150 mg) in pyridine (1.5 mL) and the resultant solution was heated at 50° C. for 16 hours. The mixture was cooled to room temperature and concentrated by evaporation. The residue was purified by preparative HPLC on Kromasil C18 reversed-phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent at a flow rate of about 10 mL/minute. The material so obtained was triturated under diethyl ether to give the title compound as a white solid (70 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 2.29 (s, 3H), 3.76 (s, 3H), 3.83 (s, 3H), 6.60 (m, 1H), 6.69 (d, 1H), 9.64 (d, 1H), 6.75 (d, 1H), 8.25 (br s, 1H), 9.80 (s, 1H); Mass Spectrum: M+H+ 483.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=1)=[O:7].O>C(O)(=O)C>[I:15][C:11]1[CH:10]=[C:9]([N:8]2[CH:3]=[CH:4][NH:5][C:6]2=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(CNC(=O)Nc1cccc(I)c1)OC
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]ccn1-c1cccc(I)c1
Temperature: 100 °C
Yield: 25.7 %

Procedure:
N(2,2-Dimethoxyethyl)-N′-(3-iodophenyl)urea (618 mg) was dissolved in acetic acid (10 ml) and water (1 ml) and the mixture was stirred at 20° C. for 17 h and then heated to 100° C. for 0.5 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with NaHCO3 solution, dried and purified by chromatography on 10 g silica Bond Elut cartridge eluting with EtOAc-petroleum ether (1:7 to 1:1) to give the title compound (130 mg) LCMS RT=2.66 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=1)[C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])#[N:7]
Reactant: CCCOC(=O)c1cccc(CCNC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: CCCOC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2g produced 3af. MS found M+H=481. The oxalate salt of 3af was recrystallized from ethyl acetate; mp 110-114° C.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22]COC)[CH:19]=[CH:18][C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]COC)=[CH:9][CH:8]=1.Cl.CO.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:3]=1[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COCOc1ccc(C=CC(=O)c2ccc(OCOC)cc2O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 50 °C
Yield: 70 %

Procedure:
Then, 1.0 g of 2'-hydroxy-4,4'-bis(methoxymethoxy)-chalcone was dissolved in 7 ml of tetrahydrofuran, and a 5-15% hydrochloric acid/methanol reagent was added to the solution and the mixture was heated at 50° C. for 30 minutes to effect a reaction. After the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 300 ml of ethyl acetate, and the ethyl acetate layer was washed with water (100 ml×3 times), shaken with a saturated aqueous solution of sodium chloride (50 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation, and the obtained residue was subjected to the silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate to obtain 521 mg (yield=70%) of 2',4,4'-trihydroxychalcone in the form of a yellow grain.