Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].Cl.C[O:39][C:40](=[O:44])[CH2:41][NH:42][CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.C(N(CC)CC)C.O.[OH-].[Li+].CO>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([C@H:30]4[CH2:35][CH2:34][C@H:33]([N:42]([CH3:43])[CH2:41][C:40]([OH:44])=[O:39])[CH2:32][CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C1CCC(=O)CC1
Reactant: CNCC(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: ClCCCl
Solvent: O
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1[C@H]1CC[C@H](N(C)CC(=O)O)CC1
Temperature: 50 °C

Procedure:
To a mixture of 4-[4-(3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]cyclohexanone (15.0 mg, 0.0290 mmol), sarcosine methyl ester hydrochloride (20.25 mg, 0.1451 mmol), sodium triacetoxyborohydride (12.30 mg, 0.05803 mmol) and 1,2-dichloroethane (4 mL, 50 mmol) was added triethylamine (14.68 mg, 0.1451 mmol), and the reaction was heated to 50° C. overnight. The material was partitioned between DCM and water, and the organic layer was concentrated in vacuo. Lithium hydroxide monohydrate (6.088 mg, 0.1451 mmol) and MeOH (2 mL, 50 mmol) were added, and the mixture was heated to 50° C. for 3 h. The solution was concentrated in vacuo, and the crude product was redissolved in minimal DMF. The solution was purified via HPLC, and the fractions containing the separate cis and trans products were concentrated in vacuo to afford the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.75-1.89 (m, 5H), 2.01-2.14 (m, 4H), 2.18-2.23 (m, 2H), 2.23 (s, 3H), 2.90 (s, 3H), 3.40 (tdd, J=12.0, 12.0, 3.1, 2.8 Hz, 1H), 3.65 (br. s., 2H), 4.22-4.34 (m, 1H), 5.06-5.14 (m, 1H), 6.43 (br. s., 1H), 7.12 (dd, J=8.3, 4.3 Hz, 1H), 7.18 (t, J=8.6 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.40 (d, J=1.3 Hz, 1H), 7.49 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). MS (ES+): m/z=590.14/592.17 (100/50) [MH+]. HPLC: tR=1.01 min (polar—2 min, UPLC-ACQUITY).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.C(N(CC)CC)C.Cl.[NH2:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([C:33]([O:35][CH3:36])=[O:34])=[C:29]([F:32])[CH:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:22]([C@H:23]1[C:31]3[C:26](=[CH:27][C:28]([C:33]([O:35][CH3:36])=[O:34])=[C:29]([F:32])[CH:30]=3)[CH2:25][CH2:24]1)[CH2:11]2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: COC(=O)c1cc2c(cc1F)[C@H](N)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(cc1F)[C@H](N1Cc3cccc(Cl)c3C1=O)CC2
Yield: 65 %

Procedure:
2-Bromomethyl-6-chlorobenzoic acid methyl ester (1.75 mmol, 1.0 eq) was dissolved in toluene (5.3 ml) and triethylamine (3.675 mmol, 2.1 eq), and (R)-methyl 1-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-05) (1.75 mmol, 1 eq) was added. The reaction mixture was refluxed for 16 h and then diluted with ethyl acetate and sat. NaHCO3 solution. The phases were separated, and the organic phase was washed with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:EA 2:1). Yield: 65%
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:12](=[O:18])[CH2:13][CH2:14][C:15]1([CH3:17])[CH2:10][C:9](=[O:11])[C:3]2[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=2[O:1]1)[CH3:21]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1(C)CC(=O)c2cc(O)ccc2O1
Yield: 64.2 %

Procedure:
Using the procedure of Example 1, 15 g of 2',5'-dihydroxyacetophenone was condensed with 14.2 g of ethyl levulinate and 12.3 ml of pyrrolidine, in 200 ml of toluene. The crude product (20.5 g) was purified by high pressure liquid chromatography (silica gel; 2:1 hexane-ethyl acetate) giving 17.6 g (64.1%) of racemic-3,4-dihydro-6-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester was a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:17][C:18]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[ClH:2].[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][N:4]=[C:3]2[NH:20][C:19]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:18]=1[F:17]
Reactant: Nc1cc(O)ccc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(O)ccc3F)c2cc1OC
Yield: 14.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline hydrochloride (342 mg, 1.3 mmol), and 2-fluoro-5-hydroxyaniline (183 mg, 1.4 mmol) in isopropanol (10 ml) were heated at reflux for 2 hours. The reaction mixture was allowed to cool, the precipitated product collected by filtration, washed with isopropanol and dried to give 6,7-dimethoxy4-(2-fluoro-5-hydroxyanilino)quinazoline hydrochloride (66 mg, 15%) as a solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>CN(C=O)C>[C:3]1([C:9]2[N:10]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1ccc(-c2nc(-c3ccncc3)c[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
60% Sodium hydride (200 mg, 5.0 mmol) was added slowly into a solution of 4-(2-phenyl-1H-imidazol-4-yl)pyridine (1.0 g, 4.5 mmol; Example 1, Step 1) in dry DMF (5 mL) at 0° C. The reaction mixture was stirred at rt for 1 h and re-cooled to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (SEM chloride; 0.88 mL, 0.83 g, 5.0 mmol) was added. The reaction was stirred at 10° C. for 2 h and quenched with water (40 mL). The mixture was partitioned and extracted with EtOAc (3×60 mL) and the organic layers were combined, dried (Na2SO4), and concentrated. The resulting residue was purified by flash chromatography (SiO2, 100:0-90:10 DCM-MeOH) to give 1.2 g (75%) of 4-(2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridine: 1H NMR (CDCl3) δ 8.61 (d, J=6.0, 1.2 Hz, 2H), 7.81 (d, J=8.0, 1.6 Hz, 2H), 7.74 (d, J=6.0, 1.2 Hz, 2H), 7.58 (s, 1H), 7.49 (m, 3H), 5.30 (s, 2H), 3.60 (t, J=8.0 Hz, 2H), 0.94 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[S:32][C:33]([C:36]#[N:37])=[CH:34][N:35]=2)[CH2:4]1)[CH3:2].O1CCOCC1.CCO.C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:31]2[S:32][C:33]([C:36]#[N:37])=[CH:34][N:35]=2)[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](Nc2ncc(C#N)s2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](Nc2ncc(C#N)s2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 50 °C
Yield: 61 %

Procedure:
A mixture of 2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile (0.21 g, 0.39 mmol), 1,4-dioxane (4.5 mL), EtOH (3.5 mL) and Na2CO3 (2 N aqueous, 5.8 mL, 15.7 mmol) was heated at about 50° C. for about 12 h. The reaction mixture was neutralized to pH 7 by the addition of AcOH (0.3 mL), washed with water (2×5 mL) and extracted with DCM (3×5 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give 2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-thiazole-5-carbonitrile (0.09 g, 60%): LC/MS (Table 1, Method c) Rt=1.95 min; MS m/z: 379 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C@H:15]1([OH:22])[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1.[H-].[Na+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:21][CH:18]2[CH2:19][CH2:20][CH:15]([OH:22])[CH2:16][CH2:17]2)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
4-Fluoro-1-nitro-2-trifluoromethyl-benz ene (11.5 mmol), trans-cyclohexane-1,4-diol (17.2 mmol), and sodium hydride (60% in oil, 11.5 mmol) are suspended in dry dimethylsulfoxide (20 mL) and the resulting mixture is reacted under stirring for 3 hours at 50° C. The reaction is allowed to reach room temperature and is then further reacted at this temperature overnight. The reaction is treated with water (20 mL), the precipitate formed is removed by filtration and the filtrate is extracted with dichloromethane (50 mL). The organic phase is washed with aqueous saturated ammonium chloride (10 mL), dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The precipitate is triturated with diethylether (20 mL), filtered and the filtrate concentrated under reduced pressure. Both fractions of crude product are combined, dissolved in dichloromethane and filtered trough a short pad of silica gel to afford the desired product (36% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])=[O:16])[CH2:6][CH2:5]2
Reactant: NCCOCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCOCCO)O2
Yield: 82.5 %

Procedure:
Following the amide coupling procedure described in protocol A, 501 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 360 mg CDI (2.23 mmol) and 231 mg 2-(2-aminoethoxy)ethanol (2.19 mmol) produced 557 mg of 6-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as an amorphous white solid.
Reaction SMILES: [N:1]1([C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:28]4[N:32]5[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]5=[N:30][CH:29]=4)=[CH:15][N:16]3S(C3C=CC=CC=3)(=O)=O)=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[N:1]1([C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:28]4[N:32]5[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]5=[N:30][CH:29]=4)=[CH:15][NH:16]3)=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(c1ccc2c(-c3cnc4ccc(F)cn34)cn(S(=O)(=O)c3ccccc3)c2c1)N1CCCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccc2c(-c3cnc4ccc(F)cn34)c[nH]c2c1)N1CCCCCC1

Procedure:
To a solution of example 133 (25 mg) in anhydrous THF (1 mL), a 1M solution of TBAF in THF (100 μL, 2.0 equiv.) was added. The reaction mixture was heated at reflux for 1 Hr, then was concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.[ClH:20].Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[CH2:26][CH2:25]1>>[ClH:20].[ClH:20].[OH:38][CH:35]1[CH2:34][CH2:33][N:32]([CH2:31][CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH2:3][C:2]([CH3:1])([CH3:19])[CH3:18])[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:29][CH2:28]2)[CH2:37][CH2:36]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: CC(C)(C)CCOc1cccc2[nH]c(C(=O)O)cc12
Agent: Cl
Product: CC(C)(C)CCOc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3,3-dimethyl-butoxy)-1H-indole-2-carboxylic acid (92) (preparation see below) and amine 21.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5]N(C)C=O.[Cl:10][C:11]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:12]=1[C:13]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][C:22]([CH2:26][OH:27])=[C:21]2[N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:14].[Na]>CO>[Cl:10][C:11]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:12]=1[C:13]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][C:22]([CH2:26][O:27][CH3:5])=[C:21]2[N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:14]
Reactant: CN(C)C=O
Reactant: O=C(Nc1cccc2c(-n3ccnc3)c(CO)cnc12)c1c(Cl)cccc1Cl
Agent: [Na]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Reaction time: 0.17 h

Procedure:
Thionyl chloride (52.8 mg) was dropwise added to dimethylformamide at ambient temperature, and the mixture was stirred for 10 minutes at the same temperature. To the mixture was added 8-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-4-(imidazol-1-yl)quinoline (141 mg), and the mixture was stirred for 20 minutes at ambient temperature. The mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The obtained residue was dissolved in dichloromethane-methanol, and the solution was added to a solution of sodium methoxide, which was prepared by adding sodium (17.3 mg) to dry methanol (1.5 ml) and then stirring for 15 minutes at ambient temperature. The mixture was stirred for 3 hours at 40° C. The mixture was partitioned between saturated ammonium chloride solution and ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography to give 8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)-3-(methoxymethyl)quinoline (55 mg).
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(S(F)(F)[F:28])CC)C>ClCCl>[F:28][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Solvent: ClCCl
Product: CC(C)(F)c1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one (55.8 mg, 0.20 mmol) in dichloromethane (0.5 ml) is cooled to −78° C. Diethylaminosulfurtrifluoride (105 μl, 0.80 mmol) is added. The reaction mixture is allowed to reach room temperature within 30 minutes (formation of a clear solution). The reaction mixture is evaporated and the residue is treated with water and saturated sodium hydrogen carbonate solution. The solids are filtered off and chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 3-[4-(1-fluoro-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one as fine white powder; HPLC/MS 1.94 min (A), [M+H] 282;
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)=[O:20].[F:29][C:30]([F:35])([F:34])[C:31]([CH3:33])=[O:32].[NH4+].[Cl-]>O1CCCC1>[F:29][C:30]([F:35])([F:34])[C:31]([OH:32])([CH3:33])[C:28]#[C:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: C#Cc1ccc(C(=O)c2ccccn2)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(C#Cc1ccc(C(=O)c2ccccn2)cc1)C(F)(F)F
Reaction time: 0.42 h
Yield: 1.1 %

Procedure:
To 150 mL tetrahydrofuran was added diisopropylamine (2.4 g), and the mixture was then cooled to -78° C. n-Butyl-lithium was added (8.1 mL, 2.5 molar solution in hexanes). To this mixture was added a solution which had been prepared by dissolving 4-(2-pyridylcarbonyl) phenyl ethyne (3.5 g) in a few mL tetrahydrofuran. The mixture was allowed to stir for 25 minutes. 1,1,1-trifluoroacetone (4.76 g) was added in one portion and the mixture was stirred for 15 minutes. The reaction mixture was then poured into 30 mL aqueous saturated NH4Cl. The ensuing mixture was extracted with 3×300 mL diethyl ether. The organic layers were combined, dried over MgSO4, filtered and evaporated to dryness. The oily residue was chromatographed on silica gel eluting with 80/20 hexane/ethyl acetate. The appropriate fractions were combined and evaporated to dryness. The remaining solid was recrystallized from diethyl ether-hexanes to yield 60 mg of the title compound; mp 116°-118° C.; (300 MHz, (CDCl3): 1.74 (s,3, methyl), 2.79 (s,1, OH), 7.49-7.53 (m,2, aromatic), 7.54-7.58 (d,2, aromatic), 7.89-7.95 (t,1, aromatic), 8.06-8.09 (d,2, aromatic), 8.71-8.73 (d,1, aromatic); Analysis for C17H12F3O2N: Calculated: C, 63.95; H, 3.79; N, 4.39; Found: C, 63.96; H, 3.97; N, 4.38.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[S:15][C:14]2[N:9]([C:10](=[O:20])[N:11]([CH2:17][CH2:18][CH3:19])[C:12](=[O:16])[CH:13]=2)[CH2:8]1>C(Cl)Cl>[Cl:3][CH2:6][CH:7]1[S:15][C:14]2[N:9]([C:10](=[O:20])[N:11]([CH2:17][CH2:18][CH3:19])[C:12](=[O:16])[CH:13]=2)[CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: CCCn1c(=O)cc2n(c1=O)CC(CO)S2
Solvent: ClCCl
Product: CCCn1c(=O)cc2n(c1=O)CC(CCl)S2
Temperature: 25 °C
Yield: 84 %

Procedure:
Thionyl chloride (0.61 ml)was added dropwise to a solution of 2-hydroxymethyl-6-propyl-2,3-dihydro-5H-thiazolo[3,2-c]pyrimidine-5,7(6H)-dione (1 g) in methylene chloride (15 ml) with stirring at room temperature, and the solution was refluxed for 16 hours. The solution was concentrated to dryness, and the resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystalized from methylene chloride-isopropyl ether to give colorless crystals (0.9 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]3[CH2:13][C:14]4([CH2:19][CH:10]3[CH2:9]2)[O:18][CH2:17][CH2:16][O:15]4)=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CC(C)=O>[CH2:31]([O:30][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH:10]3[CH2:19][C:14]4([CH2:13][CH:11]3[CH2:12]2)[O:15][CH2:16][CH2:17][O:18]4)=[C:4]([F:20])[CH:3]=1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.2 %

Procedure:
2-(4-amino-2-fluorophenyl)-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] (74.7 mmol) prepared in the step 5 was dissolved in 300 ml of acetone, and 150 ml of a 10 wt % sodium carbonate aqueous solution was added. And then, the temperature was lowered to 0° C., 13.86 ml (97.1 mmol) of benzyl chloroformate was slowly added dropwise over 30 minutes, and the mixture was stirred for 12 hours while raising the temperature to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, 300 ml of ethyl acetate was added, the mixture was washed with water and sodium chloride, and then, the organic layer was dried over magnesium sulfate and filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 24.1 g (78%) of the title compound, of which NMR data is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31]C(=O)C(C)(C)C)=[CH:27][CH:26]=3)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][C:4]=1[CH3:38].O[Li].O.C1COCC1>O>[OH:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH3:38])[CH:5]=3)[O:10][C:9](=[O:13])[C:8]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)=[CH:26][CH:27]=1
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(O)cc3)c2cc1C
Yield: 64.9 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 4-(7-methoxy-6-methyl-2-oxo-3-(4-trifluoromethyl-phenyl)-2H-chromen-4-ylmethyl)-phenyl ester (72 mg, 0.14 mmol) and LiOH.H2O (23 mg, 0.55 mmol) in an 8:1 mixture of THF:H2O (4.5 mL) was stirred at 30° C. for 4 h. THF was removed in vacuo and AcOEt was added. The pH of the aqueous layer was lowered to 5 by addition of aqueous 1N HCl. The layers were separated and the aqueous phase was extracted with AcOEt (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified using flash chromatography (99:1 CH2Cl2:MeOH) to provide the desired compound as a beige solid (40 mg, 67%). 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.25 (d, J=1.0 Hz, 1H), 6.92–6.86 (m, 2H), 6.82 (s, 1H), 6.75–6.69 (m, 2H), 3.95 (s, 2H), 3.90 (s, 3H), 2.16 (s, 3H); MS (ESI) m/z 440.9 (M+H)+; HPLC tR 6.50 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:28])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[BH4-].[Na+]>O1CCCC1.CO.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([OH:28])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(OCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(O)COc3ccc(C(=O)O)cc3)ccc21
Yield: 76 %

Procedure:
2.1 g (5 mmol) of 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-(4-ethoxycarbonylphenoxy)ethanone (from Example 5) in 100 ml of tetrahydrofuran/methanol (2:1) were stirred with 0.4 g (10 mmol) of sodium borohydride at room temperature for 30 min; the reaction solution was poured into saturated brine and extracted with ethyl acetate; the extracts were washed with water, dried over magnesium sulfate and evaporated to provide an oily residue which was subjected to alkaline hydrolysis as described in Example 6 and yielded after appropriate working up 1.4 g of the title compound; melting point (cyclohexane): 160°-162° C.