Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:12](=[O:24])[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25][O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>CN(C=O)C>[CH3:25][O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[C:12]1=[O:24]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
The product is produced as described in example 1 from 1.41 g of NaH (80% suspension in mineral oil), 14.3 g of 5-phenyl-1-(3-trifluoromethylphenyl)-4-imidazolin-2-one, 100 cc. of DMF, 11.1 g of 8-bromocaprylic acid methyl ester and 1.41 g of NaJ.
Reaction SMILES: Br[C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.[Li][CH2:13]CCC.BrC[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C1COCC1>[O:21]([CH:20]([CH3:19])[CH2:13][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1)[Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: [Li]CCCC
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Solvent: C1CCOC1
Product: CC(Cc1c[nH]c2ncnc(Cl)c12)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
A suspension of compound 2.2 (10.0 g, 43.0 mmol) in THF (140.0 mL) was cooled to −78° C. under an argon atmosphere and n-BuLi (1.6M in hexanes, 67.3 mmol) was then added via syringe over 1.5 hr. The resulting suspension was stirred for the next 30 min at −78° C. then (3-bromopropoxy)-tert-butyldimethylsilane (21.4 mL, 172.0 mmol) was slowly added via syringe at −78° C. over 1 hr. The reaction mixture was allowed to slowly reach −30° C. and stirred for the next 2 h, and −30 to 10° C. for 1 h, and −10 to 0° C. for 1 hr. The reaction mixture became dark brown in color, and was kept at 4° C. overnight. The reaction was quenched by adding aqueous NH4Cl (100 mL), and diluted with CH2Cl2 (600 mL) and water (120 mL) then extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and evaporated. The beige colored residue was purified by flash column chromatography using 25% EtOAc in hexanes as eluent to give the desired compound 4.1 (5.5 g) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6](=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)[CH3:3].[Cl:27][C:28]1[N:33]=[C:32](Cl)[C:31]([I:35])=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:27][C:28]1[N:33]=[C:32]([NH:1][C@H:2]([C:4]2[N:5]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:6](=[O:20])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[CH3:3])[C:31]([I:35])=[CH:30][N:29]=1
Reactant: C[C@H](N)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Reactant: Clc1ncc(I)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(Cl)ncc1I)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(S)-3-(1-Aminoethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (63) (570 mg, 1.66 mmol), 2,4-dichloro-5-iodopyrimidine (455 mg, 1.66 mmol) and DIEA (0.27 mL, 1.66 mmol) were dissolved in n-butanol (12 mL) in a sealed tube, and the resulting mixture was stirred at 100° C. for 16 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate (150 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the product (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1(2H)-one (64) as an oil. The product obtained was used in the next step without purification. ESI-MS m/z: 583.0 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([OH:11])=[C:7]([CH:10]=1)C#N)=[O:2].[OH:15][C:16]1C=CC(C=O)=C[C:17]=1[O:24]CCO>>[OH:11][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([CH:1]=[O:2])=[CH:10][C:7]=1[O:15][CH2:16][CH2:17][OH:24]
Reactant: N#Cc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=Cc1ccc(O)c(OCCO)c1
Product: O=Cc1cc(OCCO)c(O)c([N+](=O)[O-])c1

Procedure:
Followed procedure described for Intermediate 61, starting from the 4-hydroxy-3-(2-hydroxyethoxy)benzaldehyde to give desired product, Intermediate 71.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:3][CH:2]=1.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:15][N:14]=2)[CH3:12])=[O:9])=[CH:5][CH:6]=1
Reactant: Fc1ccccn1
Reactant: C[C@@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)Cc1ccc(-c2ccccc2)cc1)c1ccc(Oc2ccccn2)cn1
Temperature: 130 °C

Procedure:
To a mixture of 2-(1,1′-biphenyl-4-yl)-N-[(1R)-1-(5-hydroxypyridin-2-yl)ethyl]acetamide (40 mg, 0.12 mmol) and 2-fluoropyridine (31 μL, 0.36 mmol) in DMF (3.0 ml) was added cesium carbonate (137 mg, 0.42 mmol). The reaction was heated to 130° C. for 30 minutes. An additional amount of 2-fluoropyridine (31 μL, 0.36 mmol) was added and the mixture heated for one hour at 130° C. The reaction was cooled, washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give an oil. Reverse phase prep HPLC chromatography afforded the mono-trifluoroacetate salt of 2-(1,1′-biphenyl-4-yl)-N-{(1R)-1-[5-(pyridine-2-yloxy)pyridine-2-yl]ethyl}acetamide as a yellow oil. 1H NMR (CD3OD, 400 MHz) δ 8.61 (s, 1H, 8.11 (dd, J=1.60 and 4.80 Hz, 1H); 8.01 (dd, J=2.80 and 8.80 Hz, 1H); 7.89 (m, 1H); 7.71 (d, J=8.80 Hz, 1H); 7.56 (m, 4H); 7.38 (m, 5H); 7.18 (m, 1H); 7.12 (d, J=8.40 Hz, 1H); 5.12 (m, 1H), 3.63 (s, 2H), 1.58 (d, J=7.20 Hz, 3H). HRMS (ES) exact mass calcd for C26H23N3O2: 410.1863, Found: 410.1873
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1([CH3:25])[CH2:24][CH2:23]1)=O)(=O)OC.O.[NH2:27][NH2:28]>>[CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4]1[C:3]2=[N:27][N:28]=[C:20]([C:22]2([CH3:25])[CH2:24][CH2:23]2)[CH:19]=1
Reactant: COP(=O)(CC(=O)C1(C)CC1)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Solvent: O
Product: CC1(c2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)CC1

Procedure:
light yellow oil. MS (ESI): 243.2 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo [2.2.1]heptane-2,3-dione, [2-(1-Methyl-cyclopropyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[C:16]([C:18]([N:62]3[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]3)=[O:20])[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.8 %

Procedure:
To a dichloromethane (5 ml) solution of 6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]picolinic acid (130 mg, 0.307 mmol) were added N-methylmorpholine (41 μl, 0.368 mmol), 1-hydroxybenzotriazole (13 mg, 0.368 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.368 mmol) and 1-methylpiperazine (40 μl, 0.368 mmol). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give the title compound (40 mg, 0.0791 mmol, 26%) as a white amorphous substance.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18]([S:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:17]2[C:12]([N:13]([CH:27]([CH3:29])[CH3:28])[C:14](=[O:26])[N:15]([CH3:25])[C:16]2=[O:24])=[CH:11]1.S([O-])(O[O-])(=O)=[O:31].[K+].[K+].OOS([O-])=O.[K+]>CO.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[C:18]([S:19]([CH2:20][CH2:21][CH2:22][OH:23])=[O:31])=[C:17]2[C:12]([N:13]([CH:27]([CH3:29])[CH3:28])[C:14](=[O:26])[N:15]([CH3:25])[C:16]2=[O:24])=[CH:11]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)n1c(=O)n(C)c(=O)c2c(SCCCO)n(C3Cc4ccccc4C3)cc21
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)n1c(=O)n(C)c(=O)c2c(S(=O)CCCO)n(C3Cc4ccccc4C3)cc21
Reaction time: 0.25 h

Procedure:
6-(2,3-Dihydro-1H-inden-2-yl)-5-[(3-hydroxypropyl)thio]-3-methyl-1-(1-methylethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg) was dissolved in methanol (40 ml). Water (10 ml) and potassium peroxymonosulphate (commercially sold under the trade mark “OXONE”) (185 mg) were added and the solution was stirred for 15 minutes. The reaction mixture was diluted with water and then extracted with ethyl acetate thrice. The extracts were combined, washed with brine, then dried, filtered and the solvent was evaporated. The resultant oil was triturated with isohexane, then recrystallised from ethyl acetate-isohexane mixtures to give the title compound (15 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:13]([NH:18][CH2:19][C@H:20]([C@H:22]2[C@H:29]3[C@H:25]([O:26][C:27]([CH3:31])([CH3:30])[O:28]3)[CH2:24][CH2:23]2)[OH:21])=[N:14][CH:15]=[CH:16][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:13]([NH:18][CH2:19][C:20]([C@H:22]2[C@H:29]3[C@H:25]([O:26][C:27]([CH3:31])([CH3:30])[O:28]3)[CH2:24][CH2:23]2)=[O:21])=[N:14][CH:15]=[CH:16][N:17]=1
Reactant: CC1(C)O[C@H]2[C@H]([C@H](O)CNc3nccnc3Cl)CC[C@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1(C)O[C@@H]2[C@@H](CC[C@H]2C(=O)CNc2nccnc2Cl)O1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (2.75 mL, 31.6 mmol, 3.0 equiv) in DCM (35 mL) was added dropwise to DMSO (3.00 mL, 42.1 mmol, 4.0 equiv) in DCM (35 mL) at −78° C. After 30 minutes, (S)-2-(3-chloropyrazin-2-ylamino)-1-((3aS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclo-penta[d][1,3]dioxol-4-yl)ethanol (2-7) (3.30 g, 10.5 mmol, 1 equiv) in DCM (35 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 hour, at which point triethylamine (6.60 mL, 47.3 mmol, 4.5 equiv) was added. The cooling bath was removed, and after 30 minutes the reaction mixture was concentrated. The resulting yellow residue was purified via flash chromatography on a silica gel column (ethyl acetate/hexanes) to yield 2-(3-chloropyrazin-2-ylamino)-1-((3aS,4R,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl)ethanone (2-8) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.92 (d, J=2.7 Hz, 1H); 7.63 (d, J=2.7 Hz, 1H); 5.93 (s, 1H); 4.80 (d, J=5.7 Hz, 1H); 4.73 (t, J=5.4 Hz, 1H); 4.47 (dd, J=19.7, 5.0 Hz, 1H); 4.31 (dd, J=19.7, 4.7 Hz, 1H); 3.17 (d, J=8.1 Hz, 1H); 2.25-2.17 (m, 1H); 1.93-1.84 (m, 2H); 1.78-1.68 (m, 1H); 1.47 (s, 3H); 1.32 (s, 3H). LRMS m/z (M+H) 312.0 found, 312.1 required.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Br[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC[C@@H]1CCCN1CCNC(=O)OC(C)(C)C
Temperature: 85 °C

Procedure:
A suspension comprising (S)-2-(methoxymethyl)pyrrolidine (1 g, 8.68 mmol), tert-butyl 2-bromoethylcarbamate (1.946 g, 8.68 mmol), triethylamine (1.210 ml, 8.68 mmol) and potassium carbonate (1.200 g, 8.68 mmol) in MeCN (10 ml) was heated at 85° C. overnight. The resulting mixture was filtered and washed with MeCN. Purification of the crude product by chromatography on silica eluting with 0-5% MeOH in DCM afforded the title compound as a colourless oil;
Reaction SMILES: [Cl:1]C(Cl)C.S(Cl)(Cl)=O.[CH3:9][C:10]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:11]=1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>CN(C)C=O>[CH3:9][C:10]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:11]=1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([Cl:1])=[O:17]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)O)c1
Reactant: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)Cl)c1

Procedure:
Dichloroethane (20 ml), thionyl chloride (1.31 g, 0.011 mol) and dimethylformamide (0.1 ml) were added to 2-(2,5-dimethylphenoxymethyl)benzoic acid (2.56 g, 0.01 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride. 1.6M n-butyllithium/n-hexane solution (6.25 ml, 0.01 mol) was added to a mixture of 1-methylpyrazole (0.99 g, 0.012 mol) and THF (10 ml) at −70 to −60° C. over 15 minutes, and then the mixture was stirred at −70° C. to room temperature for 1 hour. The reaction mixture was cooled to −70° C., and a solution of the crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride in THF (10 ml) was added, and the mixture was stirred at −70° C. for 1 hour. After completion of the reaction, 1N hydrochloric acid (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.50 g, 15.6%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12](N(CC)CC)[CH3:13].ICC>CN(C=O)C>[CH2:12]([S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10])[CH3:13]
Reactant: O=S(O)c1ccc(F)c(F)c1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCI
Product: CCS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 90 °C

Procedure:
To 3.0 mmol 3,4-difluoro-benzenesulfinic acid and 3.0 mmol triethylamine in 10 ml DMF was added 7.5 mmol iodoethane and the mixture heated at 90° C. for 9 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:7) to afford the title compound. MS (m/e): 206.9 (M+H+, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[S:11])[CH2:5]2.Br[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:19])[C:14](OCC)=[O:15].[OH-].[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C:14](=[O:15])[C:13]([CH3:19])([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:11][C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Reactant: Oc1ccc2c(c1)CC(=S)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccccc2)Sc2cc3cc(O)ccc3n2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution (13 ml) of 1,3-dihydro-5-hydroxyindol-2-thione (1.26 g) and ethyl 2-bromo-2-phenylpropionate (1.88 g) in DMF, an aqueous 2N sodium hydroxide solution (7.3 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, made acidic by adding 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and a saturated aqueous sodium chloride solution, and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (diluting solvent: methylene chloride) to give 1.77 g (yield: 81/9 %) of 7-hydroxy-2-methyl-2-phenylthiazolo[3,2-a]indol-3(2H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([O:20]CC)=[O:19])[CH3:2].[Li+].[OH-]>CCO.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
A mixture of ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.196 mol) and LiOH (30 g, 0.6 mol) in EtOH (200 mL) and water (100 mL) was stirred at ambient temp (˜25° C.) for 16 h. The mixture was concentrated to remove EtOH. The residue was diluted with water (300 mL). The mixture was extracted with EtOAc (100 mL) to remove the impurity. The pH was adjusted with 37% HCl to pH<2. The mixture was extracted with EA (3×300 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated to remove EtOAc. Petroleum ether (PE) (200 mL) was added. The resultant precipitate was collected by filtration, washed with PE and dried to afford 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid. (43 g, 78.9% yield). 1H-NMR (400 MHz, DMSO-d4): δ 7.95 (d, J=8.0 Hz, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 6.58 (d, J=7.6 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12].N1C=CC=CC=1>>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11](=[O:8])[O-:12])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CCCC(O)C1
Solvent: c1ccncc1
Product: CC1(C)CCCCC1
Product: O=C([O-])Oc1ccc([N+](=O)[O-])cc1

Procedure:
The product from Example 5, Step 1 was prepared as described above in Example 3, Step 1 starting with 3,3-dimethyl cyclohexanol (1.07 mmol), 4-nitrophenyl chloroformate (1.18 mmol) and pyridine (1.18 mmol).1H-NMR (CDCl3): 8.3 (d, 2H); 7.4 (d, 2H); 4.85 (m, 1H); 2.1 (m, 1H); 1.1-1.8 (m, 7H); 1.05 (s, 3H); 0.95 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:23]([CH3:33])[CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1.CO.CS(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:23]([CH3:33])[CH:22]=2)(=[O:20])=[O:19])=[C:7]([CH3:16])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1OCCC(=O)O
Reactant: CCCCc1ccc(NCC(C)C)c(C)c1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CO
Product: CCCCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCC(=O)O)c(C)c2)c(C)c1
Reaction time: 2 h
Yield: 37 %

Procedure:
To (4-butyl-2-methylphenyl)(2-methylpropyl)amine (21.94 mg, 0.100 mmol, prepared, for example, according to P2, Table 1) in pyridine (1 mL) was added 3-{[4-(chlorosulfonyl)-2-methylphenyl]oxy}propanoic acid (27.9 mg, 0.100 mmol) and left to stand at RT in air for 2 hours. The sample was dissolved in a 1:1 mixture of MeOH and DMSO and was purified by method A (see Table 8) using Waters Xbridge Shield RP18 column. Yield 37%. LCMS (M+1) 462, RT 1.46 mins.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:46](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:46][N:32]1[C@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])=[O:42]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (893 mg) was dissolved in 80 mL dry dioxane and 133 mg paraformaldehyde and 20 mL trifluoroacetic acid were added. The reaction stirred 12 h at rt, then 66 mg more paraformaldehyde was added while stirring at rt. After 3 h aqueous NaHCO3 was added until a pH of 7 was achieved, then the mixture was extracted with EtOAc. The organic extract was washed with brine and dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 872 mg desired product after drying. 1H NMR (400 MHz, acetone-d6): 7.72 (d, 1H), 7.62 (d, 1H), 7.51-7.43 (m, 3H), 7.38-7.25 (m, 5H), 7.10 (m, 2H), 6.67 (s, 1H), 6.60 (s, 1H), 5.20 (s, 2H), 5.09 (m, 1H), 4.30 (m, 1H), 4.13 (m, 2H), 3.99 (m, 1H), 3.92 (m, 1H), 3.59 (m, 1H), 3.52 (s, 3H), 2.96-2.78 (m, 2H), 2.16 (m, 1H), 1.68 (m, 1H), 0.65 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].Cl[CH2:27][O:28][C:29]([N:31]1[CH2:41][CH2:40][CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:27][O:28][C:29]([N:31]2[CH2:41][CH2:40][CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:32]2)=[O:30])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8]
Reactant: CCOC(=O)C1CCN(C(=O)OCCl)CC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Product: CCOC(=O)C1CCN(C(=O)OCOc2ccc(Cl)cc2C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Yield: 65.7 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt (compound of Example 43(1)) and ethyl 1-[(chloromethoxy)carbonyl]isonipecotate as the raw materials, the same operation as the Example 98 gave the title compound.