Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:6]([CH3:31])[C:7]3[C:12]([N:13]=2)=[C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:10]=[C:9]([N:20]2[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]2[CH2:29][CH3:30])[N:8]=3)[CH2:2]1.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:29]([C:21]1[N:20]([C:9]2[N:8]=[C:7]3[C:12]([N:13]=[C:5]([CH:3]4[CH2:2][N:1]([CH:35]5[CH2:36][CH2:37][O:32][CH2:33][CH2:34]5)[CH2:4]4)[N:6]3[CH3:31])=[C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:10]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH3:30]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CNC3)n(C)c2n1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CN(C4CCOCC4)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 4-(8-(azetidin-3-yl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine 680 (100 mg, 0.24 mmol), tetrahydropyran-4-one (34 mg, 0.33 mmol) and 4 Å powdered molecular sieves (130 mg) in DCE (3 mL) was stirred for 5.5 h before the addition of sodium triacetoxyborohydride (101 mg, 0.48 mmol). The resulting mixture was allowed to stir for 16 h at r.t, then filtered through Celite®, washing with DCM. The filtrate was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-30%) followed by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting solid was triturated with EtOAc affording 747 as a white powder (37 mg, 31%). LCMS (method I): RT 2.46 min, [M+H]+ 503.1. 1H NMR (CDCl3, 400 MHz): δ 8.01-7.97 (1 H, m), 7.75-7.74 (1 H, m), 7.26 (2 H, s), 4.37 (4 H, s), 4.02-3.80 (9 H, m), 3.70 (3 H, s), 3.51-3.37 (4 H, m), 3.34 (2 H, q, J=7.48 Hz), 2.41-2.33 (1 H, m), 1.77-1.66 (3 H, m), 1.43 (4 H, t, J=7.47 Hz)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:17][CH:16]([OH:18])[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CC(C)=O.CS(C)=O>C(OCC)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:15][C:16](=[O:18])[CH2:17]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc3nc(N4CC(O)C4)sc3c2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC(C)=O
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cn1cc(-c2ccc3nc(N4CC(=O)C4)sc3c2)cn1
Temperature: 25 °C

Procedure:
A suspension of 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-ol (Reference Example 2, 0.143 g, 0.50 mmol) and Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, CAS #87413-09-0, 0.636 g, 1.50 mmol) was stirred in 15:1 acetone/dimethyl sulfoxide (15 mL/1 mL). The reaction mixture was heated to near reflux for 4 hours, then additional Dess-Martin periodinane (0.212 g, 0.50 mmol) was added. The reaction was cooled to room temperature after an additional 3 hours of heating at near reflux. The reaction mixture was diluted with diethyl ether (15 mL) and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to remove all but the dimethyl sulfoxide. This residue was partitioned between 9:1 CH2Cl2/hexane (20 mL) and water (10 mL). The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (90:10 to 40:60 CH2Cl2/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to give a gummy solid, which after trituration with diethyl ether, provided 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-one as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 3.95 (s, 3H), 5.00(s, 4H), 7.46 (dd, J=2, 8 Hz, 1H), 7.59 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.74 (d, J=2 Hz, 1H), 7.75 (s, 1H); MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:5]=2[N:6]=1.[C:14](ON=O)([CH3:17])(C)[CH3:15].[Br-].COC1C(C)=CC2N=C(N)SC=2C=1>C(#N)C>[CH:17]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[CH:7][C:5]=3[N:6]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)ON=O
Reactant: COc1cc2sc(Br)nc2cc1C
Agent: COc1cc2sc(N)nc2cc1C
Agent: [Br-]
Solvent: CC#N
Product: COc1cc2sc(C3CC3)nc2cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Preparation of (2-bromo-6-methoxy-5-methylbenzo[d]thiazole (6A): To a solution of t-butylnitrite (5.17 ml, 43.5 mmol) in acetonitrile (50 ml) was added coppeer (II) bromide (7.2 g, 32.2 mmol) slowly. The reaction mixture was stirred at room temperature for half hour. Then the reaction mixture was put to a 60° C. oil bath and 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A) (4.2 g, 21.76 mmol) was added slowly. The reaction mixture was stirred at 60° C. for 1 h. The reaction was cooled to room temperature; washed with water and extracted with EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes. LCMS-ESI+: calc'd for C9H8BrNOS: 257.9 (M+H+). Found: 258.0 (M+H+).
Reaction SMILES: C([Si](CC)(CC)[O:4][CH2:5][CH2:6][C:7]#[C:8][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])C.Cl.CCCCCC.O>CO>[CH2:14]([Si:9]([CH2:10][CH3:11])([CH2:12][CH3:13])[C:8]#[C:7][CH2:6][CH2:5][OH:4])[CH3:15]
Reactant: CC[Si](C#CCCO[Si](CC)(CC)CC)(CC)CC
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: CC[Si](C#CCCO)(CC)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
Triethyl(4-(triethylsilyl)but-3-inyloxy)silane (32.99 g, 110.66 mmole) was dissolved in MeOH (336 ml), 2N HCl (62 ml) was added, and the mixture was stirred for 4 hours at RT. Hexane (250 ml) and H2O (200 ml) were then added to the solution and the aqueous phase was extracted with hexane (3×100 ml). The combined organic phases were washed with H2O (100 ml) and then with saturated NaCl-Solution (50 ml) and dried over MgSO4. After filtering off the drying agent the solvents were removed on a rotary evaporator. Column chromatography of the residue (hexane/ether=4:1, then ether) yielded 4-(triethylsilyl)but-3-in-1-ol (19.6 g, 96%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[CH:26]1([C:31]([O:10][C:9]2[C:8]([F:11])=[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]([CH3:18])=[C:3]([C:4]#[N:5])[C:2]=2[NH2:1])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C#N)c(N)c(OC(=O)C2CCCC2)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Under nitrogen atmosphere, 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (200 mg, 0.83 mmol) was dissolved in acetonitrile (10 ml), and cooled at 0° C. Triethylamine (138 μl, 1.36 mmol) and cyclopentanecarbonyl chloride (138 μl, 1.36 mmol) were dropwise added to the solution, followed by stirring at room temperature for 2 hours. 10% citric acid was added to the reaction liquid, and the solvent was evaporated away under reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (ethyl acetate:n-hexane=1:3, v/v) to obtain the entitled compound (200 mg, 72%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A solution of 22.2 g of 2-bromopyridine in 100 ml of THF is cooled to −70° C., 87.8 ml of n-butyllithium are added dropwise and the mixture is stirred for 30 minutes. A solution of 25.6 g of 1-benzyl-4-piperidinone in 100 ml of THF is then added dropwise at −60° C., and the mixture is stirred overnight while allowing the temperature to rise to rt. The reaction mixture is poured into water and extracted with ether, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H gel, eluting with DCM and then with a DCM/MeOH mixture gradient of from (99/1; v/v) to (90/10; v/v). 21.5 g of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:18][O:19][CH:20]([O:26][CH3:27])[CH2:21][C:22](OC)=[O:23].C[O-].[Na+].[Na]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:21]([CH:20]([O:26][CH3:27])[O:19][CH3:18])[C:22]2=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)CC(OC)OC
Reactant: O=Cc1cccnc1Nc1cc(Cl)cc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: COC(OC)c1cc2cccnc2n(-c2cc(Cl)cc(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
A solution of 42.7 g of 2-(3,5-dichlorophenyl)aminonicotinaldehyde, prepared in Example 29, in 500 ml of tetrahydrofuran containing 35.6 g of methyl 3,3-dimethoxypropionate, and a solution of sodium methylate prepared from 5.5 g of sodium in 100 ml of methanol, are stirred for 24 h at room temperature. The reaction mixture is subsequently concentrated under vacuum, water is then added and the crystals formed are filtered off, washed carefully with water and dried to give 44.25 g of 1-(3,5-dichlorophenyl)-1,2-dihydro-3-dimethoxymethyl-2-oxo-1,8-naphthyridine in the form of white crystals melting at 190° C. Yield 75.7%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:23][O:24][CH2:25]Cl.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[N:10]([CH2:23][O:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: COC(=O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1nc(-c2cccc(F)c2)c2cc(C(=O)OC)ccc21
Reaction time: 0.5 h

Procedure:
A total of 1.0 g of methyl 3-(3-fluorophenyl)-1H-5-indazolecarboxylate obtained in Production Example I-4-e was dissolved in 15 ml of N,N-dimethylformamide, and 200 mg of sodium hydride (60% oily) was added under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added 0.4 ml of chloromethyl methyl ether, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.95 g of methyl 3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolecarboxylate as colorless needles. This compound was dissolved in 15 ml of tetrahydrofuran, and 8.0 ml of a solution of diisobutylaluminum hydride in toluene was added dropwise at room temperature. While cooling the reaction mixture, water was added. The mixture was acidified with diluted hydrochloric, and extracted with ethyl acetate for two times. The organic layer was washed with sodium hydrogencarbonate and water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 0.78 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[C:14]([C:15]3[O:16][C:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)=[CH:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]1([C:18]2[N:19]=[C:15]([C:14]3[CH:9]([CH2:8][C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=4)[O:1][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:10][CH2:11][CH2:12][CH:13]=3)[O:16][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
A suspension of 2-[6-[(3-hydroxyphenyl)methyl]-1-cyclohexen-1-yl]-4,5-diphenyloxazole (885 mg), ethyl bromoacetate (399 mg), and potassium carbonate (360 mg) in N,N-dimethylformamide was stirred at room temperature for 3 days and partitioned between ethyl acetate and water. The organic layer was separated, washed with water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (n-hexane--ethyl acetate (20:1)) to afford ethyl [3-[[2-(4,5-diphenyl-2-oxazolyl)-2-cyclohexen-1-yl]methyl]phenoxy]acetate (847 mg) as a solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][NH:22][CH2:23]4)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:30]([OH:32])=[O:31].[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:22]1[CH2:21][CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:15]2[N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[C:6]([C:7]#[N:8])[CH:9]=3)[O:17][N:16]=2)[CH2:23]1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNC4)no2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-[(1-methylethyl)oxy]-5-[3-(1,2,3,4-tetrahydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 3, 28.8 mg, 0.080 mmol), ethyl bromoacetate (35.5 μl, 0.32 mmol) and Cs2CO3 (130 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature for 1 h, and then irradiated to 60° C. for 5 min in the microwave. The suspension was added to an SCX cartridge, and the product eluted with methanolic ammonia. Concentration in vacuo gave a crude product (43 mg) that was purified by MDAP to give the title compound as a clear film (11.6 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 8.41 (1H, d), 8.33 (1H, dd), 8.09 (1H, br. s), 8.01 (1H, d), 7.34 (1H, apparent t), 7.21 (1H, d), 7.12 (1H, d), 4.80 (1H, sept), 4.24 (2H, q), 4.00 (2H, s), 3.52 (2H, s), 3.35 (2H, t), 3.07 (2H, t), 1.48 (6H, d), 1.31 (3H, t); m/z (ES) 447 [M+H]+.
Reaction SMILES: C([O:3][CH2:4][CH3:5])=C.[N+](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=O)=[N-].[OH2:14].[OH-].[Li+:16]>C(Cl)Cl.O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:12]([O:11][CH:9]1[CH2:8][CH:5]1[C:4]([O-:14])=[O:3])[CH3:13].[Li+:16]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=COCC
Reactant: O
Agent: [Rh]
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC1CC1C(=O)[O-]
Reaction time: 8 h

Procedure:
In a 250 mL RBF, ethyl vinyl ether (4.2 ml, 44 mmol) was dissolved in DCM (20 mL). Rhodium (II) acetate dimer (0.019 g, 0.044 mmol) was added as a green powder, and ethyl diazoacetate (0.91 ml, 8.8 mmol) was added as a solution in DCM (4 mL) to the reaction mixture. The mixture was stirred overnight and concentrated. The crude mixture was dissolved in MeOH (0.75 mL), and lithium hydroxide hydrate (0.014 g, 0.34 mmol) was added as a solution in water (0.75 mL). The reaction mixture was stirred overnight, then concentrated and the title compound was used without purification.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[S:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[C:19]=2[OH:26])(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.C(O)C>[Cl:25][C:20]1[C:19]([OH:26])=[C:18]([S:15]([N:14]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([CH:1]([OH:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)(=[O:17])=[O:16])[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: O=C(c1ccccc1)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(C(O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of N-(4-benzoylbenzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (15 mg, 0.028 mmol) in THF (0.15 mL) and ethanol (0.15 mL) at 0° C. was added sodium borohydride (4 mg, 0.11 mmol). The reaction mixture was stirred at 0° C. for 1 h. The solvents were removed in vacuo and resulting residue was purified by preparative HPLC to give the title compound (14 mg) as a white solid. MS (ESI): 527.9 (M−H2O)+.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([C:9](=[O:30])[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:26]([CH3:28])[CH3:27])[CH:19]=2)=[C:12]([Cl:29])[CH:11]=1)[CH2:5][C:6]([OH:8])=[O:7].C([O-])(=O)C.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)(=O)C>[CH3:3][N:4]([C:9](=[O:30])[C:10]1[CH:11]=[C:12]([Cl:29])[C:13]([O:17][C:18]2[CH:19]=[C:20]([CH:26]([CH3:28])[CH3:27])[C:21]([O:24][CH3:25])=[CH:22][C:23]=2[Br:1])=[C:14]([Cl:16])[CH:15]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: BrBr
Reactant: COc1ccc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Temperature: 40 °C
Reaction time: 16 h
Yield: 1.6 %

Procedure:
Bromine (13 μL, 0.26 mmol) was added dropwise to a well stirred mixture of methyl-N-[3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)benzoyl]glycine (50 mg, 0.12 mmol), acetic acid (1.0 mL), sodium acetate (35 mg, 0.26 mmol) and a few drops of water. The reaction mixture was stirred at room temperature for three hours, heated at 40° C. for 90 minutes and finally left at room temperature for 16 hours. Sodium acetate (17 mg) and bromine (6 μL) was added and the reaction mixture heated to 40° C. for two hours. The reaction mixture was left at 4° C. for three days. Sodium thiosulfate (saturated) was added and the yellow mixture concentrated. The residue was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with dichloromethane, the combined organic phases washed with brine and dried over sodium sulfate. After concentration, the residue was purified on column (hplc, C8, acetonitrile/water/formic acid, gradient elution from 20/80/0.5 to 100/0/0) to give 1.0 mg (2%) of methyl-N-[3,5-dichloro-4-(2-bromo-4-methoxy-5-isopropylphenoxy)benzoyl]glycine.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:20]=[CH:21][C:22]([OH:36])=[C:23]([N:25]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](Br)[CH:38]=[CH2:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:39]([O:36][C:22]1[CH:21]=[CH:20][C:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:24][C:23]=1[N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])[CH:38]=[CH2:37]
Reactant: CC(C)(C)[Si](Oc1ccc(O)c(N2C(=O)c3ccccc3C2=O)c1)(c1ccccc1)c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1N1C(=O)c2ccccc2C1=O
Yield: 88.9 %

Procedure:
A mixture of Example 73C (7 g, 14.2 mmol), allyl bromide (1.84 mL, 21.27 mmol) and K2CO3 (3.92 g, 28.36 mmol) in anhydrous acetone (200 mL) were stirred, and refluxed overnight. The suspension was filtered, and dried with silica gel powder (20 g). 15% ethyl acetate in hexanes (2 L) was used to run flash chromatography to give the title compound (6.74 g, 89%). MS (DCI) m/z 551.13 (M+NH4)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.09 (s, 9H) 4.37–4.43 (m, 2 H) 5.02–5.22 (m, 2 H) 5.83 (m, 1 H) 6.65–6.69 (m, 2 H) 6.83 (d, J=2.37 Hz, 1 H) 7.34–7.47 (m, 6 H) 7.70–7.78 (m, 6 H) 7.89–7.94 (m, 2 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([CH:6]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)=[O:5])[CH3:2].C(OCC)(=O)C>C(O)C.[C].[Pd]>[CH2:21]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:22]
Reactant: CCN(CC)C(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CC)C(=O)C1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound prepared in Example 31 (556 mg) was dissolved in ethanol (10 mL) and ethyl acetate (20 mL) and added with 5% palladium carbon (100 mg) and the reaction solution was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction solution was filtered with celite and the solvent was distilled off to give the titled compound having the following physical properties. The resulting titled compound was used for the next reaction without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]([NH:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:26]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:26][N:13]([CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]1[S:9][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:12][CH:11]=1
Reactant: CCOC(=O)C(=CNc1cnc(CN2CCOCC2)s1)C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C(=CN(C)c1cnc(CN2CCOCC2)s1)C(=O)OCC
Temperature: 75 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a mixture of diethyl 2-(((2-(morpholin-4-ylmethyl)-1,3-thiazol-5-yl)amino)-methylene)malonate (Preparation 28, 1.51 g) and K2CO3 (1.19 g) in DMF (15 mL) at ambient temperature is added iodomethane (0.28 mL). The mixture is heated to 75° C. in a sealed pressure tube and stirred overnight. The solution is cooled to ambient temperature and the solvent is removed. The mixture is diluted with water (75 mL) and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed to afford 0.984 g (63%) of the title compound as a light brown solid. Physical characteristics: 1H NMR (CDCl3) δ1.24-1.33, 2.60, 3.31, 3.74, 4.17-4.24, 7.60; IR (liq.) 1702, 1608, 1535, 1453, 1383, 1365, 1293, 1270, 1232, 1206, 1117, 1096, 1071, 1010, 865 cm−1; HRMS (FAB) m/z 384.1600 (C17H25N3O5S+H). Anal. Found: C, 53.18; H, 6.64; N, 10.41.