Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1.[Cl-].[C:18]([O:22][C:23]([CH:25]([NH:28][S:29]([C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[CH3:40])(=[O:31])=[O:30])[CH2:26][NH3+:27])=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:18]([O:22][C:23](=[O:24])[CH:25]([NH:28][S:29]([C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[CH3:40])(=[O:31])=[O:30])[CH2:26][NH:27][C:14]([C:12]1[S:13][C:9]([Br:8])=[CH:10][CH:11]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Cc1cc(C)c(S(=O)(=O)NC(C[NH3+])C(=O)OC(C)(C)C)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)NC(CNC(=O)c2ccc(Br)s2)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
4-methylmorpholine (3.6 mL, 32.7 mmol) was added to a mixture of 5-bromothiophene-2-carboxylic acid (3.6 g; 17.4 mmol), 2-tert-butoxycarbonyl-2-(2,4,6-trimethyl-benzenesulfonylamino)-ethyl-ammonium chloride (6.0 g; 15.85 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.34 g; 17.4 mmol) and 1-hydroxybenzotriazole (2.35 g; 17.4 mmol) in dry DMF (45 mL). The mixture was stirred at room temperature for 16 h. DMF was removed and the crude mixture was dissolved in ethyl acetate (400 mL). The solution was washed with water (25 mL), saturated NaCl (25 mL), 5% KHSO4 (25 mL), saturated NaCl (25 mL), saturated NaHCO3-saturated NaCl mixture (1:1) (25 mL), dried and evaporated. The crude was passed through a column of silica gel and the column was eluted with hexane-EtOAc mixtures (10% to 30% EtOAc) yielding 7.9 g of compound A-2 containing trace amount of ethyl acetate (90% yield).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[SH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8](O)=[O:9].S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[SH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:4][CH2:3][CH2:2][CH2:1][O:5][C:8](=[O:9])[CH:7]([SH:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: OCCCO
Reactant: O=C(O)C(S)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCCCOC(=O)C(S)c1ccccc1)C(S)c1ccccc1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
1,3-Propanediol (9.50 g, 0.125 mol), a 55:45 mixture of the respective 4- and 3- isomers of mercaptophenylacetic acid (45.00 g, 0.268 mol), concentrated sulfuric acid (0.2 mL), and toluene (200 mL) were combined in a round-bottom flask equipped with a magnetic stirring bar, a water separator, and a condenser. During 6 h of heating under reflux with stirring, the solid organic acid isomers disappeared, and 4.46 mL (0.248 mol) of water was collected by the water separator. The mixture was allowed to cool to room temperature, washed in succession with 20 mL of saturated NaHCO3 solution and two 50-mL portions of brine, then dried over anhydrous MgSO4 and freed of solvent on a rotary evaporator. Dissolution of the residue in 400 mL of dichloromethane, followed by treatment at the boiling point with a small amount of decolorizing carbon, hot filtration, and rotary evaporation to remove solvent, gave 46.4 g (yield, 99%) of 1,3-propanediol bis(mercaptophenylacetate) as a viscous pale yellow oil that was shown by NMR analyses to contain the 4- and 3-isomers in a ratio of ca. 55:45, respectively: 1H NMR (in CDCl3 w/TMS, ppm): 1.91-1.96 (m, 2H, CH2CH2CH2); 3.44 (s, 4-isomer SH) and 3.47 (s, 3-isomer SH), 2H in toto; 3.53-3.63 (m, 4H, CH2C═O); 4.10-4.14 (m, 4H, CH2O); 7.03-7.44 (m, 8H, aromatic CH); {1H}13C NMR (in CDCl3 w/TMS, ppm): 28.14 (CH2CH2CH2); 40.99 (4-isomer CH2C═O) and 41.31 (3-isomer CH2C═O); 61.64 (CH2O); 126.80-132.36 (at least 9 peaks, aromatic C); 171.20 (3-isomer C═O) and 171.41 (4-isomer C═O).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH:11]=[CH:10][C@H:9]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]3[CH:22]=[CH:23][S:24][C:14]=23)[CH2:8][O:7]1)(=O)C>[Pd].CO>[NH2:19][C:18]1[C:13]([NH:12][C@@H:9]2[CH2:8][O:7][C@@H:6]([CH2:5][OH:4])[CH2:11][CH2:10]2)=[C:14]2[S:24][CH:23]=[CH:22][C:15]2=[N:16][CH:17]=1
Reactant: CC(=O)OCC1C=C[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CO1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Yield: 52.5 %

Procedure:
A mixture of {(5S)-5-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]-5,6-dihydro-2H-pyran-2-yl}methyl acetate (366 mg, 1.05 mmol) and 10% palladium on carbon (0.18 g) in methanol (7.0 mL) was subjected to balloon pressure of H2 at room temperature for 2 h. The mixture was filtered and treated with 1 M NaOH (1 mL) for 1 h. The mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give two peaks in 5:1 ratio. The major peak is the title compound (154 mg, 58%). LCMS calculated for C13H18N3O2S (M+H)+: m/z=280.1. Found: 280.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CS(C)=O>CCOC(C)=O>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cc2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (100 mg, 0.41 mmol), potassium carbonate (114 mg, 0.83 mmol), 2-bromothiazole (0.38 mL, 4.2 mmol), and dimethyl sulfoxide (2.5 mL) was stirred at 135° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:11]=[N:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16](=[O:22])[NH:17]3)=[C:4]([O:30]C)[CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:25])([F:24])[F:26])[CH:11]2[NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16](=[O:22])[NH:17]3)=[C:4]([OH:30])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(C)(C)CC(O)(C=Nc1cccc2c1CC(=O)N2)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c2CC(=O)N3)c2cc(Br)cc(O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
235.9 mg of 4-{[4-(4bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}-1,3-dihydroindol-2-one is mixed at 0° C. with 6.42 ml of a 1 M solution of BBr3 in dichloromethane and stirred for four hours at room temperature. At 0° C., saturated sodium bicarbonate solution is carefully added in drops. After being extracted three times with ethyl acetate, the organic phases are dried on sodium sulfate. The desiccant is suctioned off, and the solvent is spun off. The residue is chromatographed on a Flashmaster. 125.4 mg (54%) of the desired compound is isolated.
Reaction SMILES: C([N:3]1[CH2:22][CH2:21][C@:10]23[C:11]4[C:12]5[O:20][C@H:9]2[C:8](=[O:23])[CH2:7][C@@H:6]([CH3:24])[C@@:5]3([O:25][CH3:26])[C@H:4]1[CH2:17][C:16]=4[CH:15]=[CH:14][C:13]=5[O:18][CH3:19])#N.[ClH:27]>>[ClH:27].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][C@H:4]3[NH:3][CH2:22][CH2:21][C@:10]45[C:11]=2[C:12]=1[O:20][C@H:9]4[C:8](=[O:23])[CH2:7][C@@H:6]([CH3:24])[C@@:5]35[O:25][CH3:26]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)N(C#N)CC[C@]314
Agent: Cl
Product: COc1ccc2c3c1O[C@H]1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)NCC[C@]314

Procedure:
17-Cyano-3,14-dimethoxy-4,5α-epoxy-8α-methylmorphinan-6-one (3) (6.0 g, 16.9 mmol) was combined with 250 ml of 2N HCl and refluxed under a nitrogen atmosphere for 3 hours. The contents of the reaction flask were concentrated under reduced pressure to give 6.1 g (99% theory) of a brownish solid which was dried and used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH:16]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:17]([NH:19][CH2:20][C:21]#[N:22])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:27]1(=O)[CH2:31]C[CH2:29][CH2:28]1.C([BH3-])#N.[Na+].[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>>[C:21]([CH2:20][NH:19][C:17](=[O:18])[CH:16]([S:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:1]3[CH2:29][CH2:28][CH2:27][CH2:31]3)=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[CH2:23][CH:24]([CH3:26])[CH3:25])#[N:22]
Reactant: O=C1CCCC1
Reactant: CC(C)CC(Sc1ccc(-c2ccc(CN)cc2)cc1)C(=O)NCC#N
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Product: CC(C)CC(Sc1ccc(-c2ccc(CN3CCCC3)cc2)cc1)C(=O)NCC#N
Reaction time: 18 h

Procedure:
2-{[4′-(Aminomethyl)-1,1′-biphenyl-4-yl]thio}-N-(cyanomethyl)-4-methylpentanamide (120 mg, 0.33 mmol) was mixed with cyclopentanone (234 μL, 2.64 mmol), sodium cyanoborohydride (25 mg, 0.40 mmol) and MgSO4 (200 mg) and stirred for 18 h. Aqueous sat. NaHCO3 was added, the product was extracted with EtOAc (3×), dried over MgSO4, concentrated in vacuo, and purified by flash chromatography (100% EtOAc to 2% methanol/EtOAc) to afford N-(cyanomethyl)-4-methyl-2-{[4′-(pyrrolidin-1-ylmethyl)-1,1′-biphenyl4-yl]thio}pentanamide. MS (+APCI): 436.3 [M+1]+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25]CC)=[O:24])=[C:16]3[N:15]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH2:10]1)(C(C)(C)C)(C)C.[Li+].[OH-]>CCO>[F:34][C:30]1[CH:29]=[C:28]([C@H:11]2[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[C:16]3[N:15]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3cccc(F)c3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Ethyl 5-((2R,4R)-4-(tert-butyldimethyl silyloxy)-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (205 mg, 0.422 mmol) was suspended in EtOH (2.0 mL) and 1M LiOH (0.845 ml, 0.845 mmol) was added. The mixture was heated at reflux for 4 hours and another portion of 1M LiOH (0.845 ml, 0.845 mmol) was added. The mixture was heated at reflux overnight, cooled to ambient temperature and concentrated. The residue was diluted in water and the mixture was treated with 2N HCl to achieve pH 1. The mixture was extracted with DCM and EtOAc and the combined extracts were dried with MgSO4, filtered and concentrated to afford 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (124 mg, 86%) as a light orange solid.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=O)[C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1.[OH-].[Ca+2].[OH-].CN(C)C=O>COC(C)(C)C>[Cl:18][C:19]1[CH:20]=[C:21]([C:26]([C:27]([F:30])([F:28])[F:29])=[CH:2][C:1]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C(C)=O)c2ccccc12
Agent: [Ca+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)c2ccccc12
Reaction time: 15 h

Procedure:
A mixture of methyl 4-acetyl-1-naphthalenecarboxylate (5.36 g, 23.4 mmol), 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (5.68 g, 23.4 mmol), calcium hydroxide (0.172 g, 2.3 mmol), N,N-dimethylformamide (16 mL), and tert-butyl methyl ether (32 mL) was placed in a thermometer-equipped reaction vessel. The reaction vessel was connected to a ten-plate Oldershaw column, the output of which was condensed and fed into a decanter initially filled with tert-butyl methyl ether. A nitrogen atmosphere was maintained in the apparatus. The upper part of the decanter was connected to return condensate to the fifth plate of the Oldershaw column. This arrangement ensured that wet (containing dissolved water) tert-butyl methyl ether from the decanter was not returned to the reaction vessel. A drain valve at the bottom of the decanter allowed removing tert-butyl methyl ether in addition to water from the decanter. The reaction mixture was heated to distill the tert-butyl methyl ether/water azeotrope. As the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Because the reaction mixture initially contained mostly tert-butyl methyl ether, the mixture boiled at a temperature not much exceeding the normal boiling point of tert-butyl methyl ether (e.g., about 65-70° C.). The reaction appeared to proceed relatively slowly at this temperature, so condensate was gradually drained from the decanter trap to remove tert-butyl methyl ether. As the concentration of tert-butyl methyl decreased in the reaction mixture, the temperature of the boiling mixture increased. Tert-butyl methyl ether was removed by draining the decanter until the temperature of the boiling reaction mixture reached about 75 to 80° C. To maintain this temperature range, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from beginning heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 15 h. During this time period a further portion of calcium hydroxide (1.34 g, 18.1 mmol) was added to increase the reaction rate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([OH:28])[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2].[N:31]1([CH2:37][CH2:38][CH2:39]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:39][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccccc3)c2)cc1C
Reactant: OCCCN1CCOCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCCN3CCOCC3)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (0.25 g; 0.60 mmol), 3-morpholin-4-yl-propan-1-ol (0.12 g; 0.84 mmol) and tributylphosphine (0.27 mL; 1.08 mmol) were dissolved in THF (20 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.27 g; 1.08 mmol) dissolved in THF (10 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, acetonitrile added, and the mixture filtered. The solution was purified by prep HPLC (method A). Yield: 150 mg. HPLC-MS: m/z: 546.6 (M+H); Rt: 2.08 min.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[C:27]([F:28])=[CH:26][N:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(C(=O)C2CC2)c(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1cc(OC)ncc1F)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (2.76 g) in THF (100 mL) was added ethyl diethylphosphonoacetate (15.2 mL) at 0° C., and the mixture was stirred at 0° C. for 5 min. To the obtained colorless solution was added cyclopropyl(5-fluoro-2-methoxypyridin-4-yl)methanone (entire amount) obtained in Example 42, step B, at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCCCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCCCC2)c2sc(NC(=O)c3ccnc(N4CCN(C)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methylpiperazine. ES-MS m/e (%): 467 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[C:35](O)([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[N:3]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:4]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:5]([C:35](=[O:36])[C:37]([F:40])([F:39])[F:38])[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)Cn1c(-c2ccccc2)cc(Cc2ccccc2S(=O)(=O)N2CCOCC2)c1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCOCC2)c(C(=O)C(F)(F)F)c1-c1ccccc1
Temperature: 0 °C
Yield: 67 %

Procedure:
Ethyl 2-(2-methyl-3-(2-(morpholinosulfonyl)benzyl)-5-phenyl-1H-pyrrol-1-yl)acetate (0.259 g, 0.537 mmol) (mixture of regioisomers—1.5:1.0) was dissolved in DCM (5.37 ml) and cooled to 0° C. DMAP (0.262 g, 2.147 mmol) was then added to the reaction in one portion, followed by TFA (0.758 ml, 5.37 mmol) in a drop-wise fashion. The ice bath was removed and the reaction was warmed to rt then refluxed for 16 h. At this time, the reaction was quenched with 1N HCl, and then diluted with 50 mL DCM. The layers were separated and the aqueous portion was then back-extracted with DCM (50 mL). The organics were combined, dried, filtered, and concentrated. The crude material ethyl 2-(2-methyl-3-(2-(morpholinosulfonyl)benzyl)-5-phenyl-4-(2,2,2-trifluoroacetyl)-1H-pyrrol-1-yl)acetate was then purified by silica gel chromatography using a 0-70% EtOAc/hexane gradient to furnish the desired material in 67% yield.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[C:5]([F:14])[CH:4]=1.[B:15](OC)([O:18]C)[O:16]C.Cl>C1COCC1.C(OCC)(=O)C>[F:14][C:5]1[CH:4]=[C:3]([B:15]([OH:18])[OH:16])[CH:8]=[CH:7][C:6]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)(F)F)c(F)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
Well-dried magnesium (3.05 g) and THF (20.0 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 55° C. Then, 1-bromo-3-fluoro-4-trifluoromethoxybenzene (T-13; 25.0 g) dissolved in THF (100 ml) was slowly added dropwise thereto in the temperature range of 47° C. to 60° C., and stirred for additional 60 minutes. The obtained Grignard reagent was added dropwise to trimethyl borate (14.0 g) in a THF (100 ml) solution in the temperature range of −74° C. to −65° C., and stirred for additional 180 minutes while allowing temperature to come to 25° C. After the reaction mixture had been cooled to −30° C., 6N-hydrochloric acid (90 ml) was slowly added dropwise and stirred for additional 180 minutes while temperature was allowed to come to 25° C. Then, the reaction mixture was poured into a vessel containing ice-water (250 ml) and 3,000 ml, and mixed. Ethyl acetate (300 ml) was added to separate the mixture into organic and aqueous layers, and an extraction operation was carried out. The obtained organic layer was fractionated, washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, whereby 11.7 g of 3-fluoro-4-trifluoromethoxy phenylboronic acid (T-14) was obtained. The yield based on the compound (T-13) was 54%.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=3[O-:17])[CH2:7][CH2:6]2)[O:4]CC1.C(O)(=O)C.Cl.[OH-].[Na+]>O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])[CH2:7][CH2:6]1
Reactant: [O-][n+]1ccccc1C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(c2cccc[n+]2[O-])CC1
Temperature: 45 °C
Yield: 73.8 %

Procedure:
2-(1,4-Dioxaspiro[4.5]dec-8-yl)pyridine N-oxide (3 g, 12.75 mmol) was combined with glacial acetic acid (20 mL), concentrated hydrochloric acid (10 mL), and water (10 mL). The resulting mixture was heated to 45° C. for 24 hours. The reaction was cooled to 0° C. and the pH was adjusted to 6 with 20% sodium hydroxide solution. The phases were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water and brine, then dried (sodium sulfate), and concentrated under reduced pressure to yield 1.8 g of the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCCc1ccc(Cl)nc1
Reaction time: 0.83 h
Yield: 110.4 %

Procedure:
To a stirred solution of 2-chloropyridine-5-acetic acid (800 mg, 4.60 mmol) in THF (30 mL) at 0° C. under a nitrogen atmosphere was added triethylamine (2.20 mL, 10.3 mmol) and isobutyl chloroformate (1.20 mL, 9.33 mmol). The reaction was stirred for 50 minutes then sodium borohydride (1.77 g, 46 mmol) was added and the suspension stirred at r.t. for 16 h then at reflux for a further 4 h. The resulting mixture was partitioned between DCM (50 mL) and water (50 mL). The organic fraction was washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound (800 mg, quantitative) as a brown oil. LCMS (ES+) 158.0 (M+H)+, RT 1.81 minutes (85% purity) (Method 1).