Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8](I)[C:9](=[O:10])[N:4]2[CH:3]=1.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]([C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=3)[C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2I)c1OCC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC(C)(C)C
Yield: 108.8 %

Procedure:
The title compound was prepared from Intermediate 19 (65 mg, 0.122 mmol) and 4-trifluoromethoxyphenyl boronic acid (27 mg, 0.132 mmol) using Pd[(C6H5)3P]4 (5 mg, 0.004 mmol) in toluene (10 ml) and ethanol (5 ml) followed by sodium carbonate (77 mg, 0.734 mmol) in water (5 ml) according to the procedure outlined in Example 1 to afford 75 mg of the desired compound; 1H NMR (300 MHz, DMSO-d6) δ 0.99 (s, 9H), 3.50 (s, 2H), 3.76 (s, 3H), 6.81 (d, J=16.2 Hz, 1H), 6.88-6.94 (m, 1H), 6.99 (d, J=4.2 Hz, 2H), 7.42-7.48 (m, 4H), 8.18 (d, J=15.6 Hz, 1H), 8.26 (s, 1H); ESI-MS (m/z) 565.55, 567 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:11][C:12](=[O:22])[CH2:13][NH:14][C:15](OC(C)(C)C)=[O:16])C(OC)=O.C(O)=O>C1(C)C=CC=CC=1.C(O)CCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][C:12](=[O:22])[CH2:13][NH:14][C:15]1=[O:16]
Reactant: COC(=O)C(NC(=O)CNC(=O)OC(C)(C)C)c1cccs1
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=C1CNC(=O)C(c2cccs2)N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 6.4 g of methyl 2-thienyl-N-(tert.-butoxycarbonylaminoacetyl)aminoacetate and 200 ml of formic acid is stirred at room temperature for 15 h. The volatile fractions are stripped off in vacuo, and the residue is heated to boiling in a mixture of 80 ml of toluene and 300 ml of butanol under reflux for 3 h. The solvents are then removed in a rotary evaporator, and the residue is recrystallized from methanol.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[C:10]([C:11]([NH:13]/[C:14](=[C:20](\[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[C:30]3[C:35]([Cl:36])=[CH:34][N:33]=[CH:32][C:31]=3[Cl:37])=[CH:24][CH:23]=2)/[CH3:21])/[C:15]([O:17]CC)=[O:16])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.CO>O1CCOCC1.O>[Cl:4][C:5]1[C:10]([C:11]([NH:13]/[C:14](=[C:20](\[C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:38])[C:30]3[C:31]([Cl:37])=[CH:32][N:33]=[CH:34][C:35]=3[Cl:36])=[CH:26][CH:27]=2)/[CH3:21])/[C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)/C(NC(=O)c1cccnc1Cl)=C(\C)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: C/C(=C(/NC(=O)c1cccnc1Cl)C(=O)O)c1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1
Yield: 35.4 %

Procedure:
Lithium hydroxide monohydrate (4.4 mg, 1.05 mml) was added to the compound of Example 16 (280 mg, 0.525 mmol) in a mixture of dioxane (10 ml) and water (10 ml). The mixture was heated at reflux for 2 h. The dioxane was removed in vacuo, the aqueous residue acidified with dilute HCl, the precipitate formed filtered off, washed with water and dried to give a brown solid. Trituration with hot methanol gave the title compound as a pale brown solid (94 mg). δH (DMSO-d6), 12.75 (1H,v br s,CO2H), 10.99 (1H, s, CONH), 9.75 (1H, s, CONH), 8.79 (2H, s, PyH), 8.44 (1H, dd, 14.8, 1.9 Hz, PyH), 7.68-7.64 (3H, m, ArH+PyH), 7.46 (1H, dd, J 7.5, 4.8 Hz, PyH), 7.38 (2H, d, J 8.6 Hz, ArH) and 2.33 (3H, s, Me); m/z (ESI, 70V) 505 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[F:75][CH2:76][CH2:77][NH2:78]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:78][CH2:77][CH2:76][F:75])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCCF)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2-fluoroethylamine hydrochloride (8.09 mg, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (11.1 mg, 33%). LC-MS m/z 619 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][C@H:6]([C:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][C:32](=[O:34])[CH3:33])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][CH2:13]3)[CH2:10][CH:9]=1)[CH3:7].[H][H]>C(O)C.[Pt]>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][C:32](=[O:34])[CH3:33])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 98.5 %

Procedure:
To a solution of 8.8 g of 1α,3β-diacetyloxychola-5,16-dien-24-oic acid methyl ester in 200 ml of absolute ethanol was added, under a nitrogen atmosphere, 0.8 g of 5% platinum on charcoal. The suspension was then stirred under a hydrogen atmosphere at 23° C. until hydrogen absorption ceased (2.75 h; 423 ml; theory, 437 ml). Filtration through diatomaceous earth did not remove all colloidal particles. The evaporated filtrate was dissolved in 50 ml of ethyl acetate--methylene chloride (1:1) and was then percolated through a column of 20 g of silica gel using the same solvent mixture. Evaporation of the solvents gave 8.7 g (99%) of 1α,3β-diacetyloxychol-5-en-24-oic acid methyl ester as a white solid, mp 108°-113° C. An analytical sample, recrystallized from methanol, had mp 110.5°-112° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.C([Li])(C)(C)C.[CH3:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([CH3:29])[C:20]=1C=O.[O:30]1CCC[CH2:31]1>CCOCC>[CH3:29][C:23]1[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:19]([CH3:18])[C:20]=1[O:30][CH2:31][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1
Reactant: C1CCOC1
Reactant: COc1cc(C)c(C=O)c(C)c1
Reactant: COc1ccc(Br)cc1C(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cc(C)c(OCc2ccc(OC)c(C(C)C)c2)c(C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To 4-bromo-2-isopropylanisole (3) (12 g, 52.4 mmol) in 300 mL of tetrahydrofuran at -78° C. was added 68 mL of tert-Butyllithium (1.7M in pentane). The reaction mixture was stirred for 10 min at -78° C. and then 2,6-dimethyl-4-methoxybenzaldehyde (6) (8.6 g, 52.4 mmol) was added. The reaction mixture was stirred for 1 hour at -78° C. and for 1.5 hours at room temperature, diluted with 150 mL of ether, washed with 150 mL of water, acidified with 1N HCl, and washed with 5×50 mL of brine. The organic portion was dried (MgSO4), filtered, and evaporated to give the crude product, which was purified by flash column chromatography (silica gel, 95:5 hexane/ethylacetate) to yield 3,5-dimethyl-4-(3'-isopropyl-4'-methoxybenzylhydroxy) anisole (7) (12 g, 38.2 mmol, 73%) as an oil; 1HNMR (CDC13) δ 1.2 (dd, 6H), 2.27 (s, 6H), 3.30 (heptet, 1H), 3.80 (s, 6H), 6.26 (s, 1H), 6.59 (s, 2H) 6.76 (d, 1H), 6.89 (d, 1H), 7.24 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[OH:28][CH2:29][CH2:30][NH2:31].Cl>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:31][CH2:30][CH2:29][OH:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of 50% aqueous 2-hydroxyethylamine. The mixture is stirred at room temperature for 16 hours, then acidified with hydrochloric acid and cooled to 0°-5° C. The precipitate of 4-acetyl-N-(2-hydroxyethyl)benzenesulfonamide is collected by filtration, washed with water and dried; m.p. 119°-121° C. after crystallization from water.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([O:43][C:44](Cl)=[O:45])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:44]([O:43][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:45])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)cc1OCCCOC
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)C)C2CC2)C(C)C)cc1OCCCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-cyclopropylaminomethyl-4-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.470 mmol) in CH2Cl2 (3 mL) are added isobutylchloroformate (84 mg, 0.611 mmol) and triethylamine (85 μL, 0.611 mmol) under a N2 atmosphere. The mixture is stirred overnight at RT, diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 90:10) to give the title compound. MS (LC-MS): 532 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 8.22 min.
Reaction SMILES: [C:1]1([C:7]2[S:11][N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16]I.[N+]([O-])(O)=O>CCOC(C)=O>[I:16][C:8]1[C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][S:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: II
Reactant: COC(=O)c1cc(-c2ccccc2)sn1
Solvent: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: COC(=O)c1nsc(-c2ccccc2)c1I
Temperature: 80 °C
Yield: 21.4 %

Procedure:
To methyl 5-phenylisothiazole-3-carboxylate (500 mg, 2.280 mmol) in a tube were added iodine (579 mg, 2.280 mmol) and nitric acid (2.280 mmol). The resulting mixture was heated to 80° C. for 1 h. After the reaction was cooled to room temperature, EtOAc (50 mL) was added. The resulting mixture was washed with saturated Na2S2O3 solution until the brown color disappeared. The organic layer was concentrated. HPLC and flash chromatography yielded methyl 4-iodo-5-phenylisothiazole-3-carboxylate (168 mg, 0.487 mmol, 21.34% yield). The compound had an LC/MS M+1=345.9.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(S[C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)C>C(OCC)(=O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCNCC1
Reactant: CCSc1nc2ccccc2c(=O)[nH]1
Solvent: CCOC(C)=O
Product: C=CCN1CCN(c2nc3ccccc3c(=O)[nH]2)CC1
Reaction time: 5 h
Yield: 89 %

Procedure:
N-allylpiperazine (37 g) was added to 30 g of 2-ethylthio-4(3H)-quinazolinone [J. Med. Chem., 11, 392 (1968)], and the mixture was stirred at 140° to 160° C. for 5 hours in a stream of nitrogen. After cooling, the reaction mixture was suspended in ethyl acetate and filtered. The resulting crude crystals were recrystallized from ethanol/ethyl acetate to give 35 g of 2-(4-allyl-l-piperazinyl)-4(3H)-quinazolinone.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22](SC)=[N:23][CH:24]=2)[N:19]1[C:30]1[N:35]=[C:34]([N:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]2=[O:43])[CH:33]=[CH:32][CH:31]=1)[CH:16]=[CH2:17]>>[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:23][CH:24]=2)[N:19]1[C:30]1[N:35]=[C:34]([N:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]2=[O:43])[CH:33]=[CH:32][CH:31]=1)[CH:16]=[CH2:17]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(-n2cc(F)ccc2=O)n1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(-n2cc(F)ccc2=O)n1

Procedure:
The entitled compound was obtained as a yellow solid (23.6 mg) in the same manner as in Production Example 12-2, for which, however, 4-(4-methylpiperazin-1-yl)aniline was used in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Production Example 12-2, and 6′-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-5-fluoro-2H-1,2′-bipyridin-2-one was used in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:10]([CH:15]=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ncccc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ncccc1OCc1ccccc1

Procedure:
3-Benzyloxy-2-(hydroxymethyl)pyridine (35.1 grams; 0.16 mole) was dissolved in 1 liter of CHCl3. Manganese dioxide (174 grams; 2.0 moles) was added and the mixture refluxed for a period of five hours. The reaction mixture was filtered hot through celite, and the solvent removed from the filtrate to afford a brown liquid weighing 23.5 grams.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15](O)=O)=[CH:6]2.[ClH:18].[CH3:19][O:20][C:21](=[O:36])[CH2:22][C@@H:23]([NH2:35])[CH2:24][S:25]CC1C=CC(OC)=CC=1>>[CH3:19][O:20][C:21](=[O:36])[CH2:22][C@@H:23]1[CH2:24][S:25][C:15]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([CH2:2][Cl:18])=[CH:11][C:10]=3[N+:12]([O-:14])=[O:13])=[N:35]1
Reactant: COC(=O)C[C@@H](N)CSCc1ccc(OC)cc1
Reactant: Cl
Reactant: O=C(O)c1cc2cc(CO)cc([N+](=O)[O-])c2[nH]1
Product: COC(=O)C[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
5-Hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid prepared in Preparation 38 and (R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl ester hydrochloride prepared in Preparation 27 were reacted according to the same procedures as Steps B and C of Preparation 40 to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH2:22][CH:23](O)[CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])=[O:20])[CH:16]([CH3:18])[CH3:17].N12CCCCC1CNCC=C2.Cl>C(Cl)Cl.C(N(CC)CC)C.S(Cl)(C)(=O)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:20])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CCCCC(O)CS(=O)(=O)N(c1ccc(C(F)(F)F)cc1OCOC)C(C)C
Agent: C1=CN2CCCCC2CNC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC=CS(=O)(=O)N(c1ccc(C(F)(F)F)cc1OCOC)C(C)C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a solution of 2-(N-isopropyl-2-hydroxyhexylsulfonylamino)-5-trifluoromethylphenyl methoxymethyl ether (160 mg; prepared in Reference Example 31) in methylene chloride (2.0 ml), triethylamine (104 μl) and mesylchloride (35 μl) were added in a stream of argon at 0° C. The mixture was stirred for 10 minutes. To the mixture, 1,5-diazabicyclo[5,4,0]undecene (134 μl) was added. The mixture was stirred for 2 hours at room temperature. To the reaction mixture, diluted HCl was added. The mixture was extracted with ethyl acetate, washed, dried over and concentrated with the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=8:1) to give the title compound (140 mg) having the following physical data.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=4)=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Cl)ccn1
Reactant: CC(C)c1cccc(Nc2nc3cc(O)ccc3s2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Oc2ccc3sc(Nc4cccc(C(C)C)c4)nc3c2)ccn1
Reaction time: 0.25 h

Procedure:
The mixture containing 2-(3-isopropylphenylamino)benzo[d]thiazol-5-ol (1 eq), N-(4-chloropyridin-2-yl)acetamide (1.4 eq), potassium bis(trimethylsilyl)amide (4 eq) and potassium carbonate (1.2 eq) in dimethylformamide was subjected to the microwave at 200° C. for 15 minutes. The reaction was then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give the crude product. Purification on HPLC to yield N-[4-({2-[(3-isopropylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]acetamide. HPLC=4.87 min; MS: MH+=419.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Br:15])=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([CH3:34])OS1(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:32]([CH3:34])[CH2:33][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[Br:15])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cccc(Br)c2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(Br)c2n1[C@H](C)CNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 8.1 g (30.1 mmol) 7-bromo-1H-indole-2-carboxylic acid ethyl ester in 120 ml N,N-dimethylformamide was cooled to 0° C. and 3.55 g (31.6 mmol) potassium tert-butoxide was added. After 30 min., 7.86 g (33.1 mmol) (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester were added and the cooling bath was removed. After 20 h the reaction mixture was poured on 10% aqueous citric acid solution and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting yellow oil was chromatographed on silica gel (0.032-0.063 mm) with tert-butyl methyl ether: n-hexane (1:8) as eluant to give the desired compound as a yellow oil. ISP-MS: m/e=427.3 ([M+H+]).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>CN(C)C=O.O>[CH2:20]([O:22][C:23](=[O:28])[C:24]([CH3:26])([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:3]=1)[CH3:25])[CH3:21]
Reactant: Oc1cccc(-c2cccnc2)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(3-hydroxyphenyl)pyridine (40.91 g, 0.239 mol) in 500 mL dimethylformamide was added potassium carbonate (148.62 g, 1.075 mol) and ethyl-2-bromoisobutyrate (157.8 mL, 1.075 mol). The mixture was heated to reflux under N2 with stirring for 18 h and cooled to ambient temperature. The resultant brown suspension was diluted with 1 L water and extracted with diethyl ether (3×500 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to a volume of 1 L. The organic solution was diluted with 1 L water and made acidic with 6N HCl. The layers were separated and the organic phase extracted with 500 mL water. The acidic extractions were combined and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with diethyl ether (4×500 mL) and the extracts were combined, washed with 500 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield crude 2-methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid ethyl ester as a pale yellow oil which was taken on to the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].CCOC(C)=O.CCCCCC>CN(C=O)C>[CH3:15][Si:16]([CH3:18])([CH3:17])[O:1][C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 0 °C

Procedure:
Tert-butyl 4-oxopiperidine-1-carboxylate, 1.1 (250 g, 1.256 mol) was taken in dry DMF (150 mL) under N2 atmosphere and added TEA (230 g, 2.27 mmol) at room temperature. The reaction mixture was cooled to 0° C., added trimethylsilyl chloride (178 g, 1.64 mol) drop wise for 30 minutes. After addition completed the reaction mixture heated at 80° C. for 16 h. The reaction was monitored by TLC (20% EtOAc/hexane), and allowed to cool the reaction mixture to room temperature, poured into ice water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, brine solution, dried over Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography on silica gel (5-10% EtOAc-Hexane) to afford tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate, 2.2 (300 g, 87.79%). 1HNMR (CDCl3, 400 MHz): δ 4.78 (s, 1H), 3.87-3.80 (m, 2H), 3.55 (t, 2H), 2.15-2.05 (m, 2H), 1.45 (s, 9H), 0.19 (s, 9H).