Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]2[N:12]3[C:13](C(OCC)=O)=[CH:14][C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C(OCC)(=O)C.O>C(O)C.[Cu]>[CH:1]1([C@H:7]2[N:12]3[CH:13]=[CH:14][C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cc2cccc3c2n1[C@H](C1CCCCC1)CO3
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: c1cc2c3c(c1)ccn3[C@H](C1CCCCC1)CO2
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 85.7 %

Procedure:
To a solution of ethyl (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5-carboxylate (1.49 g, 4.76 mmol) in ethanol (50 ml) was added 4 N sodium hydroxide (5.94 ml, 23.8 mmol). The mixture was stirred at 70° C. for 40 min. Ethanol was removed in vacuo, and the residue was neutralised with 2 N hydrochloric acid, and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in quinoline (20 ml), then copper powder (453 mg, 7.13 mmol) was added. The mixture was stirred at 210° C. for 1 h. Ethyl acetate and water were added to the mixture at room temperature, and the mixture was filtered through a plug of Celite, and the filter cake washed with ethyl acetate. The filtrate was acidified with 5 N hydrochloric acid and partitioned. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with 1 N hydrochloric acid and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 0-10% (v/v) ethyl acetate in heptane to afford (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (984 mg, 4.08 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4](Cl)[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([O:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH:24]=[CH:25][CH:26]=2)[N:3]=1
Reactant: C=CC(=O)Nc1cccc(O)c1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1cccc(Oc2nc(Cl)nc3c2ncn3COCC[Si](C)(C)C)c1
Temperature: 60 °C
Yield: 84.4 %

Procedure:
To a solution of 2,6-dichloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine (1.78 g, 5.58 mmol) and N-(3-hydroxyphenyl)prop-2-enamide (1.00 g, 6.13 mmol) in DMF (28 mL) was added K2CO3 (2.34 g, 16.7 mmol). The reaction was heated to 60° C. for 30 min, at which point LCMS showed consumption of starting material. The mixture was cooled to rt and partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc twice more. The combined organics were washed with water (three times) and brine, dried over Mg2SO4, and filtered. The filtrate was concentrated, and the crude material was purified by flash chromatography on a Biotage 40M column; product was eluted with 0%-40% EtOAc/heptane to yield the title compound (2.10 g, 85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (s, 1H) 8.69 (s, 1H) 7.74 (t, J=2.02 Hz, 1H) 7.50-7.56 (m, 1H) 7.41-7.48 (m, 1H) 7.05 (ddd, J=7.96, 2.27, 0.88 Hz, 1H) 6.39-6.50 (m, 1H) 6.22-6.32 (m, 1H) 5.75-5.81 (m, 1H) 5.62 (s, 2H) 3.57-3.66 (m, 2H) 0.84-0.91 (m, 2H) −0.05 (s, 9H). m/z (APCI+) for C20H24ClN5O3Si 446.00 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[C:52](Cl)=[O:53].C(N(CC)CC)C>O1CCCC1>[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[C:52]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:53]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccco1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.125 g, 0.207 mmol), in tetrahydrofuran (5 mL), were added, 2-furoyl chloride (0.041 g, 0.315 mmol, 0.031 mL) and triethyl amine (0.107 g, 1.06 mmol, 0.147 mL). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification (0.150 g, 99% yield): ES-MS (m/z) 697 [M+1]+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[NH:10][C:11]([CH3:27])=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.C1CCCCC1.CCOC(C)=O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:12]([C:23]([O:25][CH3:26])=[O:24])=[C:11]([CH3:27])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(C)NC(SCc2ccccc2)=NC1c1ccc(Cl)cc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(C)nc(SCc2ccccc2)nc1-c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
The crude methyl 2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.22 mmol) from Step 1 was dissolved in CH2Cl2 (2 mL) and DDQ (50 mg, 0.22 mmol) was added. After 1 hr, The reaction was diluted with cyclohexane/EtOAc solution (4:1, 10 mL) and the organic layer was extracted with saturated NaHCO3 solution (2×6 mL), brine (5 mL). The organic layer dried (MgSO4), filtered and concentrated under reduced pressure to give methyl 2-(benzylthio)-4-(2,4-dichlorophenyl)-6-methylpyrimidine-5-carboxylate. The crude reaction product (>95% purity) was moved onto next step without further purification.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:13][CH2:14][C@H:15]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:16](=[O:32])[NH:17][C@@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>CO>[CH2:1]([C@@H:8]([CH2:13][CH2:14][C@H:15]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:16](=[O:32])[NH:17][C@@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]1=[O:31])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCCCN(c2ccccc2)C1=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
To a round bottom flask was added (2R,5R)-methyl 2,5-dibenzyl-6-oxo-6-((R)-2-oxo-1-phenylazepan-3-ylamino)hexanoate (300 mg, 0.570 mmol), 2 M LiOH in water (5.0 mL, 10 mmol) and MeOH (5 mL). The reaction was stirred at rt for 2 days. The reaction mixture was then cooled in an ice-bath and aqueous 1 M HCl was added slowly to adjust the pH to 4. A white precipitant was formed. The product was collected by filtration and washed with water (2×5 mL) to give (2R,5R)-2,5-dibenzyl-6-oxo-6-((R)-2-oxo-1-phenylazepan-3-ylamino)hexanoic acid (280 mg, 0.546 mmol, 96% yield) as a white solid. Anal. Calcd. for C32H36N2O4 m/z 512.4. found: 513.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([N:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]2=[O:43])[CH:29]=[CH:30][C:31]=1[F:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:35]5[C:34](=[O:43])[N:33]([C:28]6[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=6)[C:38]([CH3:39])=[CH:37][CH:36]=5)=[O:41])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)c(F)c1
Yield: 85.6 %

Procedure:
Using a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol) and 1-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (244 mg, 0.919 mmol) in N,N-dimethylacetamide (2.0 mL), HATU (350 mg, 0.919 mmol) and N,N-diisopropylethylamine (160 μL, 0.919 mmol) and in the same manner as in Example 44, the title compound (301 mg, 86%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:20]=[C:19]1[C:40](=[O:44])[N:41]([CH3:43])[CH3:42])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[C:40](=[O:44])[N:41]([CH3:42])[CH3:43])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 90.2 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethyl-silyloxy)methyl)-4-(dimethylcarbamoyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 138, 4 g, 6.11 mmol) in THF (20 mL) was charged with nitrogen and cooled in an ice-bath. To this solution was added 1M TBAF in THF (7.33 mL, 7.33 mmol) dropwise and stirred for 1 h. The solvent was then removed and the crude product loaded onto silica gel and purified via flash chromatography (0-20% MeOH-DCM) to obtain the desired product (2.98 g, 90%) as a beige solid.
Reaction SMILES: [OH:1][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].COC1C=C(C2C=CC(N)=C(OC)C=2)C=CC=1N.Cl.Cl>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:11]([OH:12])[CH:9]1[O:10][CH:2]([OH:1])[CH:3]([OH:4])[CH:5]([OH:6])[CH:7]1[OH:8]
Reactant: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: COc1cc(-c2ccc(N)c(OC)c2)ccc1N
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: OCC1OC(O)C(O)C(O)C1O

Procedure:
The assay was based on the method described by Sullivan and Ikawa (Biochimica et Biophysica Acta, 1973, 309:11-22), but modified to run in microtiter plates. An assay mixture contained 150 μl β-D-glucose (0.1 M in 0.1 M sodium phosphate buffer, pH 6.3), 120 μl 0.1 M sodium phosphate buffer, pH 6.3, 10 μl o-dianisidinedihydrochloride (Sigma D-3252, 3.0 mg/ml in H2O), 10 μl peroxidase (POD) (Sigma P-8125, 0.1 ml in 0.1 M sodium phosphate buffer, pH 6.3) and 10 μl enzyme (HOX) solution. Blanks were made by adding buffer in place of enzyme solution.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])[C:5]([F:16])=[CH:4][CH:3]=1.[F:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[Ca+2].[Ca+2].[Ca+2]>C(O)C.[Pd]>[F:16][C:5]1[C:6]([CH2:8][NH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][OH:12])=[N:7][C:2]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[C:23]([F:24])[C:22]=2[F:25])=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: CC(C)[C@H](CO)NCc1nc(Br)ccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: CC(C)[C@H](CO)NCc1nc(-c2ccc(F)c(F)c2F)ccc1F

Procedure:
A 4 mL vial was charged with SiliaCat DPP-Pd (0.1 equivalent., 26 mg, purchased from Silicycle). Solutions of Example 73A (20 mg, 0.07 mmol) in ethanol (1.0 mL) and 2,3,4-trifluorophenylboronic acid (14 mg, 0.08 mmol) in ethanol (0.3 mL) were added followed by 1 M aqueous Cs2CO3 (0.21 mL). The mixture was heated (Synthos 3000 Anton Paar microwave reaction system) for 30 minutes at 120° C., then filtered and concentrated. The residue was purified by reverse phase HPLC to provide the title compound. MS (ESI+) m/z 343 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([OH:18])[CH:6]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:6][C@H:7]([OH:18])[C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1)=[O:4]
Reactant: COC(=O)C1=C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 14 h

Procedure:
Palladium-on-carbon (1 g, 10 wt %) was added under nitrogen to a solution of (3S,4R)-4-tert-butoxycarbonylamino-3-hydroxycyclopent-1-enecarboxylic acid methyl ester (70 g, 0.29 mol) in methanol (300 ml). The reaction mixture was transferred to a bomb, and, after purging with nitrogen and then hydrogen, a hydrogen pressure of 2 bar was applied and the reaction stirred for 14 h (periodically, additional hydrogen was added to the reaction, to reestablish and initial reaction pressure). The pressure was released and the bomb purged with nitrogen. The reaction mixture was cautiously filtered through Celite® and then concentrated to give the title compound as a syrup of 90% d.e. in quantitative yield.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:39][CH:38]=1>CCOC(C)=O>[CH3:29][N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:36][C:37]4[CH:38]=[CH:39][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:41][CH:42]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CC(=O)O)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added (4-Amino-phenyl)-acetic acid (41.4 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. EtOAc (3 mL) was added to the mixture and was washed with 5% HCl(aq) (2 mL) and H2O (2×2 mL). The organic layers were combined dried over anhydrous Na2SO4, filtered and concentrated in vacuo The solid was then recrystallized from EtOAc/Hexanes affording 51% (0.068 g, 0.127 mmol) of the title compound.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[C:15]2[S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:14]=2[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][CH:11]=1>O>[N+:23]([C:13]1[C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]=2[C:10]([OH:9])=[CH:11][CH:12]=1)([O-:25])=[O:24]
Reactant: COc1ccc([N+](=O)[O-])c2c1sc1ccccc12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(O)c2sc3ccccc3c12
Temperature: 165 °C

Procedure:
Solid pyridine hydrochloride (1 kg, 8.7 mol) was added to 4-methoxy-1-nitro-dibenzothiophene (iii)(35.44 g, 187 mmol) and the reaction mixed well before heating to 165° C. with continuous stirring. The mixture was maintained like this for 8 hrs, cooled, diluted with water (500 ml) and extracted into dichloromethane (3×200 ml). 3M sodium hydroxide solution was added to the organic extract until a dark solid precipitated from the solution. The filtrate was removed and the liquor acidified to pH1 using concentrated HCl. The resulting bright yellow solid that formed on acidification was then removed by filtration, washed with water and dried to give the title compound that was suitably pure to be used without any further purification. (35.44 g, 77%) m/z (LC-MS, ESP), RT=3.69 min, (M+H)=246.2, (M−H)=244.1
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:26])=[C:12]([N:16]2[CH2:19][CH:18]([CH2:20]CS([O-])(=O)=O)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:26][C:11]1[C:12]([N:16]2[CH2:17][CH:18]([CH2:20][O:34][C:31]3[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=3)[CH2:19]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(CCS(=O)(=O)[O-])C2)c1F
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CN(c3cccc(CO)c3F)C2)cn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methylmethanesulfonate (150 mg), 6-methylpyridin-3-ol (70 mg), and DMF (2 ml) were mixed, and potassium carbonate (120 mg) were added thereto, followed by stirring at 80° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. THF (2 ml) and a 1M TBAF/THF solution (0.6 ml) were added to the obtained residue, followed by stirring at room temperature for 1 hour. CHCl3 and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-3-(3-{[(6-methylpyridin-3-yl)oxy]methyl}azetidin-1-yl)phenyl]methanol (74 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.[CH3:11]OS(OC)(=O)=O.S(C)C.[OH-].[Na+]>CS(C)=O>[CH3:1][C:2]1[C:3]2([C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1)[O:10][CH2:11]2
Reactant: CC1=CCCC(C)(C)C1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CSC
Product: CC1=CCCC(C)(C)C12CO2
Yield: 73 %

Procedure:
Prepared under the conditions described in a., starting from 25.0 g (181 mmol) of 2,6,6-trimethyl-2-cyclohexen-1-one, 31.9 g (253 mmol) of (CH3)2SO4, 17.0 g (274 mmol) of (CH3)2S and 43.0 g (1086 mmol) of NaOH in 60 ml of DMSO. 22.09 G of the desired product, 91% pure, were obtained.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([S@:27]([NH2:29])=[O:28])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[N:29][S@@:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@@](=O)N=Cc1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To a solution of 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carbaldehyde (5.2 g, 16.49 mmol) in THF (55.0 mL) was added (R)-(+)-t-butylsulfinamide (2.2 g, 18.14 mmol), and Ti(OEt)4 (7.52 mL, 36.3 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with brine (50 mL) and EtOAc (70 mL) followed by addition of Celite®. Then, the mixture was vigorously stirred for 1 h, and filtered. The filtrate was extracted by EtOAc. The organic layers was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by automatic column chromatography to yield (R)—N-((5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (6.5 g, 94%) as pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.91 (1H, s), 8.04 (1H, m), 7.38-7.22 (5H, m), 7.16-7.05 (2H, m), 4.62 (2H, s), 1.25 (9H, s). LC/MS (uplc): MH+ 419.1, 1.31 min.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([F:25])=[N:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:9]1)=O)(C)(C)C.ClC1C=CC(CN)=CC=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[F:25][C:19]1[C:18]([CH2:17][C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8][CH:9]=2)=[CH:23][CH:22]=[C:21]([F:24])[N:20]=1
Reactant: CC(C)(C)OC(=O)n1cc(Cc2ccc(F)nc2F)c2cccnc21
Agent: NCc1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Fc1ccc(Cc2c[nH]c3ncccc23)c(F)n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To 3-(2,6-difluoro-pyridin-3-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (536, 0.35 g, 1.0 mmol, prepared as described in Example 49, Scheme 164, replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 532 with 1H-pyrrolo[2,3-b]pyridine in step 1) in N-methylpyrrolidinone (3.00 mL) were added p-chlorobenzylamine (0.20 mL, 1.6 mmol) and N,N-diisopropylethylamine (0.30 mL, 0.0017 mol). The reaction was stirred at 50° C. for 72 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the crude intermediate was dissolve in dichloromethane (15.0 mL) and trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 2 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% ethyl acetate in hexane to give a white solid (P-0154, 0.18 g, 72%). MS (ESI) [M+H+]+=246.2.
Reaction SMILES: O[C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1nnc(SC)nc1O
Product: CCOC(=O)c1nnc(SC)nc1Cl
Temperature: 75 °C

Procedure:
To 17.0 g (78.98 mmol) of 5-hydroxy-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester was added 86 mL (1184.7 mmol) of thionyl chloride. The reaction mixture was heated to 75° C. for 2 hours, cooled, and concentrated. The residue was twice suspended in toluene and concentrated to give a yellow-orange solid, 5-chloro-3-methylsulfanyl-1,2,4-triazine-6-carboxylic acid, ethyl ester.