Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11]C(=O)C(F)(F)F)[N:10]=2)[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1
Reactant: O=C(Nc1cn2cc(Br)ccc2n1)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Nc1cn2cc(Br)ccc2n1
Temperature: 25 °C

Procedure:
A stirred solution of N-(6-bromo-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (9.0 g, 29.2 mmol) in DME (90 ml) and 1.27 M aqueous potassium phosphate (80.5 ml, 102.3 mmol) is heated at 90° C. overnight. After cooling to room temperature, the two layers are separate and the aqueous portion is extracted with EtOAc. The combined organic extracts are concentrated in vacuo to afford a brown oil. Iso-hexanes is added to the oil resulting in the formation of a solid. The excess iso-hexanes is decanted off and the remaining DME is azeotroped with THF (2×50 ml) to afford the title compound as a solid [MH+ 211.93].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([CH2:14][NH:15][OH:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C[Si]([N:21]=[C:22]=[O:23])(C)C.[Cl-].[NH4+]>O1CCOCC1>[OH:16][N:15]([CH2:14][C:12]1[S:13][C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:10][CH:11]=1)[C:22]([NH2:21])=[O:23]
Reactant: C[Si](C)(C)N=C=O
Reactant: ONCc1ccc(Sc2ccc(Cl)cc2)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)N(O)Cc1ccc(Sc2ccc(Cl)cc2)s1
Reaction time: 2 h

Procedure:
To a solution of N-[5-(4-chlorophenylthio)thien-2-ylmethyl]hydroxylamine (6.65 g) in dioxan (100 ml) at room temperature under nitrogen, was added trimethylsilylisocyanate (4.25 g) and the resulting solution stirred for 2 hours, poured onto saturated aqueous ammonium chloride, extracted with ether (2×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a yellow oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using ether to give a white solid. Recrystallised from ether/petroleum ether (40°-60° C.) to give a white crystalline solid m.p. 158°-160° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].[O:10]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:11]1[C:12](OC)=[O:13]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[C@H:11]([OH:10])[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[S:9][C:3]=2[CH:4]=1
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Reactant: Nc1ccc(Cl)cc1S
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1

Procedure:
In the same way as in Example 1, the reaction between 2-amino-5-chlorothiophenol and methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate affords (+)-(2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one. Melting point: 237°-241° C. [α]D20 =+91.9° (c=0.1; DMF).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=2)O1>O.O1CCOCC1>[N:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[O:35])[CH:28]=[CH:27][CH:32]=2)[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Brc1cnc2ccccn12
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3ccccn23)c1
Temperature: 90 °C

Procedure:
To a stirred solution of 3-Bromoimidazo[1,2-a]pyridine (commercially available, ex Bionet, 394 mg, 2 mmol) was added a solution of K3PO4 (1.27 g, 6 mmol) in H2O (2 mls). 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (905 mg, 2.5 mmol) dissolved in dioxane (8 ml) was added to the reaction mixture and the reaction deoxygenated by evacuation and refill of the flask with N2 (×2). PdCl2dppf (150 mg, 0.2 mmol) was added and the reaction mixture was deoxygenated (×3). The reaction mixture was heated at 90° C. for 16 h, cooled to RT and partitioned between CH2Cl2 and H2O, then filtered. The layers were separated and the aqueous layer further extracted with CH2Cl2. The organic fractions were combined and passed through a phase separating cartridge, then the solvent removed in vacuo. The residue was purified using a SCX cartridge, washing with MeOH and eluting with 2M NH3/MeOH. The resulting solid was further purified by silica column chromatography (0-3% 2M NH3/MeOH in CH2Cl2) to afford a beige solid (335 mg). MS: [M+H]+=335.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:9]=3[CH:8]=2)=[N:3]1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:22]([O:16][C:15]1[C:9]2[CH:8]=[C:7]([C:4]3[O:5][CH2:6][C:2]([CH3:17])([CH3:1])[N:3]=3)[O:11][C:10]=2[CH:12]=[CH:13][CH:14]=1)[C@H:23]1[O:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CC1(C)COC(c2cc3c(O)cccc3o2)=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)COC(c2cc3c(OC[C@@H]4CO4)cccc3o2)=N1

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4,4-dimethyloxazolin-2-yl)-4-hydroxybenzo(b)furan (1.50 g), (S)-glycidyl nosylate (1.68 g) and potassium carbonate (2.69 g), a crude product of the title compound was quantitatively obtained as a pale-yellow oil.
Reaction SMILES: [N:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[O:9])=[CH:6][C:5]=1[I:18])=[N+:2]=[N-:3].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[C:20]#[CH:21]>C1(C)C=CC=CC=1>[I:18][C:5]1[CH:6]=[C:7]([C:8]([NH:10][CH2:11][C:12]([F:14])([F:15])[F:13])=[O:9])[CH:16]=[CH:17][C:4]=1[N:1]1[CH:21]=[C:20]([C:19]([O:23][CH2:24][CH3:25])=[O:22])[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1I
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(C(=O)NCC(F)(F)F)cc2I)nn1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
To a solution of 4-azido-3-iodo-N-(2,2,2-trifluoroethyl)benzamide (2.93 g, 7.92 mmol) obtained in Example 379b) in toluene (80 ml) was added ethyl propiolate (2.33 g, 23.7 mmol), the reaction mixture was stirred with heating under reflux for 18 hr. After cooling to room temperature, the precipitate was collected by filtration, washed with hexane and dried to give the title compound as a pale-yellow powder (2.80 g, 76%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:48]=[C:49]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:50]=[N:51][CH:52]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:48]=[C:49]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:50]=[N:51][CH:52]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: CC1(C)OB(c2cncc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cncc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was dissolved in 1.9 mL N,N-dimethylformamide. N-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (225 mg, 0.76 mmol) and sodium carbonate (86 mg, 0.81 mmol) were added and the mixture was submitted to three vacuum-argon cycles. Tetrakis(triphenylphosphine)palladium(0) (44 mg, 0.04 mmol) was added under argon conditions. The mixture was stirred at 130° C. during 1.5 h. The reaction was poured into a saturated ammonium chloride solution and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 53 mg (45% yield, 73% purity) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>>[C:10]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: c1cn[nH]c1
Reactant: Brc1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ccc(-n3cccn3)cc2)cc1

Procedure:
Following general procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 4-bromo-1,1′-biphenyl (446 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 410 mg (93% isolated yield) of the desired product as a white crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH:11]([C:13]([CH3:15])=O)=[CH2:12]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:6]2[C:5]=1[C:13]([CH3:15])=[CH:11][CH:12]=[N:7]2)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2cccc([N+](=O)[O-])c12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
To a stirred solution of 3-nitroaniline (1 g. 7.2 mmol.) in acetic acid (10 ml), activated silferc (1.15 g. ferric chloride 7.2 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.55 g, 7.9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.0 g. 7.2 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 64%.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:28][C:29]1[CH:46]=[CH:45][C:32]([CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:46][CH:45]=3)=[CH:41][CH:40]=2)[C:3]=1[N:22]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1Br
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(C)(C)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
The Pd(Ph3P)4 (57.6 mg, 0.05 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (110 mg, 0.25 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (71.3 mg, 0.27 mmol), and sodium carbonate (185 mg, 1.74 mmol) in dioxane (3 mL) and water (0.6 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(3,3-dimethylazetidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 97 mg (67.5%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.32 (br. s, 1H), 7.14 (t, J=8.4 Hz, 2H), 6.99 (d, J=8.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.78 (br. s, 1H), 5.20 (s, 1H), 5.02-4.97 (m, 1H), 4.20 (t, J=6.2 Hz, 2H), 3.44 (s, 4H), 3.05 (t, J=6.6 Hz, 2H), 1.99 (s, 3H), 1.89 (s, 3H), 1.21-1.18 (m, 6H), 1.11 (s, 9H), 1.02 (s, 6H). UPLC (M+H)=577.5.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCCCC=1>CCO.[Pd]>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCNc1cccc[n+]1[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)NCCNc1ccccn1
Reaction time: 16 h
Yield: 200 %

Procedure:
10% Pd/C (106.4 mg, 0.10 mmole) was added to a solution of 2-[[2-(Boc-amino)ethyl]amino]pyridine-N-oxide (126.7 mg, 0.5 mmole) and cyclohexene (0.25 mL, 0.25 mmole) in absolute EtOH (5 mL), and the mixture was heated to reflux. After 16 hr, the reaction was filtered through celite® and the filtrate was concentrated. The residue was combined with the residue obtained from a separate preparation (0.5 mmole scale), and the combined materials were purified by silica gel chromatography (5% MeOH/CHCl3). The title compound (148.4 mg, 63% based on 1 mmole of 2-[[2-(Boc-amino)ethyl]amino]pyridine-N-oxide) was obtained as a yellow oil: TLC (5% MeOH/CHCl3) Rf 0.43; 1H NMR (400, CDCl3) δ 8.05-8.12 (m, 1 H), 7.37-7.46 (m, 1 H), 6.53-6.61 (m, 1 H), 6.41 (d, J=8.3 Hz, 1 H), 5.12 (br s, 1 H), 4.86 (br s, 1 H), 3.26-3.51 (m, 4 H), 1.44 (s, 9 H); MS (ES) m/e 238 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].[CH2:9]=O>C(O)(C)C>[CH:1]([N:4]1[CH2:5][CH2:6][CH2:7][NH:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)NCCCN
Solvent: CC(C)O
Product: CC(C)N1CCCNC1
Yield: 78 %

Procedure:
A solution of N-isopropyl-1,3-propanediamine (116 g, 1 M) in isopropyl alcohol (1 l ) maintained ca 10° was treated dropwise with 40% aqueous HCHO solution (75 ml, 1 M). After 1 hour the solvents were evaporated under reduced pressure and the residue distilled to give N-isopropylhexahydropyrimidine (100 g, 78%), Bp 65° /20 mbar.
Reaction SMILES: [CH3:1][C:2]([S:28]([CH3:31])(=[O:30])=[O:29])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(CCc1ccc(Oc2ccccc2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (247.2 mg, 0.552 mmol) was dissolved in methylene chloride (10 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 4.14 mL, 16.6 mmol) and the solution was stirred at RT for 5 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4-phenoxyphenyl)butanamide as a solid. 94.4 mg. LCMS: (M−1) 362.3
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CN(C)[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18].[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH3:18][C:17]1([CH3:19])[CH:27]([C:26]2[CH:29]=[CH:30][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH2:28][C:16]1=[O:20]
Reactant: CC(C)C(=O)N(C)C
Reactant: C=Cc1ccc(C)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: Cc1ccc(C2CC(=O)C2(C)C)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
Trifluoroacetic anhydride (25 g, 0.09 mol) was added portionwise over a period of 10 minutes at −10° C., to a solution of N,N-dimethyl-isobutyramide (9.16 g) in DCM (100 mL). The resulting mixture was stirred at −10° C. for 10 minutes and then a viscous solution of 4-methylstyrene (8.2 g) and collidine (11.9 mL) in DCM (15 mL) was added portionwise at −10° C. The resulting mixture was heated at reflux for 22 hours then cooled and concentrated under reduced pressure. The oil residue was washed with ethyl ether and the organic phase was decanted away. DCM (75 mL) and water (75 mL) were added to the oil and the mixture was heated at 100° C. for 6 hours. The mixture was cooled to room temperature, separated, and the aqueous layer was extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure to give 35 g of crude oil, which was purified by flash chromatography (5% to 50% of EtOAc in hexane) to give 6.45 g (50% yield) of 2,2-dimethyl-3-p-tolyl-cyclobutanone as a yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[N:9]([CH3:27])[C:10](=[O:26])[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]([NH:16][CH3:17])=[O:15])[N:13]=1.[CH3:28][C:29]1[CH:30]=[C:31]([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][CH:34]=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH3:17][NH:16][C:14]([C:12]1[N:13]=[C:8]([NH:7][S:36]([CH2:35][C:31]2[CH:30]=[C:29]([CH3:28])[CH:34]=[CH:33][CH:32]=2)(=[O:38])=[O:37])[N:9]([CH3:27])[C:10](=[O:26])[C:11]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:15]
Reactant: CNC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Reactant: Cc1cccc(CS(=O)(=O)Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(NS(=O)(=O)Cc2cccc(C)c2)n(C)c(=O)c1OCc1ccccc1
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
Potassium tert-butoxide (75.9 mg, 676 μmol) was added to a solution of 2-amino-5-(benzyloxy)-N,1-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (150 mg, 520 μmol) in THF (15.0 ml) and DMF (3 ml). The resulting mixture was stirred for 10 min and then cooled with an ice-bath. To this mixture was slowly added a solution of (3-methylphenyl)methanesulfonyl chloride (140 mg, 684 μmol) in THF (1 ml). The reaction mixture was stirred at room temperature overnight. A further solution of (3-methylphenyl)methanesulfonyl chloride (140 mg, 684 μmol) in THF (1 ml) was added and then the mixture was stirred at room temperature for 48 hours. The resulting mixture was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine. The organic layers were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (silica gel, 0% to 2% MeOH in DCM) provided the desired product as a light yellow solid (0.070 g; 29%). LCMS: m/z=457 (MH+).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.C([BH3-])#N.[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=O.CC(O)=O>CN(C=O)C>[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][C:36]([F:37])([F:38])[F:39])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(OC(F)(F)F)c(Br)c4)CC3)OC2=O)cc1
Yield: 66.2 %

Procedure:
To methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (300 mg, 0.918 mmol; Example 1, Step 2), MP-cyanoborohydride (1192 mg, 2.75 mmol), 3-bromo-4-trifluoromethoxybenzaldehyde (272 mg, 1.01 mmol) and AcOH (79 μl, 1.38 mmol) was added 5 mL of DMF. The reaction mixture was filtered, the resin was washed with DMF and the solvent was evaporated. The residue was dissolved in saturated aqueous NaHCO3 and extracted with DCM. The combined organic layers were evaporated to yield the title compound as a light yellow solid (330 mg) that was used without any further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13]3=[C:14]([C:16](=[O:19])[CH:17]=[CH:18][N:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=3)[CH:15]=1)#[N:2].[OH-:20].[Na+]>C(OCCO)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:13]3=[C:14]([C:16](=[O:19])[CH:17]=[CH:18][N:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=3)[CH:15]=1)(=[O:20])[NH2:2]
Reactant: N#Cc1cc2c(=O)ccn3c4ccccc4c(c1)c23
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOCCO
Product: NC(=O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Yield: 20 %

Procedure:
2-cyano-4H-pyrido[3,2,1-jk]carbazole-4-one (880 mg) produced in Example 173 was suspended in ethylene glycol monoethylether (88 ml), and 1N aqueous solution of sodium hydroxide (5.3 ml) was added to the suspension. The mixture was heated under reflux in an argon atmosphere for 4 hours, and allowed to cool. The reaction mixture was added to 2N aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate) to obtain the title compound (180 mg, 20%).
Reaction SMILES: [C:1]1([CH2:13][C:14]#[N:15])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH:11]=[CH:12][C:6]=3[C:5]=12>N.CO.[Co]>[C:1]1([CH2:13][CH2:14][NH2:15])[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]3[O:10][CH:11]=[CH:12][C:6]=3[C:5]=12
Reactant: N#CCc1cnn2ccc3occc3c12
Agent: [Co]
Agent: N
Solvent: CO
Product: NCCc1cnn2ccc3occc3c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
Furo[3,2-c]pyrazolo[1,5-a]pyridin-1-ylacetonitrile (55.0 mg, 0.279 mmol) and Raney cobalt (500 mg) were suspended in 2M ammonia/methanol solution (10 mL), and the suspension was stirred at room temperature for 3 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (55.5 mg, yield 99%).