Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=O)=O.O[C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:29]=[C:25]1[CH:24]=[C:23]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[CH:28]=[CH:27][NH:26]1
Reactant: CS(=O)(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=c1cc(O)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 140 °C
Yield: 33.5 %

Procedure:
A stirring suspension of benzyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.97 g, 6.30 mmol), 4-hydroxypyridin-2(1H)-one (0.50 g, 4 5 mmol, Aldrich), potassium carbonate (1.43 g, 10 6 mmol, EMD) and DMF (25 mL) was heated at 140° C. for 2.5 h and then cooled to room temperature. The resulting mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo to a light yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 10% MeOH in CH2Cl2) to yield 550 mg of desired product as a white solid. MS (ESI) 329 (M+H).
Reaction SMILES: [CH:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1>>[C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][C:12]([C:7]3([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:17]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)C1(C2CCCCC2)CCCC1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1(C2CCCCC2)CCCC1

Procedure:
1-Cyclohexyl-1-cyclopentanecarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-cyclohexyl-1-cyclopentanecarboxamide.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])c(Cl)c12
Reactant: CN
Solvent: CO
Product: CNc1c([N+](=O)[O-])ccc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Chloro-6-nitroquinazolin-4-one, from Example 3 (0.26 g, 1.15 mmol) was suspended in MeOH (3 mL) at −20° C. Methylamine gas was passed into the mixture for a few minutes, resulting in a clear solution. The solution was stirred at room temperature for 5 h and evaporated to give 5-methylamino-6-nitroquinazolin-4-one in quantitative yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([O:20][C:21]4[N:22]=[CH:23][C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=4)[CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[CH:5]1([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([O:20][C:21]4[N:22]=[CH:23][C:24]([C:27]([Cl:3])=[O:29])=[N:25][CH:26]=4)[CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (5 ml) was added slowly to 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-pyrazine-2-carboxylic acid (E123a) (485 mg). The resulting reaction mixture was stirred at room temperature for 1 hour and then heated at reflux for a further 1 hour. The reaction mixture was cooled, diluted with toluene and concentrated in vacuo to afford the title compound which was used without further characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:22]([O:29][CH:30]1[CH:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:32][C:31]1=[O:61])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1>[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:32][C:31]1([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:9]=1)[OH:61])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: COc1ccc(Cc2cccc(Br)c2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cccc(C3(O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Reaction time: 0.42 h
Yield: 29.2 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-1-bromobenzene (155 mg, 0.559 mmol) in THF (0.80 mL), an n-butyllithium 2.44 M hexane solution (0.23 mL, 0.559 mmol) was added dropwise at −78° C. and the mixture solution was stirred for 25 minutes. Then, a solution of 2,3,4-tribenzyloxy-5-(benzyloxy-methyl)cyclohexanone (200 mg, 0.373 mmol) in THF (0.70 mL) was added dropwise thereto and the reaction mixture was stirred for 75 minutes. To the reaction mixture was added a saturated ammonium chloride aqueous solution and the mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel chromatography [developing solution=ethyl acetate:n-hexane (2:5)] to obtain the title compound (80 mg, 27%) as a mixture of 1R-isomer and 1S-isomer.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:26]2[CH:27]=[CH:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33]O)[CH:31]=2)=[CH:21][CH:20]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:33][CH2:32][N:30]3[CH:31]=[C:26]([CH:25]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH:27]=[CH:28][C:29]3=[O:35])[C:10]=2[N:9]=[C:8]1[CH3:11])[CH3:17]
Reactant: CCOC(=O)Cn1c(C)nc2c(O)cccc21
Reactant: O=c1ccc(C(c2ccc(F)cc2)c2ccc(F)cc2)cn1CCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(C)nc2c(OCCn3cc(C(c4ccc(F)cc4)c4ccc(F)cc4)ccc3=O)cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl (4-hydroxy-2-methyl-1H-benzimidazol-1-yl)acetate (476 mg), 5-[bis(4-fluorophenyl)methyl]-1-(2-hydroxyethyl)pyridin-2(1H)-one (694 mg), 1,1′-azobis(N,N-dimethylformamide) (385 mg) and toluene (9.5 mL) was added tributylphosphine (452 mg) at ambient temperature. The mixture was stirred at ambient temperature for 20 hours. The reaction mixture was diluted with a mixture of EtoAc (50 mL) and THF (20 mL), and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was crystallized from solvent(EtOAc and n-hexane) to give ethyl[4-(2-{5-[bis(4-fluorophenyl)methyl]-2-oxopyridin-1(2H)-yl}ethoxy)-2-methyl-1H-benzimidazol-1-yl]acetate (1.07 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1>>[CH3:4][C:3]([CH2:2][S:13][C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)=[O:5]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)CCl
Product: CC(=O)CSc1ccc(Cl)cc1

Procedure:
Reaction of chloroacetone with 4-chlorothiophenol gave (4-chlorophenyl)thiomethyl methyl ketone, which was cyclized by reaction with polyphosphoric acid to 5-chloro-3-methylbenzothiophene. Bromination of the latter compound by photochemical reaction with N-bromosuccinimide provided 5-chloro-3-bromomethylbenzothiophene, which was reacted with sodium cyanide to give 5-chloro-3-cyanomethylbenzothiophene. The latter compound was hydrolyzed and esterified to give methyl α-(5-chloro-3-benzothienyl)acetate. Reaction of the ester with sodium methoxide and n-butyl nitrite afforded methyl α-hydroxyimino-α-(5-chloro-3-benzothienyl)acetate. Reduction of the oxime by reaction with zinc and formic acid and subsequent reaction with di-tert.-butyl carbonate gave N-tert.-butoxycarbonyl-(5-chloro-3-benzothienyl)glycine. NMR (CDCl3): δ 1.1-1.5 (broad s, 9H); δ 5.4-5.7 (broad s, 1H); δ 7.2-8.0 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][CH:46]([N:49]2[CH2:54][CH2:53][S:52](=[O:55])[CH2:51][CH2:50]2)[CH2:45][CH2:44]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=3)[C:29](=[O:30])[N:43]3[CH2:44][CH2:45][CH:46]([N:49]4[CH2:50][CH2:51][S:52](=[O:55])[CH2:53][CH2:54]4)[CH2:47][CH2:48]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: O=S1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCS(=O)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 1.21 from 80 mg (0.17 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 77 μL (0.55 mmol) triethylamine and 47 mg (0.17 mmol) 4-piperidin-4-yl-thiomorpholine-1-oxide (used as the bis-hydrochloride salt).
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][CH:5]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].C([Mg]Cl)(C)C>O1CCCC1>[CH3:25][O:24][N:23]([CH3:22])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: -30 °C
Yield: 99.7 %

Procedure:
6-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester (20 g, 71.2 mmol) is dissolved into anhydrous tetrahydrofuran (TVF) (300 mL) and then cooled to −30° C. while stirring under nitrogen. N,O-dimethylhydroxylamine hydrochloride (10.4 g, 107 mmol) is then added to the solution in one portion. Isopropyl magnesium chloride (107 mL, 2M soln. in THF, 252 mmol) is slowly added to the cooled suspension over 2 h. After complete consumption of starting material, 30% solution of ammonium chloride is added with stirring. The reaction is diluted with diethyl ether, water, and extracted. The organic layer is collected and washed with cold water (2×) and brine. The solution is then dried over anhydrous sodium sulfate, filtered, and concentrated. The N-Methoxy-N-methyl-6-(4-trifluoromethyl-phenyl)-nicotinamide (22 g, 71 mmol) is obtained in purified form after flash column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:21][CH2:20][CH2:19][Cl:18])[C:9]#[N:10]
Reactant: COc1cc(C#N)ccc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1OCCCCl
Temperature: 37 °C
Yield: 103 %

Procedure:
2-methoxy-4-cyano-phenol (0.25 g, 1.67 mmol) and anhydrous DMF (2.00 mL) were added into a round bottom flask. The solution was stirred and cooled in a water bath. Several batches of anhydrous K2CO3 (0.347 g, 2.50 mmol) were added to the solution and the mixture was stirred at 20° C. to react for 1 h. 1-chloro-3-bromopropane (0.23 ml, 2.14 mmol) was added, and the mixture was stirred at room temperature (25° C.) to react overnight. The mixture was heated to 37° C. to react for 6 h and then poured into a mixture of ice/H2O (25 mL). After stirring for 10 min, a precipitate was formed. Filtered, washed with H2O, and air-dried to yield white solid product (0.388 g) with a recovery rate of 90%.
Reaction SMILES: [C:1]([CH2:4][C:5]1([C:14]([OH:16])=[O:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([OH:3])=O>C(Cl)(=O)C>[CH2:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]21[CH2:4][C:1](=[O:3])[O:16][C:14]2=[O:15]
Reactant: O=C(O)CC1(C(=O)O)Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C1CC2(Cc3ccccc3C2)C(=O)O1

Procedure:
A solution of 2-(carboxymethyl)indane-2-carboxylic acid from Step C (1.10 g, 4.99 mmol) in acetyl chloride (18 mL) was heated at reflux for 18 h, then concentrated in vacuo. The residue was recrystallized from toluene to give 1′,3′-dihydrospiro[furan-3,2′-indene]-2,5(4H)-dione as an ivory solid. This solid was dissolved in CH2 Cl2 (25 mL) and NH3 (g) was bubbled into the mixture for 20 min. After a further 30 min, the solvent was evaporated under reduced pressure. The resulting solid was dried under high vacuum for 1 h, then resuspended in acetyl chloride (20 mL) and heated to reflux for 18 h. The solvent was removed in vacuo and the crude solid was recrystallized from EtOH:Et2O to afford the title compound. MS: m/z=202 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[O:20][C:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:18][N:17]=3)=[CH:15][C:10]=2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[O:20][C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[N:18][N:17]=3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(-c5nnc(C6CCN(C(=O)OC(C)(C)C)CC6)o5)ccc43)cc2OC)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5nnc(C6CCNCC6)o5)ccc43)cc2OC)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
To a −20° C. solution of tert-butyl 4-(5-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (0.090 mg, 0.14 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1.0 mL). The resulting mixture was stirred at −20° C. After 1 h, the mixture was concentrated. The residue was purified by Prep-HPLC to afford 0.010 g (14%) of the product as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.02-8.01 (m, 2H), 7.67 (dd, J=8.5, 2.0 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.76-6.72 (m, 3H), 5.32 (s, 2H), 5.03 (s, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 3.31-3.29 (m, 2H), 3.23-3.21 (m, 1H), 2.92-2.88 (m, 2H), 2.23-2.21 (m, 2H), 2.02-1.98 (m, 2H) ppm; (M+1)=527.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3([C:36]4[C:27](=[CH:28][C:29]5[O:34][CH2:33][CH2:32][O:31][C:30]=5[C:35]=4[F:37])[O:26][CH2:25]3)[C:17]2=[O:38])=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C.CO>[F:37][C:35]1[C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=[C:27]2[O:26][CH2:25][C:18]3([C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=4)[C:17]3=[O:38])[C:36]=12
Reactant: O=C1N(Cc2ccc(OCc3ccccc3)cn2)c2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1N(Cc2ccc(O)cn2)c2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Reaction time: 5 h
Yield: 46 %

Procedure:
Following the procedure as described in EXAMPLE 5.25 and making non-critical variations using 5-(benzyloxy)-2-(chloromethyl)pyridine hydrochloride to replace 2-(bromomethyl)pyridine hydrobromide, 1′-{[5-(benzyloxy)pyridine-2-yl]methyl}-9-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (59%) was obtained as a colorless solid: MS (ES+) m/z 511.0 (M+1). A mixture of the 1′-{[5-(benzyloxy)pyridine-2-yl]methyl}-9-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one from the last step, palladium on carbon (10% w/w, 0.2 g), methanol (50 mL) and acetic acid (1 drop) was hydrogenated at a pressure of 50 psi at ambient temperature for 5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 70% gradient of ethyl acetate in dichloromethane to afford 9-fluoro-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.37 g, 46%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ9.88 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.25-7.09 (m, 4H), 7.01-6.87 (m, 2H), 6.12 (d, J=1.8 Hz, 1H), 4.88 (ABq, 2H), 4.82 (ABq, 2H), 4.29-4.09 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.0, 152.8, 145.2, 142.6, 141.5, 141.4, 138.7, 138.0, 137.1, 134.8, 133.4, 133.2, 131.0, 128.8, 123.5, 123.0, 122.8, 122.4, 122.2, 109.5, 106.0, 80.2, 64.3, 63.6, 57.5, 44.2; MS (ES+) m/z 421.1 (M+1).
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)=O>C1COCC1>[CH2:2]([O:9][CH2:10][CH2:11]/[CH:12]=[CH:42]\[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[CH2:46][CH2:45]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(/C=C\CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(3-Benzyloxypropyl)triphenylphosphonium bromide (2.88 g, 5.86 mmol) was suspended in 15 mL THF and cooled to 0° C. Sodium bis(trimethylsily)amide (1M in THF, 5.63 mL, 5.63 mmol) was added dropwise. The mixture turned deep orange. tert-Butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69 mmol) in 3 mL THF was added after 5 minutes. Color faded to slight yellow. The reaction was stirred at room temperature for 1.5 hours, before quenching with saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, concentrated and purified by passing through a 40 gram Biotage silica gel cartridge using 20% EtOAc/hexanes to afford the product as colorless oil. NMR integration indicated >20:1 Z/E selectivity. LRMS calc: 345.2; obs: 346.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35]C(=O)C)[CH:10]=1.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][CH2:30][C:31]([OH:34])([CH3:32])[CH3:33])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35][S:42]([CH:39]2[CH2:41][CH2:40]2)(=[O:44])=[O:43])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CCC(C)(C)O)nn4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: CC(C)(O)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)nn1

Procedure:
The compound was prepared from the compound of Example 44 using the procedures of Example 45 and cyclopropane sulfonyl chloride. 1H NMR (400 MHz, CD3OD): δ 9.09 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.0 (d, 1H), 7.83 (d, 1H), 7.69-7.60 (m, 4H), 7.17-7.10 (m, 2H), 4.62-4.58 (m, 2H), 2.78-2.69 (m, 1H), 2.17-2.13 (m, 2H), 1.29-1.15 (m, 8H), 1.10-1.02 (m, 2H); LC-MS (ESI): Calculated mass: 578.63; Observed mass: 579.2 [M+H]+ (rt: 1.449 min).
Reaction SMILES: O1CCCC1.C([NH:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:17]([F:35])=[CH:16][C:15]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40])=[O:37])C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[NH2:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[C:17]([F:35])=[CH:16][C:15]=1[C:36]([NH:38][C:39]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:40])[CH3:41])=[O:37]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(NCc2ccccc2)c(C(=O)NC(C)(C)c2ccccc2)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(N)c(C(=O)NC(C)(C)c2ccccc2)cc1F
Yield: 72.1 %

Procedure:
Palladium hydroxide (0.29 g) was added to a solution of tetrahydrofuran (7.2 ml) and methanol (14.3 ml) containing tert-butyl cis-2-(6-benzylamino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (1.43 g), followed by stirring at room temperature for 1 hour in a hydrogen atmosphere. Insoluble matter was removed by filtration, and filter cake was washed with ethyl acetate. The filtrate was mixed with the washing solution, and the solvent was distilled away under reduced pressure. Diisopropylether and hexane were added to the obtained residue, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-amino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (870 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[F:26][C:27]([F:38])([F:39])[C:28]1[CH:29]=[CH:30][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:32][CH:33]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(C(F)(F)F)cc4)c3)c2c1
Yield: 11.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-(trifluoromethyl)phenylacetic acid (0.15 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 28 mg (11% yield) of the title compound. 1H NMR (DMSOd6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.22 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.8-7.68 (m, 3H), 7.6 (m, 3H), 7.5 (t, 1H), 7.35 (s, 1H), 7.17 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 439 [M+H]+.