Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[C:40](O)(=[O:42])[CH3:41].C(=O)([O-])[O-]>>[C:40]([N:37]1[CH2:38][CH2:39][CH:35]([NH:34][C:32]([C:5]2[C:6]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]5[N:21]([CH3:29])[C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=4)[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=2)=[O:33])[CH2:36]1)(=[O:42])[CH3:41]
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Product: COc1cc(-c2csc3c(C(=O)NC4CCN(C(C)=O)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 20 h

Procedure:
4-Amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-pyrrolidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (100 mg, 0.185 mmol) and acetic acid (9.6 μL, 0.168 mmol) were treated according to General Procedure D. MP-carbonate (184 mg, 0.504 mmol) was added and mixture placed on shaker for 20 hours. The mixture was then filtered and solvent removed in vacuo. The product was purified via flash chromatography to furnish the title compound as a off-white powder. (3.2 mg, 0.0051 mmol): LCMS (Conditions b): MH+=583, Rt=2.85 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (1H), 8.62 (1H), 8.54 (1H), 8.00 (1H), 7.71 (1H), 7.59 (2H), 7.35 (2H), 7.19 (1H), 7.15 (1H), 7.06 (1H), 6.04 (2H), 4.46-4.56 (1H), 4.04 (3H), 3.91 (3H), 3.80 (1H), 3.61 (1H), 3.50 (1H), 3.39 (1H), 2.00-2.22 (2H), 1.96 (3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.O>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1
Reactant: CCCCCCCCCBr
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCOc1cc(C(=O)Nc2c(Cl)cncc2Cl)ccc1OC
Temperature: 25 °C

Procedure:
A stirred solution of N-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (2.0 g; that is prepared as described in Reference Example 12) in dimethylformamide (20 mL) at room temperature under nitrogen is treated portionwise with a suspension of sodium hydride (60% dispersion in oil; 0.26 g), and then it is stirred for a further hour at room temperature. It is then treated dropwise with 1-bromononane (1.2 mL) and stirred at 60° C. for 5 hours. The solution is then cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated, to give a white solid, which is subjected to flash chromatography on silica gel, eluting with t-butyl methyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-nonyloxy-4-methoxybenzamide (0.56 g), m.p. 151-153° C. [Elemental analysis: C,60.3; H,6.45; N,6.3%; calculated: C,60.1; H,6.4; N,6.4%].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:7]=[N:8][CH:9]=1.[CH3:17]I>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH3:17])[C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:7]=[N:8][CH:9]=1
Reactant: Brc1cncc(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 143.3 %

Procedure:
NaH (17 mg, 0.71 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (1.2 mL) was added. The slurry was cooled to 0° C. and compound 10 (164 mg, 0.653 mmol, 1.00 eq) was added as a solution in THF (1.2 mL). After stirring at 0° C. for 30 minutes methyl iodide (44.8 μL, 0.708 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 248 mg (93%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.62 (s, 2H), 8.35 (d, J=2.4 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.78 (t, J=2.2 Hz, 1H), 3.36 (s, 3H); [M+1]+: 265.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@H:25]4[CH3:37])[CH:19]=[N:20][C:21]=3[F:22])[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>C(Cl)Cl>[F:22][C:21]1[C:16]([C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH2:7][C:6]3[CH:47]=[CH:48][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)=[CH:17][C:18]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:26][C@H:25]2[CH3:37])=[CH:19][N:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3F)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@H]4C)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a slightly cooled stirred solution of (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (1.01 g, 1.535 mmol) in DCM (5.0 mL, 78 mmol) was added slowly TFA (4.00 mL, 51.9 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the sticky residue was taken up in a solution of DCM (10.0 mL) to which TEA (2.140 mL, 15.35 mmol) and methanesulfonyl chloride (0.598 mL, 7.68 mmol) was slowly added subsequently at 0° C. The mixture was stirred at the same temperature for 1 h, concentrated, and the crude product was partitioned between 1 N NaOH(aq) and DCM (20 mL each). The separated aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 10% ethyl acetate/hexanes to 70% ethyl acetates in hexanes) to obtain the desired product (R)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.4779 g, 0.752 mmol, 49.0% yield) as a pale yellow foam. m/z (ESI, +ve ion) 636 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]=O)([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:20][CH2:19]1)=[O:17]
Reactant: O=CCc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](CNCCc2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of (2-Nitro-phenyl)-acetaldehyde (1 g, 5.98 mmol), trans-4-Aminomethyl cyclohexanecarboxylic acid methyl ester hydrogen chloride salt (1.37 g, 6.58 mmol) and TEA (0.92 mL, 6.58 mmol) in dry DCM was stirred at room temperature for 2.5 h. Sodium triacetoxy borohydride (2.53 g, 11.96 mmol) was added and the mixture stirred at room temperature for 25 min. Then (2N) HCl was added until acidic pH and the aqueous layer extracted with DCM. The organic layer was washed with a saturated solution of NaHCO3 and dried over Na2SO4 anhydrous and then evaporated to afford crude product. Finally, the crude product was purified by flash chromatography on silica (ETP/EtOAc 9/1→0/1) to obtain the titled compound (0.51 g, yield: 27%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:19]([O:21][P:22]([O-:26])[O:23][CH2:24][CH3:25])[CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9]([CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:22](=[O:26])([O:23][CH2:24][CH3:25])[O:21][CH2:19][CH3:20])=[CH:3][CH:4]=1)=[O:10]
Reactant: COC(=O)C(c1ccccc1)c1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)OC)c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of compound Methyl 2-(4-bromophenyl)-2-phenylacetate, 14-d, (1.52 g, 5.0 mmol), diethylphosphite (2.42 g, 17.5 mmol) and triethylamine (3.13 g, 31 mmol) in toluene (20 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dicholoropalladium (100 mg). The mixture was allowed to stir overnight at 110° C. and filtrated. The solution was concentrated to afford the crude product which was purified by column chromatography to give compound 14-e as colorless oil (1.7 g, 94%). 1H NMR (300 MHz, CDCl3) δ1.29-1.35 (m, 6H), 3.73 (s, 3H), 4.10-4.13 (m, 4H), 5.03 (s, 1H), 7.23-7.40 (m, 7H), 7.69-7.77 (m, 2H). LC-MS: (M+H)+ 363.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[C:17]([CH2:29][CH2:30]O)[N:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Br:2][CH2:30][CH2:29][C:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=2)[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=1
Reactant: COc1ccc(-c2nc(CCO)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(-c2nc(CCBr)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 75 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Phosphorus tribromide (PBr3)(0.95 g) was added dropwise to a solution of 4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)-6,7-dimethoxyquinazoline (2.6 g) in benzene (50 ml) at room temperature. The mixture was stirred at 75° C. for 1 hour, poured into ice-cold water, neutralized with an aqueous saturated solution of sodium bicarbonate, and then extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (3:1, v/v) gave 2-(2-bromoethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (1.1 g, 37%). This was recrystallized from ethyl acetate. Colorless needles, mp. 166°-167° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1CCCC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(Cl)c(C[C@H](CC=O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c(Cl)c1
Yield: 49 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)-2-(4-methoxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (6.65 g, 14.87 mmol), tetrahydrofuran (140 mL) and water (45 mL) with 2.5% osmium tetroxide in t-butanol (378 mL, 1.487 mmol). Add sodium periodate (9.55 g, 44.63 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 3.35 g (49%) of desired product. MS (m/z): 451 (M+).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[C@@H:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=2)=[O:17])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.Br[C:41]1[S:42][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]([CH3:46])[N:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([NH:8][C@H:9]1[C@@H:14]([NH:15][C:16]([C:18]2[NH:19][C:20]([CH2:24][CH3:25])=[C:21]([Cl:23])[N:22]=2)=[O:17])[CH2:13][CH2:12][N:11]([C:41]2[S:42][C:43]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:44]([CH3:46])[N:45]=2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NCc2ccccc2)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](NCc3ccccc3)C2)nc1C
Yield: 57.2 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-3-(benzylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (203a) (26.0 mg, 0.056 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (17 mg, 0.068 mmol) and sodium carbonate (60 mg, 0.563 mmol), to obtain 17 mg of the title compound (57%) as a colorless solid.
Reaction SMILES: [CH2:1]1[O:12][CH:4]([CH2:5][CH:6]2[CH:10]=[CH:9][CH2:8][C:7]2=[O:11])[S:3][CH2:2]1.CC(O)([C:16]#[N:17])C.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[CH2:1]1[O:12][CH:4]([CH2:5][CH:6]2[CH:10]([C:16]#[N:17])[CH2:9][CH2:8][C:7]2=[O:11])[S:3][CH2:2]1
Reactant: CC(C)(O)C#N
Reactant: O=C1CC=CC1CC1OCCS1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC1CCC(=O)C1CC1OCCS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
18 g of the mixture of (2-oxo-cyclopent-4-enyl)acetaldehyde-ethylenethioacetal and (2-oxo-cyclopent-5-enyl)acetaldehyde-ethylene-thioacetal according to stage 2 were dissolved in 150 ml of methanol and 9.2 g of acetonecyanohydrin and a solution of 7.5 g of Na2CO3 in 20 ml of water were added. After stirring for 3 hours at room temperature, all the solvent was distilled off in vacuo, the residue was taken up in 500 ml of diethyl ether and 100 ml of H2O, and the ether phase was washed twice with 50 ml of H2O, dried over sodium sulfate and condensed. The residue was triturated with a small amount of ether and 12 g of crude product were obtained which melted at about 98° C.
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.[CH3:26][O:27][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>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][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:30][CH:29]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Product: COc1ccc(CC(=O)Nc2cccc(-c3n[nH]c4ccc(C(N)=O)cc34)c2)cc1
Yield: 9.1 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with 4-methoxyphenylacetic acid (0.15 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 27 mg (11% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.3 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (bs, 1H), 7.9 (d, 1H), 7.7 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4–7.1 (m, 2H), 6.9 (d, 1H), 3.7 (s, 3H), 3.6 (s, 2H); ES-MS (m/z) 401 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:24]=[N+:25]=[N-:26])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2N=[N+]=[N-])cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to Example 193E, (500 mg, 1.36 mmol) was dissolved in DMF (10 mL) and treated with NaN3 (100 mg, 1.5 mmol). After 2 hours at room temperature, the reaction was diluted with ethyl acetate and washed with water, 4 times, and dried over MgSO4. After filtration of the drying agent and concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (Biotage 40S) eluted with 2:1 hexanes-ethyl acetate. The product fractions were combined and evaporated to provide the azido intermediate, 2-(2,2,2-Trifluoroethyl)-4-azido-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 481 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:57])[C:30]([CH3:56])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:57])[C:30]([CH3:56])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.9 %

Procedure:
p-Methoxyaniline (0.056 g, 0.457 mmol), triethylamine (0.046 g, 0.457 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.077 g, 0.457 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenoxy)benzoic acid (0.100 g, 0.228 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=2:3) to obtain the titled compound (0.058 g, 0.107 mmol, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10]Cl)=[CH:4][CH:3]=1.[CH3:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][P:14]([CH3:13])(=[O:18])[O:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCOP(C)OCC
Reactant: O=C(CCCl)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CCOP(C)(=O)CCC(=O)c1ccc(Br)cc1

Procedure:
1-(4-bromophenyl)-3-chloropropan-1-one (4.5 g, 18.18 mmol) and diethyl methylphosphonite (6 g, 44.1 mmol) were stirred in refluxing toluene (9 mL) for 5 hours. Room temperature was attained and the solvent removed in vacuo. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave ethyl [3-(4-bromophenyl)-3-oxopropyl]methylphosphinate as a pale yellow oil that crystallised on standing.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([C:37]([OH:40])([CH3:39])[CH3:38])[CH:34]=[C:33]([F:41])[C:32]=1[C:42]1[N:47]=[C:46]([C:48](O)=[O:49])[CH:45]=[CH:44][C:43]=1[F:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:48]([C:46]3[CH:45]=[CH:44][C:43]([F:51])=[C:42]([C:32]4[C:31]([F:30])=[CH:36][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:34][C:33]=4[F:41])[N:47]=3)=[O:49])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (299 mg, 0.739 mmol), 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (230 mg, 0.739 mmol) and HATU (562 mg, 1.48 mmol) in DMF (0.7 mL) and DIPEA (0.386 mL, 2.22 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water, the mixture was extracted with EtOAc (2 times). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to give an amide intermediate, 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[CH2:13]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])[CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:13]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](=[NH:22])[O:21][CH2:6][CH3:7])[CH2:14][CH2:15][CH3:16]
Reactant: CC[O+](CC)CC
Reactant: CCCCOc1ccccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCCOc1ccccc1C(=N)OCC
Reaction time: 20 h
Yield: 54.5 %

Procedure:
A solution of triethyloxonium fluoroborate (32.4 g., 0.171 mole) in methylene chloride (75 ml.) was added to a stirred solution of 2-n-butoxybenzamide [J. Pharm. Pharmacol., 4, 872 (1952) ](33.0 g., 0.171 mole) in methylene chloride 8200 ml.) at 25°. The mixture was stirred at 25° for 20 hours. The solution was concentrated to about one fifth of the original volume and then diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride-diethyl ether to give ethyl 2-n-butoxybenzimidate fluoroborate (28.7 g.), m.p. 82°-88°. To a stirred, cooled (ice-water) suspension of the fluoroborate (28.7 g.) in ethanol (75 ml.) was added 8% ethanolic ammonia (150 ml.). The mixture was stirred at 25° for 20 hours. The ethanol was removed and the residue partitioned between ether and 5N sodium hydroxide (100 ml.). The ether layer was washed with brine, dried over sodium sulfate, and then concentrated. A solution of the residual oil in ether was treated with hydrogen chloride to precipitate the title compound (16.8 g.), m.p. 150°-155°.