Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH2:11]=O>CO.O.[Pd]>[CH3:11][N:5]1[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3][C@@H:4]1[C:8]([OH:10])=[O:9]
Reactant: C[C@@H]1CCN[C@@H](C(=O)O)C1
Reactant: C=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: C[C@@H]1CCN(C)[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of (2R,4R)-4-methylpiperidine-2-carboxylic acid (2 g, 13.97 mmol) in MeOH (40 mL) and water (40.0 mL) was added paraformaldehyde (2.52 g, 27.94 mmol) and Pd/C (10%) (0.8 g, 7.52 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature overnight. From TLC, the reaction was not completed. Another one equivalent of paraformaldehyde (2.52 g, 27.94 mmol) was added and the reaction mixture was stirred another 24 hours. TLC indicated the reaction was completed and reaction mixture was filtered, washed the catalyst with MeOH (2×30 mL). The filtrate was concentrated in vacuo to give crude product as a white solid, which was washed with ether (3×30 mL), dried in high vacuum overnight to yield (2R,4R)-1,4-dimethylpiperidine-2-carboxylic acid (1) (1.870 g, 85%) as a white solid. LC-MS: 158 (M+1); 1H NMR (400 MHz, D2O) δ ppm 0.97 (d, J=5.52 Hz, 3H), 1.54 (br. s, 1H), 1.71-1.87 (m, 3H), 1.91-2.07 (m, 1H), 2.84 (s, 3H), 3.13 (td, J=8.41, 3.76 Hz, 1H), 3.35 (m, 1H), 3.65 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[C:27]([CH3:29])([CH3:28])[N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:37])[CH2:9]2)=[CH:4][CH:3]=1.[ClH:40]>CO.CCOCC>[ClH:40].[ClH:40].[F:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[C:27]([CH3:28])([CH3:29])[NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:37])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)C(C)(C)N(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)cc31)C(C)(C)NCC2
Reaction time: 18 h

Procedure:
tert-Butyl 7-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-1,1,5-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (106 mg, 0.240 mmol) was dissolved in MeOH (5.00 mL), and 2 M HCl in Et2O (1.20 mL) was added. The reaction was allowed to proceed for 18 h. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic phase was separated, and the aqueous phase was back extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. Purification by preparative thin layer chromatography (silica gel, 90:9:1 CH2Cl2/MeOH/NH4OH) gave the free base of the title compound (19.0 mg) as a white solid. The free base was dissolved in MeOH (2.00 mL) and treated with 1.25 M HCl in MeOH (0.108 mL). The mixture was concentrated to provide the title compound (22.0 mg, 17%) as an off-white solid. Free Base: 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J=8.5 Hz, 1H), 7.21-7.17 (m, 3H), 7.02-6.94 (m, 3H), 3.75 (t, J=5.0 Hz, 2H), 3.59 (s, 3H), 3.43 (s, 2H), 3.26 (t, J=5.5 Hz, 2H), 2.90 (t, J=5.5 Hz, 2H), 2.86-2.82 (m, 2H), 2.74-2.69 (m, 4H), 1.55 (s, 6H); HPLC (Method B) 97.0% (AUC), tR=10.7 min. HCl salt: 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=8.5 Hz, 1H), 7.45 (s, 1H), 7.39-7.35 (m, 2H), 7.12-7.06 (m, 3H), 4.20-4.04 (m, 4H), 3.71-3.65 (m, 7H), 3.45-3.44 (m, 2H), 3.17-3.14 (m, 4H), 1.85 (s, 6H); ESI MS m/z 435 [M+H]+; HPLC (Method B) 95.2% (AUC), tR=10.8 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:31]=[CH:30][C:25]([CH:26]=[CH:27][CH2:28]Br)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH2:28]/[CH:27]=[CH:26]/[C:25]4[CH:30]=[CH:31][C:22]([F:21])=[CH:23][CH:24]=4)[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C=CCBr)cc1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: Fc1ccc(/C=C/CN2CCN(c3ccc(Cc4ccc(F)cc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (10) synthesized in Example 3 and 4-fluorocinnamyl bromide to produce the above.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[CH3:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>C(Cl)Cl>[OH:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][C:19](=[O:20])[CH:18]([CH3:22])[CH3:17])[CH:9]=1
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(=O)Oc1cc(O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
To 2.0 g of 2,4-bis(trimethylsilyloxy)-pyridine in 20 ml of methylene chloride was added 1.01 g of 2-methylpropionyl chloride and the mixture was stirred at room temperature for one hour. Following thereafter the general procedure of Example 27, 230 mg of the title compound was obtained in a yield of 16.1%.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH2:12]2)=[CH:7][C:6]=1[Br:29])=[N+]=[N-].C1(C)C=CC=CC=1.CP(C)C.O>O1CCCC1>[Br:29][C:6]1[CH:7]=[C:8]([N:11]2[CH2:15][CH2:14][C:13]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:18])([F:17])[F:19])[CH2:12]2)[CH:9]=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Br
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
1-[4-(Azidomethyl)-3-bromophenyl]-3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-pyrrolidine (0.634 g) was dissolved in tetrahydrofuran (10 ml), to the solution was added a 1 M toluene solution (1.37 ml) of trimethylphosphine, and stirred for 10 minutes. To the reaction solution, water (0.09 ml) was added and stirred overnight at room temperature. The volatile compound was distilled off under reduced pressure to obtain almost pure 1-{2-bromo-4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]phenyl}methanamine (0.520 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1COCC1.CO.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: NC1CCN(c2ccc(F)cn2)CC1
Yield: 96 %

Procedure:
A solution of tert-butyl (1-(5-fluoropyridin-2-yl)piperidin-4-yl)carbamate (0.36 g, 1.22 mmol) in HCl in Dioxane (4M, 2 mL), THF (2 mL) and MeOH (2 mL) was stirred at rt. After 4 h the reaction mixture was filtered, the residue washed with EtOAc and dried to give the title compound (0.31 g, 96%) as a solid. 1H NMR (500 MHz, CD3OD): 8.10-8.02 (m, 2H), 7.52 (dd, 1H), 4.34-4.26 (m, 2H), 3.61-3.50 (m, 1H), 3.38 (dt, 2H), 2.28-2.21 (m, 2H), 1.80 (dq, 2H); 13C NMR (CD3OD): 153.2, 151.2, 151.0, 134.5, 134.3, 123.9, 123.6, 115.0, 114.9, 45.3, 29.1; Mass Spectrum: M+H 196.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].OP(O)(O)=O>C1(C)C=CC=CC=1>[CH2:6]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[C:3](=[O:4])[CH2:2][Br:1])[CH2:7][CH2:8][CH3:9]
Reactant: O=C(Br)CBr
Reactant: CCCCNCCCC
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of bromoacetyl bromide (72.3 mL, 830 mmol) in toluene (500 mL) cooled to 0° C. was added a solution of dibutylamine (280.0 mL, 1.66 mol) in toluene (220 mL) via an addition funnel maintaining the reaction temperature below 10° C. Upon completion of the addition, the reaction mixture was stirred at 0° C. for 15 minutes. A solution of 2.5% aqueous H3PO4 (500 mL) was slowly introduced, and the reaction mixture was allowed to warm to room temperature with vigorous stirring. The solution is 2.5% phosphoric acid by weight. The layers were separated and the organic phase washed with water (500 mL) and concentrated to provide the bromoacetamide as a solution in toluene.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:28]=[CH:29][C:30]([N+:41]([O-])=O)=[C:31]([NH:33][CH2:34][C:35]6[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=6)[CH:32]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[C:31]([NH:33][CH2:34][C:35]6[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=6)[C:30]([NH2:41])=[CH:29][CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(NCc6cccnc6)c5)CC4)cccc3[nH]2)cc1
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc(N)c(NCc6cccnc6)c5)CC4)cccc3[nH]2)cc1
Reaction time: 2 h

Procedure:
To a solution of (5-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-2-nitro-phenyl)-pyridin-3-ylmethyl-amine (0.05 g, 0.087 mMol) in methanol (10 mL) under nitrogen was added platinum on carbon (0.034g, 0.0087 mMol) and the reaction mixture evacuated. A hydrogen filled balloon was attached and the mixture stirred under a hydrogen atmosphere for two hours. The balloon was removed, the flask purged with nitrogen, and the mixture filtered thru Celite with a large excess of methanol. The resulting solution was concentrated to dryness on a rotory evaporator to yield 4-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-N2-pyridin-3-ylmethyl-benzene-1,2-diamine as a crude oil (0.047 g, 100% yield). LC/MS (Method A), rt=0.86 mins., purity=68%, calculated mass=545, [M+H]+=546, [M−H]−=544.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([N+]([O-])=O)[CH3:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].C([OH:20])C>>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:20])[CH3:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(C=C(C)[N+](=O)[O-])cc1
Product: CCOC(=O)c1ccc(CC(C)=O)cc1

Procedure:
The title compound was prepared in an identical manner to that described in Description 2 using 1-(4-carboethoxyphenyl)-2-nitroprop-1-ene and replacing the solvent with ethanol. γ (CDCl3) 8.62 (3H, t, J=7 Hz), 7.87 (3H, s), 6.29 (2H, s), 5.64 (2H, q, J=7 Hz), 2.76 (2H, d, J=9 Hz), 2.0 (2H, d, J=9 Hz).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CN(c1cccc2cc(C3=NCC(C)(CN4CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(C3=NCC(C)(CN4CCN(S(C)(=O)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of N-methyl-N-{2-[5-methyl-5-(piperazine-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.28 g), triethylamine (0.17 ml) and tetrahydrofuran (6 ml) was added methanesulfonyl chloride (0.06 ml) at 0° C., and the reaction mixture was stirred overnight at room temperature, and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.26 g, yield 81%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). melting point 209-210° C.
Reaction SMILES: N1SC=C2C=C(N)C=CC=12.[C:11]1([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[S:26]([C:30]1[CH:31]=[C:32]([NH-:36])[CH:33]=[CH:34][CH:35]=1)(=[O:29])(=[O:28])[NH2:27]>>[S:26]([C:30]1[CH:31]=[C:32]([NH:36][C:23]([C:20]2[CH:21]=[N:22][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:18][CH:19]=2)=[O:25])[CH:33]=[CH:34][CH:35]=1)(=[O:28])(=[O:29])[NH2:27]
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: [NH-]c1cccc(S(N)(=O)=O)c1
Agent: Nc1ccc2nscc2c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnc(-c3ccccc3)nc2)c1

Procedure:
Following procedures similar to those of Example 8 but substituting 3-amino-benzenesulfonamide (0.3 mmol) for 2,2-dioxo-2,3-dihydro-1H-2lamda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid (3-sulfamoyl-phenyl-amide as a solid. MS: 355 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](N(OC)C)=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:23][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](=[O:18])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cc2ccccc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.30 g, 1.0 mmol) in tetrahydrofuran (6 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (1.1 mL, 1.5 mmol). The reaction was stirred at room temperature for 2 hours, then quenched with saturated NH4Cl solution, extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (0.27 g). The crude product was used directly in next step. LCMS calculated for C16H13FNO(M+H)+: m/z=254.1. Found: 254.1.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12].[N:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[CH:25][C:18]=12.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:25]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][N:17]=3)[NH:23][CH:24]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Reactant: c1cnc2[nH]ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.4 %

Procedure:
To propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (18, 50 mg, 0.42 mmol) in 0.8 mL of methanol, 5H-pyrrolo[2,3-b]pyrazine (3, 103 mg, 0.42 mmol) and potassium hydroxide (71 mg, 1.3 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 48 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 60% ethyl acetate in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (19, 74 mg, 49%). MS (ESI) [M−H+]−=363.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:36].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:36])=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC=C(CC)C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 74.3 %

Procedure:
In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1-hydroxycarbonyl-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 0.33 mmol) prepared in example 81c was reacted with cyanuric fluoride (0.044 mL, 1.64 mmol) (Alfa) and pyridine (0.13 g, 1.64 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.12 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[CH:10]=2)=[CH:5][CH:4]=1.[C:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[NH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CSc2ccnc(Cl)c2)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CSc2ccnc(N=C(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
4-(4-methoxybenzylthio)-2-chloropyridine (12 g, 45.2 mmol) and diphenylmethanimine (8.7 ml, 52.0 mmol) were dissolved in toluene (300 mL). The solution was evacuated and purged with nitrogen. Pd(OAc)2 (0.51 g, 2.3 mmol), rac-Binap (1.41 g, 2.26 mmol), and NaOtBu (6.1 g, 63.2 mmol) were added. The mixture stirred under N2 at 100° C. for 90 minutes. After cooling to ambient temperature, the mixture was quenched with water and the material was extracted with EtOAc, dried, and concentrated to afford the 4-(4-methoxybenzylthio)-N-(diphenylmethylene)pyridine-2-amine crude intermediate (18.5 g). The crude imine was dissolved in MeOH (200 mL) and hydroxylamine hydrochloride (11.0 g, 158 mmol) and sodium acetate trihydrate (30.7 g, 226 mmol) were added. The reaction was stirred at ambient temperature for 2 hours, then diluted with 1N HCl and extracted with EtOAc. The aqueous layer was basified to pH 9 and extracted with EtOAc. This second EtOAc layer was dried and concentrated to provide 4.7 g of the desired product. An additional 4.3 g of product was isolated by concentrating the first EtOAc layer extraction and purified via flash chromatography (70% EtOAc/hexanes) to provide the desired product (Total yield: 9.0 g, 80%) was isolated as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@H:35]([CH3:38])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@H:35]([CH3:38])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C[C@@H](N)CO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (R)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H33N6O5SF2 [(M+H)+] 543.2196, observed 543.2201.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Oc1ccccc1F
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccccc5F)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2-fluorophenol (0.163 ml, 1.763 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added and the reaction became dark red. The reaction was heated to 70° C. After 1 h, the temperature was increased to 90° C. After 4 h, the reaction was cooled to RT and stirred overnight. The reaction was then cooled to 0° C. and quenched with TFA (0.136 ml, 1.763 mmol), diluted with 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo then treated with saturated aq. NaHCO3 and DCM. The aq. layer was extracted 3×DCM and combined organics dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(2-fluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.036 g, 0.096 mmol, 38% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (1H, br. s), 8.52 (1H, d, J=8.8 Hz), 8.12 (1H, dd, J=7.6, 1.4 Hz), 7.74-7.89 (1H, m), 7.36-7.66 (6H, m), 6.85-6.99 (2H, m), 3.32-3.36 (2H, m), 2.43 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 374.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
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: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(S(C)(=O)=O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.14 g, 0.22 mmol), 4-methylsulfonylphenylboronic acid (0.06 g, 0.28 mmol), sodium carbonate (0.07 g, 0.67 mmol) in THF (26 mL) and water (13 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.02 g, 0.01 mmol). Raise the reaction temperature to 80° C. and stir for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% to 50% ethyl acetate in hexanes gradient to afford 0.12 g of (R)-3-(3,5-Dichloro-4′-methanesulfonyl-biphenyl-4-ylmethyl)-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one.