Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][O:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][Si](C(C)(C)C)(C)C)=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][O:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(CO[Si](C)(C)C(C)(C)C)cc3)c3ccccc23)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(CO)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
The pyrazole amine Intermediate N (100 mg, 0.278 mmol) was added portionwise to a stirred suspension of CDI (45.1 mg, 0.278 mmol) in DCM (0.5 mL) over 1 hr and the reaction mixture was stirred at RT for 16 hr. A solution of the naphthylamine, Intermediate M, (47 mg, 0.139 mmol) in DCM (0.5 mL) was added dropwise over 2 hr. After a further 2 hr the mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 12 g, 30-70% EtOAc in isohexane, gradient elution) to yield N-(4-((4-(3-(3-tert-butyl-1-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide (67) (42 mg, 20%): m/z 723 (M+H)+ (ES+) To a solution of the silyl ether (67) (42 mg, 58 μmol) in THF under nitrogen at −5° C. was added a solution of TBAF (1M in THF, 58 μL, 58 μmol). The mixture was warmed to RT and a second aliquot of TBAF (1M in THF, 58 μL, 58 μmol) was added. After 1 hr the mixture was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, 2-6% MeOH in DCM, gradient elution) to provide the title compound (Example 49) (23 mg, 63%): m/z 609 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9 H, s), 3.37 (3H, s) 4.08 (2H, s), 4.59 (2H, d), 5.32 (1H, t), 5.39 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.29 (1H, dd), 7.48 (2H, m), 7.52 (2H, m), 7.54-7.63 (3H, overlapping m), 7.93 (1H, m), 8.30-8.37 (3H, overlapping m), 8.63 (1H, s), 8.81 (1H, s), 10.02 (1H, br s).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:35])[N:8]([CH2:25][CH2:26][CH2:27][N:28]2[C:32](=[O:33])[CH2:31][CH2:30][C:29]2=[O:34])[C:9]2[C:14]([C:15]=1[OH:16])=[N:13][CH:12]=[C:11]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:10]=2)=[O:5])C.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[O:34]=[C:29]1[CH2:30][CH2:31][C:32](=[O:33])[N:28]1[CH2:27][CH2:26][CH2:25][N:8]1[C:9]2[C:14](=[N:13][CH:12]=[C:11]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:39][CH2:38][CH2:36][OH:37])=[O:5])[C:7]1=[O:35]
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O

Procedure:
This compound was prepared from ethyl1-[3-(2,5-dioxo-1-pyrrolidinyl)propyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.36 (t, J=5.3 Hz, 1 H), 8.55 (d, J=1.2 Hz, 1 H), 7.34 (s, 1 H), 7.19 (dd, J=8.5, 5.4 Hz, 2 H), 7.04 (t, J=8.5 Hz, 2 H), 4.17-4.13 (m, 4 H), 3.85 (t, J=5.0 Hz, 2 H), 3.63 (m, 2 H), 3.56 (t, J=7.1 Hz, 2 H), 2.72 (s, 4 H), 1.92 (m, 2 H); HRMS C25H25FN4O6 (M+H)+ calcd 497.1758, found 497.1832.
Reaction SMILES: [CH3:1][CH:2](C)[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].Br[C:40]1C=C2C(=C[CH:48]=1)C(=O)N(C1(C(OC)=O)CCCC1)C2.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[CH2:16][N:8]1[C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:48][CH2:40][CH2:1][CH2:2]1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Reactant: COC(=O)C1(N2Cc3cc(Br)ccc3C2=O)CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)C1(N2Cc3cc(-c4ccc(NC(=O)Nc5cccc(C(F)(F)F)c5)cc4)ccc3C2=O)CCCC1

Procedure:
The compound of example 369 was prepared analogous to compound of example 360 by reaction of the compound of example 368, compound of example 357 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([CH2:40][CH2:41][NH2:42])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>>[CH2:15]([N:14]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:42][CH2:41][CH2:40][C:36]3[CH:35]=[C:34]4[C:39](=[CH:38][CH:37]=3)[NH:31][CH:32]=[CH:33]4)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:16]
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCCc1ccc2[nH]ccc2c1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc4[nH]ccc4c3)n2)c1)C1CCNCC1

Procedure:
4-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (intermediate 84) was coupled with 2-(1H-indol-5-yl)-ethylamine (intermediate 124) following procedure F then deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 455. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.7 (m, 1H) 8.4 (m, 3H) 7.9 (m, 1H) 7.6 (m, 4H) 7.4 (m, 1H) 7.2 (m, 1H) 4.4 (m, 1H) 3.9 (m, 2H) 3.7 (m, 7H) 3.2 (m, 3H) 2.5 (m, 2H) 2.3 (m, 2H) 1.3 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[F:36][C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:36][C@H:37]1[CH2:41][CH2:40][N:39]([C:25]([C:21]2[CH:20]=[C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)[CH:24]=[CH:23][N:22]=2)=[O:27])[CH2:38]1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: F[C@H]1CCNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CC[C@H](F)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61A starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61A, Step 2) and (S)-(+)-3-fluoropyrrolidine hydrochloride (Oakwood, Cat. No. 013157). LCMS (M+H)+: m/z=531.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
To a cooled (0° C.) solution of methyl-2-pyrrole carboxylate (8.00 g, 63.9 mmol) in DMF (320 mL) was added NaH (60% by weight 5.10 g, 128 mmol). After 20 min, benzylbromide (11.4 mL, 95.9 mmol) was added and the reaction was warmed to rt. Stirring was continued for 2 h before quenching with saturated aq NH4Cl (0.5 L). The mixture was extracted 3× with EtOAc and the combined organic layers were washed with H2O (3×) and brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The crude product was chromatographed over silica gel (0 to 10% EtOAc in heptane over 25 min) to give methyl 1-benzyl-1H-pyrrole-2-carboxylate as a colorless oil (7.75 g, 56%). Rf=0.48 (25:75 heptane/EtOAc); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.28-7.34 (m, 2H) 7.23-7.27 (m, 1H) 7.09-7.13 (m, 2H) 7.01 (dd, J=4.0, 1.8 Hz, 1H) 6.88-6.91 (m, 1H) 6.19 (dd, J=4.0, 2.6 Hz, 1H) 5.57 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:37])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:38]([O:40]CC)=[O:39].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:37])[NH:20][C:21]3[N:22]=[N:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(C(F)(F)F)cc5)nn4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (1.83 g, 3.07 mmol) in 40 mL of 3:1 THF/EtOH was added sodium hydroxide (12.3 ml, 12.3 mmol). The reaction was stirred for 3 hours, then concentrated. The crude material was combined with 1M HCl (50 mL) and stirred for 3 hours. The material was resolved via supercritical fluid chromatography employing a CHIRALCEL® OJ-H column (3×15 cm) eluting with 35% ethanol/carbon dioxide at 100 bar, using 3 mL injections and a flow rate of 140 mL/min. Collection of fractions containing peak 2 and removal of volatiles provided Enantiomer 2 of 6-chloro-7-(4-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.730 g, 1.29 mmol, 41.9% yield) as a white solid. MS (apci, positive) m/z=569.9.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>C(OCC)(=O)C.O>[CH3:16][S:17]([O:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:19])=[O:18]
Reactant: C[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)O[C@H]1CC[C@H](C)CC1

Procedure:
To a solution of trans-4-methylcyclohexanol (4.55 g) in ethyl acetate (50 ml) were added successively triethylamine (7.22 ml) and methanesulfonyl chloride (3.38 ml) with stirring under ice-water bath. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added ethyl acetate (50 ml), water (50 ml) and 1N hydrochloric acid (20 ml) with stirring. The organic layer was separated, washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give trans-4-methylcyclohexyl methanesulfonate (8.36 g).
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([CH2:31][OH:32])[CH2:20][CH2:21][N:22]2[CH2:29][CH2:28][C:25]3([CH2:27][CH2:26]3)[C@H:24]([OH:30])[CH2:23]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Cl>[Pd]>[OH:30][C@@H:24]1[CH2:23][N:22]([CH2:21][CH2:20][C@H:19]([N:14]2[C:15](=[O:18])[CH2:16][CH2:17][NH:11][CH2:12][CH2:13]2)[CH2:31][OH:32])[CH2:29][CH2:28][C:25]21[CH2:26][CH2:27]2
Reactant: O=C(OCc1ccccc1)N1CCC(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CC1
Agent: [Pd]
Agent: Cl
Product: O=C1CCNCCN1[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1

Procedure:
In analogy to the procedure described in intermediate 5E, 4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and 0.1 eq. of 1 M aq. hydrochloric acid solution and Pd/C was hydrogenated to give the title compound in quantitative yield as a white gum. MS: 312.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22].Cl>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:22]1[O:10][C:5]2[C:4]([O:11][CH3:12])=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:23])[CH3:20]
Reactant: COc1cc(Br)cc(C=O)c1O
Reactant: CC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
10.0 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde was dissolved in 39 ml of N,N-dimethylformamide, and the resulting solution was mixed with 11.9 g of anhydrous potassium carbonate and stirred at room temperature. 5.0 g of chloroacetone was added dropwise to the above reaction solution at the same temperature, followed by additional 1 hour of stirring at an elevated temperature of 80° C. The resulting reaction solution was diluted with ethyl acetate and adjusted to pH 2 with concentrated hydrochloric acid, and the resulting organic layer was collected. The organic layer was dried to distill off the solvent, and the resulting residue was purified by silica gel column chromatography, thereby obtaining 4.0 g of 2-acetyl-5-bromo-7-methoxybenzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:17])[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ncc(Br)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(Br)c(=O)[nH]1
Temperature: 50 °C

Procedure:
To a 0° C. cooled solution of 5-bromo-2-(ethoxycarbonyl)pyrimidine 1-oxide (3, 0.62 g, 2.5 mmol) in dimethylformamide (6 mL), trifluoroacetic anhydride (3.1 g, 15 mmol) was added dropwise. The reaction mixture was heated at 50° C. for 18 h. TLC showed consumption of starting material and solvent was removed under reduced pressure. The residue was triturated with methanol (2 mL) and filtered. The solid was washed with diethyl ether and dried under reduced pressure to afford ethyl 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate (4) as off white solid. Yield: 0.21 g, 34%; MS (ESI) m/z 245.09 [M−1]−.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:11][N:12]2[N:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13]2)[S:9][CH:10]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH2:17])[CH:14]=[N:13]2)[S:9][CH:10]=1
Reactant: COCc1csc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COCc1csc(Cn2ncc(N)n2)n1
Temperature: 75 °C
Reaction time: 0.42 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 4-(methoxymethyl)-2-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)thiazole (85 mg, 0.31 mmol), iron powder (66 mg, 1.17 mmol) and NH4Cl (108 mg, 2.0 mmol) in a mixture of EtOH (2.0 mL) and water (1.0 mL) was stirred at 75° C. for 25 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (15 mL) was added followed by 1N NaOH (10 mL). The layers were separated and the aq. layer was extracted with CH2Cl2 (3×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.47 min, [M+H]+=226.30.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[CH2:34]([OH:39])[CH2:35][CH2:36][C:37]#[CH:38]>[Pd].[Cu]I.CCOC(C)=O.O.COCCOC>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:38]#[C:37][CH2:36][CH2:35][CH2:34][OH:39])=[CH:3][CH:4]=1
Reactant: Nc1ccc(I)cc1
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ccc(C#CCCCO)cc1
Temperature: 85 °C
Yield: 76.1 %

Procedure:
4-Iodoaniline (10 g, 45 mmol), palladium on carbon (2.86 g, 1.35 mmol, 5% w/w), PPh3 (1.4 g, 5.4 mmol), CuI (513 mg, 2.7 mmol), and K2CO3 (15 g, 5.4 mmol) were added to DME (50 mL) and H2O (50 mL). The mixture is degassed while stirring by bubbling nitrogen vigorously into the solution. Pent-4-yn-1-ol (10.5 mL, 114 mmol) was added by syringe. The mixture was heated at 85° C. After cooling, water (100 mL) and EtOAc (200 mL) were added. The mixture was extracted with EtOAc. The organic layer and the water layer were independently neutralized with 1N HCl. The aqueous layer was extracted with EtOAc and the combined organic layers dried over MgSO4. The material was concentrated by rotary evaporation and the oil was purified by chromatography (gradient 10-100% EtOAc/Hex) to give the title compound as a dark oil (6 g, 76%). 1H NMR (400 MHz, CDCl3) δ 7.19 (dd, 2H, J=8.9, 1.5 Hz), 6.58 (dd, 2H, J=8.9, 1.5 Hz), 3.85 (t, 2H, J=8.0 Hz), 3.75 (brs, 2H), 2.55 (t, 2H, J=8.0 Hz), 1.86 (m, 2H); ES/MS calcd. for C11H14NO+ 176.1. Found m/z=176.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN
Reactant: Clc1ccc(Br)nc1
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 440 [M+1]+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11]>C1COCC1.[Cl-].[Zn+2].[Cl-].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[F:15])[CH:10]=[O:11])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=Cc1ccc(F)c(C2CC2)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
A flask was charged with cyclopropyl magnesium bromide (29.6 ml, 14.8 mmol) and placed under nitrogen. Zinc chloride (14.8 ml, 14.8 mmol) was added and the reaction was stirred for 20 minutes. 3-Bromo-4-fluorobenzaldehyde (1.0 g, 4.93 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.126 g, 0.246 mmol) were diluted in 600 μL of THF and added to the reaction mixture. After stirring for 4 hours, the reaction was heated to 50° C. and stirred overnight. The reaction was cooled and quenched with saturated NH4Cl and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M cartridge eluting with hexanes:ethyl acetate (4:1) to yield 3-cyclopropyl-4-fluorobenzaldehyde (400 mg, 49.5% yield)
Reaction SMILES: Cl.[CH:2]12[CH2:9][CH2:8][CH:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:10][C@@H:11]([C:13]1[C:14]([CH3:23])=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][CH2:16]2)[OH:12].[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:28]=[N:27][N:26]=[N:25]1>>[N:24]1([C:29]2[CH:30]=[CH:31][C:32]([S:35]([N:6]3[CH2:7][CH:2]4[CH2:9][CH2:8][CH:5]3[CH2:4][N:3]4[CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[CH:28]=[N:27][N:26]=[N:25]1
Reactant: Cc1c([C@@H](O)CN2CC3CCC2CN3)ccc2c1COC2=O
Reactant: O=S(=O)(Cl)c1ccc(-n2cnnn2)cc1
Agent: Cl
Product: Cc1c([C@@H](O)CN2CC3CCC2CN3S(=O)(=O)c2ccc(-n3cnnn3)cc2)ccc2c1COC2=O

Procedure:
5-((1R)-2-(5-(4-(1H-Tetrazol-1-yl)phenylsulfonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1 (3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 14 starting from 5-((1R)-2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride (INTERMEDIATE 16) and commercially available 4-(1H-tetrazol-1-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH:32]1([NH:36][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:22][CH:23]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC5CCC5)cc4)cc23)CC1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (40 mg, 0.091 mmol) in DMSO (900 μL) and acetic acid (2 drops) was added cyclobutylamine (94 μL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (120 mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 26.3 mg of the title compound (59%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:40].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:40])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 25 (0.84 g, 1.90 mmol) in CHCl3 (9 mL) was added triethylamine (0.50 mL, 3.59 mmol) and POCl3 (1.60 mL, 17.1 mmol). After heating at reflux for 16 h, the reaction mixture was cooled to room temperature and poured onto ice and sat. aq. NaHCO3 (150 mL). The resulting mixture was extracted with CH2Cl2 (3×75 mL) and the combined organic layers dried (MgSO4). Concentration followed by flash chromatography (9:1/CH2Cl2:EtOAc) afforded 708 mg (87%) of product as a white solid, m.p. 101-103° C. 1H NMR (400 MHz, CDCl3) δ 6.10 (d, J=2.8 Hz, 1H), 6.01 (dd, J=5.6, 3.2 Hz, 1H), 5.92 (t, J=6.0 Hz, 1H), 5.42 (s, 2), 4.97 (dd, J=11.6, 3.6 Hz, 1H), 4.32 (m, 1), 4.21 (dd, J=12.0, 5.2 Hz, 1H), 2.12 (s, 6H), 2.06 (s, 3H).