Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19](OCC)=[O:20].Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[C:4](=[O:18])[C:3]=1[C:19]([NH:32][CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:33])=[O:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(C(F)(F)F)ccc2C(C)(C)C1=O
Temperature: 23 °C
Reaction time: 14 h
Yield: 61.5 %

Procedure:
A solution of crude ethyl 4-hydroxy-1,1-dimethyl-2-oxo-6-(trifluoromethyl)-naphthalene-3-carboxylate (562 mg, 1712 μmol), glycine tert-butyl ester hydrochloride (316 mg, 1883 μmol) and DIPEA (447 μL, 2568 μmol) in 1,4-dioxane (20 mL) was heated to 120° C. in a sealed vessel. After 14 hours, the reaction was cooled to 23° C., and the solvent was removed under vacuum. The residue was diluted with EtOAc (100 mL), washed with water (75 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 4-8% EtOAc/hexane) affording 435 mg of the title compound. MS m/e=358.1 (M-C4H8+H)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][S:41][C:42]2[C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:36][CH:35]=1.[Cl:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:51][C:52]1[CH:58]=[CH:57][C:55]([NH:56][C:48]([C:47]2[C:42]([S:41][CH2:40][C:37]3[CH:36]=[CH:35][N:34]=[CH:39][CH:38]=3)=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:50])=[CH:54][CH:53]=1
Reactant: O=C(O)c1cccnc1SCc1ccncc1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1SCc1ccncc1
Yield: 91 %

Procedure:
N,N-Diisopropylethylamine (1.6 mL,8.9 mmol) and o-(7- azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.6 g, 4.3 mmol) were added to a solution of 2-(4-pyridylmethylthio)pyridine-3-carboxylic acid (1.0 g, 4.1 mmol, Reference compound No. 1-1) and 4-chloroaniline (0.54 g, 4.3 mmol) in N,N-dimethylformamide (20 mL), then the mixture was stirred for 3 hours. A saturated aqueous sodium hydrogencarbonate solution (150 mL) was added to the reaction mixture, then the whole was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution (150 mL) twice and saturated brine (150 mL) twice, and was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was filtered off, was washed with diethyl ether:ethyl acetate (10:1), and was dried under reduced pressure to give 1.3 g of the target compound as a white solid. (Yield 91%)
Reaction SMILES: Cl[S:2]([C:5]1[N:14]=[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][N:7]2[N:6]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:17]=1[NH2:18].N1C=CC=CC=1.CS(C)=O>C(#N)C.ClCCl>[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:17]=1[NH:18][S:2]([C:5]1[N:14]=[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][N:7]2[N:6]=1)(=[O:4])=[O:3]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: Cc1ccn2nc(S(=O)(=O)Cl)nc2c1
Solvent: CS(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
2-Chlorosulfonyl-7-methyl[1,2,4]triazolo[1,5-a]pyridine (1.2 g, 0.0052 mol), 2,6-dichloroaniline (1.7 g, 0.010 mol) and pyridine (0.40 g, 0.0052 mol) were dissolved in anhydrous acetonitrile (20 mL). Dimethyl sulfoxide (60 μL, 0.0008 mol) was added with stirring. The reaction was allowed to stir overnight. The volatiles were removed by evaporation under reduced pressure and the residue obtained was taken up in dichloromethane. The resulting mixture was washed well with dilute aqueous hydrochloric acid and the organic solution phase was recovered and concentrated by evaporation under reduced pressure. The resulting residue was triturated with hexane and the solids that formed were recovered by filtration and dried to obtain 0.7 g (38 percent of theory) of the title compound as a tan powder melting at 232°-234° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:3]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: COc1ccc2cc(-c3cccnc3)nc(Cl)c2c1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2cc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
N—(N-(3-chloro-4-fluorophenyl)-7-methoxy-3-(pyridin-3-yl)isoquinolin-1-amine was prepared using Method J. A mixture of 1-chloro-7-methoxy-3-(pyridin-3-yl)isoquinoline (40 mg, 0.17 mmol, 1.0 eq.), 3-chloro-4-fluoro aniline (30 mg, 0.21 mmol, 1.2 eq.), Pd2(dba)3 (10 mg, 0.011 mmol, 0.06 eq.), Xantphos (15 mg, 0.026 mmol, 0.15 eq.), cesium carbonate (167 mg, 0.52 mmol, 3.0 eq.) was suspended in the mixed solvent of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was stirred at 120° C. for 30 min under the microwave conditions. After cooling, the resulting mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by prep-HPLC to afford 3 mg of xli-a as a yellow solid (yield 5.2%). LCMS m/z=380.1 (M+1) (Method B). 1H NMR (400 MHz, DMSO-d6): δ 9.35 (s, 1H), 9.30 (d, J=2.0 Hz, 1H), 8.57 (dd, J=4.7, 1.5 Hz, 1H), 8.41 (td, J=8.0, 1.8 Hz, 1H), 8.30 (dd, J=6.9, 2.6 Hz, 1H), 7.94-7.87 (m, 4H), 7.43-7.49 (m, 3H), 3.99 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[O:5].[CH:8]([Mg]Br)=[CH2:9].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]([OH:5])[CH:8]=[CH2:9]
Reactant: CC(C)(C)CC=O
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)CC(C)(C)C
Temperature: -20 °C
Yield: 15.3 %

Procedure:
A solution of 3,3-dimethylbutyraldehyde (5.0 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (0.780 g, 15%). 1H NMR (300 MHz, CDCl3): δ ppm 0.98 (m, 9 H) 1.45 (m, 2 H) 4.26 (m, 1 H) 5.06 (m, 1 H) 5.21 (m, 1 H) 5.90 (m, 1 H).
Reaction SMILES: [C:1]1([N:7]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(Cl)Cl.C(O)C>CO.[Pd]>[C:1]1([N:7]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCN(C(=O)c1ccc(N)cc1)c1ccccc1

Procedure:
22 g (67 mmol) of 4-nitro-benzoic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide were hydrogenated in 500 ml of methanol with 2 g of 10% palladium on charcoal at 3 bar hydrogen pressure for 3 hours. After filtration and distillation of the solvent the reaction mixture was washed with 100 ml of ether and the white crystalline product was further reacted directly. Yield: 18.6 g (94% of theory), Rf value: 0.70 (silica gel; methylene chloride/ethanol=19:1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH2:16]([S:32](Cl)(=[O:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(C)=O.C1(NC2CCCCC2)CCCCC1>[CH2:16]([S:32]([O:8][CH2:7][C:6]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14])(=[O:34])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: COc1cc(CO)c([N+](=O)[O-])cc1OC
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCS(=O)(=O)OCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 5.33 g (0.025 mol) of 4,5-dimethoxy-2-nitrobenzyl alcohol and 8.15 g (0.025 mol) hexadecanesulfonyl chloride in 100 ml of acetone, dicyclohexylamine (5 ml, slight excess) was added via motor driven syringe over 30 minutes. After the addition was complete, the reaction was stirred an additional 30 minutes. The precipitated dicyclohexylamine hydrochloride was removed by filtration and the acetone filtrate reduced in volume in vacuo until most of the product had precipitated (yield 9.5 g, m.p. 81°-82° C.).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:13][CH:12]1[CH2:14][CH:15]1[CH2:17][CH:16]1[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Li+].O1CCOCC1.[Cl-].[NH4+]>C(OCC)(=O)C>[CH2:18]([CH:16]1[CH2:17][CH:15]1[CH2:14][CH:12]1[CH2:13][CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC1CC1CC1CC1CCCCCCCC(=O)OC
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCCC1CC1CC1CC1CCCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 8-(2-((2-pentylcyclopropan-1-yl)methyl)cyclopropyl)octanoic acid methyl ester (4.89 g), 1N aqueous solution (33.4 ml) of lithium hydroxide and dioxane (33 ml) was stirred at 60° C. overnight. The mixture was poured into a mixture of ethyl acetate (EA) and a saturated aqueous solution of ammonium chloride. The separated organic layer was washed with water and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was purified by chromatography on silica gel (eluted with 20% EA in n-hexane). The fractions including 8-(2-((2-pentylcyclopropan-1-yl)methyl)cyclopropyl)octanoic acid were collected and concentrated in vacuo to give 8-(2-((2-pentylcyclopropan-1-yl)methyl)cyclopropyl)octanoic acid (4.01 g) as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30](O)[CH:29]=1>CO.C(Cl)Cl>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([O:1][CH:2]2[C:3]3[C:8](=[N:7][CH:6]=[C:5]([C:12]4[CH:13]=[CH:14][C:15]([C:18]([N:20]5[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]5)=[O:19])=[CH:16][CH:17]=4)[CH:4]=3)[NH:9][CH2:10][CH2:11]2)[CH:29]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(F)cc1OC1CCNc2ncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)cc21
Yield: 53 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (30 mg) was reacted with 1-(4-fluoro-2-hydroxyphenyl)ethanone (39.4 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (53% yield). LCMS: m/z=489.14 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.11-2.25 (m, 2H), 2.32 (s, 3H), 2.32-2.58 (m, 4H), 2.45 (s, 3H), 3.40-3.68 (m, 4H), 3.70-3.90 (m, 2H), 5.31 (bs, 1H), 5.51 (t, J=3.3 Hz, 1H), 6.75-6.82 (m, 1H), 6.89 (dd, J=2.1 and 10.7 Hz, 1H), 7.41-7.51 (m, 4H), 7.57-7.61 (m, 1H), 7.80 (dd, J=7.1 and 8.6 Hz, 1H, 8.33 (bs, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH:18]=[CH:19]2)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(=CC(=O)C=C3)C=C4)CC2)C)[O:31]C1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[C@@H:18]4[O:31][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 74.8 %

Procedure:
The procedure of Example 6 was repeated except that 4.16 g (11.3 mmoles) of 20-(1,3-dioxolan-2-yl)pregna-1,4,6-trien-3-one was used in lieu of 4.66 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one to give 3.25 g of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one (yield: 75%).
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:8]=[CH:7][C:6]=1[C:17]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[N:18]=1.C([Si]([O:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH:61]2[CH2:63][O:62]2)=[CH:55][CH:54]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[Cl:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:8]=[CH:7][C:6]=1[C:17]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][CH2:63][CH:61]([OH:62])[CH2:60][O:59][C:56]3[CH:57]=[CH:58][C:53]([OH:52])=[CH:54][CH:55]=3)=[CH:28][CH:27]=2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[N:18]=1
Reactant: Cc1ccn(-c2ccc(-c3nc4cccnc4n3-c3ccc(CCN)cc3)c(Cl)c2)n1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccn(-c2ccc(-c3nc4cccnc4n3-c3ccc(CCNCC(O)COc4ccc(O)cc4)cc3)c(Cl)c2)n1
Yield: 49.1 %

Procedure:
2-(4-{2-[2-Chloro-4-(3-methyl-1 H-pyrazol-1-yl)phenyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenyl)-1-ethanamine formate (0.212 g, 0.447 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.18 g, 0.44 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.18 g, 0.216 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C:7]([N:9]1[C@H:13]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[CH2:12][C@@H:11]2[CH2:24][CH2:25][CH2:26][C@H:10]12)=[O:8])=[O:4]>[Pd].C(O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:27]([CH3:30])[CH2:28][CH3:29])[C:7]([N:9]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]2[CH2:24][CH2:25][CH2:26][C@H:10]12)=[O:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 72 h
Yield: 117.8 %

Procedure:
To a 250 mL round bottom flask charged with a stirbar and (2S,3aS,6aS)-benzyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylate (19.53 g crude, assumed 35.49 mmol) was added 10% Palladium on carbon (3.55 g). Ethanol was poured over the mixture and the reaction mixture was evacuated and flushed with hydrogen gas three times. The suspension was stirred at room temperature under and atmosphere of hydrogen for 3 days. Upon completion, the reaction mixture was filtered through celite and concentrated to give (2S,3aS,6aS)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (13.65 g, >99%). LCMS-ESI+ calc'd for C16H26N2O5: 327.18. Found: 327.13.
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[CH3:10][CH2:11][O:12]CC>C(O)C>[ClH:1].[CH2:8]([O:7][C:5]([CH2:4][C:2](=[NH:3])[O:12][CH2:11][CH3:10])=[O:6])[CH3:9]
Reactant: CCOC(=O)CC#N
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)CC(=O)OCC
Reaction time: 8 h

Procedure:
Hydrochloric acid gas is passed at 0°-10° C. into a solution of 678 g (6 mol) of ethyl cyanoacetate in 400 ml of ethanol and 3 1 of ether for 7 h, the mixture is allowed to stand overnight at 25° C., and the deposited solid is filtered off with suction and dried in vacuo.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][CH:14]=[CH:13]3)[CH2:5][CH2:4]1.C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(#N)C>[CH3:1][N:2]([CH3:23])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][CH:14]=[CH:13]3)[CH2:5][CH2:4]1
Reactant: CN[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)[C@H]1CC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Reaction time: 0.33 h

Procedure:
A couple of drops of glacial acetic acid were added to a solution of trans-6(4-methylaminocyclohexyloxy)-2H-isoquinolin-1-one (Example 12; 25 mg, 92 μmol) and formaldehyde (40 μL) in acetonitrile (1 ml). The mixture was stirred for 20 minutes and then sodium triacetoxyborohydride (100 mg) was added. The mixture was stirred at ambient temperature for 16 hours then concentrated in vacuo. The residue was partitioned between chloroform/isopropanol (3:1) and aqueous sodium hydrogen carbonate. The organic layer was separated then concentrated to give a residue that was purified by prep-HPLC to give trans-6(4-dimethylaminocyclohexyloxy)-2H-isoquinolin-1-one, EI-MS: m/z=287.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].O[Li].O.CO.O>C(OCC)(=O)C.CCCCCC>[CH2:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(C(=O)OC)cc1
Agent: [Li]O
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCNc1ccc(C(=O)O)cc1
Temperature: 55 °C
Yield: 46.1 %

Procedure:
A 500 mL round-bottom flask, equipped with a magnetic stir bar and condenser was charged with compound 2 (2 g, 10.4 mmol), LiOH.H2O (1.18 g, 15.7 mmol), 100 mL MeOH and 60 mL H2O. The mixture was heated at 55° C. for 24 hours. The solution was concentrated in vacuo to remove methanol and most of H2O. Ehther/H2O=100 mL/100 mL was used to remove most of the unreacted starting material. The aqueous layer was acidified to pH 4.0 with 1M HCl and some white precipitation was formed. The product was extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with brine and dried over NaSO4. After removal of the solvent, the crude product was purified by silica gel chromatography (eluent: Hexane/Ethyl acetate from 100:5 to 100:25). Recrystallization from ethyl acetate/hexane twice yielded white crystal (0.85 g, 46.1% yield). 1H NMR (400 MHz, CDCl3): δ 3.82 (d, 2H), 5.10 (dd, 1H), 5.23 (dd, 1H), 5.80-5.96 (m, 1H), 6.62 (d, 2H), 7.78 (d, 2H); 13C NMR (400 MHz, CDCl3): δ 46.07, 112.19, 116.06, 118.44, 132.30, 136.14, 153.63, 168.01; ESI-MS: Calcd for C10H12NO2 [M+1] 178.1, found 178.0; Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.81; H, 6.28; N, 7.86. MP: 144-146° C.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]1(C)[CH:16]=CC(S([O-])(=O)=O)=C[CH:12]=1.[NH+]1C=CC=CC=1.ClCCl.CO>COC(OC)(C)C>[CH3:12][C:11]1([CH3:16])[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: NC(=O)c1ccccc1O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: COC(C)(C)OC
Solvent: CO
Product: CC1(C)NC(=O)c2ccccc2O1
Yield: 93.4 %

Procedure:
To a solution of salicylamide (20.0 g, 0.146 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in 2,2-dimethoxypropane (300 mL) was added pyridinium p-toluenesulfonate (11.0 g, 0.044 mol) and then heated to reflux for 2 h. TLC (dichloromethane: methanol=20:1) indicated the reaction was complete. The solvent was removed and then the residue was taken up in ethyl acetate (150 mL). The solution was washed twice with sodium bicarbonate and once with brine. The organic layer was dried and concentrated under reduced pressure to afford (I-30a) (26.0 g, yield: 93.4%) as a yellow solid, which was used to next step without any purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:19][N+:20]([CH3:29])=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:21]([N:20]([CH3:19])[CH3:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C=[N+](C)C
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [Cl-]
Product: Cc1ccccc1C(c1c[nH]c2ccc(OCc3ccccc3)cc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-benzyloxy-1H-indole and dimethyl-(2-methyl-benzylidene)-ammonium chloride, which had been prepared in accordance with example 32.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:26]([CH:27]([OH:37])[CH2:28][CH2:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C1COCC1.CCO>[OH:37][CH:27]([C:26]1[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4ncccc4C(O)CCCc4ccccc4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1(c2ccc(-c3ccc(-c4ncccc4C(O)CCCc4ccccc4)cc3)cc2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-(1-Hydroxy-4-phenyl-butyl)-pyridin-2-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.258 g, 0.52 mmol) was dissolved in THF (2 mL) and EtOH (1 mL). NaOH (3N aq., 1.1 eq.) was added and the reaction stirred at 45° C. overnight. The reaction was concentrated to dryness, diluted with H20, washed with EtOAc, acidified and extracted with EtOAc. The solution was dried and concentrated to yield the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][C:16]1[N:17]=[C:18]([SH:22])[S:19][C:20]=1[CH3:21]>>[N:5]1([C:3](=[O:4])[CH2:2][S:22][C:18]2[S:19][C:20]([CH3:21])=[C:16]([CH3:15])[N:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Cc1nc(S)sc1C
Product: Cc1nc(SCC(=O)N2CCCc3ccccc32)sc1C
Yield: 74 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4,5-dimethylthiazole-2-thiol as the nucleophile to yield 33 as a cream solid (690 mg, 74%). MS (APCI): m/z 319 [M+H]+. Anal. Calcd. for C16H18N2OS2: C, 60.34; H, 5.70; N, 8.80. Found: C, 60.51; H, 5.71; N, 8.72.