Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH2:26]([OH:30])[CH:27]([CH3:29])[CH3:28].[H-].[Na+]>O1CCOCC1>[CH2:26]([O:30][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CO
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccnc(F)c3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ccnc(OCC(C)C)c3)CC2)cc1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
To a mixture of 34 mg (0.10 mmol) (S)—N-{1-[4-(2′-fluoro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-phenyl]-ethyl}-acetamide (XIX.1) and 74 mg (1.0 mmol) isobutyl alcohol in 2 mL dioxane is added 20 mg (0.50 mmol) NaH (60% in mineral oil). The mixture is stirred at 130° C. for 12 h. The solvent is removed in vacuo and the residue is purified by HPLC (RP X-Bridge; water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1([CH2:23][C@H:24]([NH2:31])[C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][C@H:24]([NH:31][C:17]([C:9]2[CH:8]=[CH:7][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:11]([O:12][CH2:13][CH:14]3[CH2:15][CH2:16]3)[N:10]=2)=[O:19])[C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH2:22][CH2:21]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(C3CCCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (LC/MS): 411.2 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH2:11][C:12]([O:14][C@@H:15]([C@@H:54]([C:56]([OH:58])=[O:57])[CH3:55])[C@@H:16]([C@H:18]1[O:23][C@:22]2([O:27][C@@:26]([C@@H:29]3[O:33][C@@:32]([C@@H:35]4[O:39][C@@H:38]([C@H:40]5[O:45][C@@:44]([OH:48])([CH2:46][OH:47])[C@H:43]([CH3:49])[CH2:42][C@@H:41]5[CH3:50])[CH2:37][C@@H:36]4[CH3:51])([CH3:34])[CH2:31][CH2:30]3)([CH3:28])[CH2:25][CH2:24]2)[CH2:21][C@H:20]([OH:52])[C@H:19]1[CH3:53])[CH3:17])=[O:13]>N1C=CC=CC=1.ClCCl>[CH3:10][CH2:11][C:12]([O:14][CH:15]([CH:54]([C:56]([OH:58])=[O:57])[CH3:55])[CH:16]([CH:18]1[O:23][C:22]2([O:27][C:26]([CH:29]3[O:33][C:32]([CH:35]4[O:39][CH:38]([CH:40]5[O:45][C:44]([OH:48])([CH2:46][O:47][C:8]([NH:7][C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[O:9])[CH:43]([CH3:49])[CH2:42][CH:41]5[CH3:50])[CH2:37][CH:36]4[CH3:51])([CH3:34])[CH2:31][CH2:30]3)([CH3:28])[CH2:25][CH2:24]2)[CH2:21][CH:20]([OH:52])[CH:19]1[CH3:53])[CH3:17])=[O:13]
Reactant: O=C=Nc1ccccc1
Reactant: CCC(=O)O[C@H]([C@H](C)[C@H]1O[C@@]2(CC[C@@](C)([C@H]3CC[C@@](C)([C@@H]4O[C@@H]([C@H]5O[C@@](O)(CO)[C@H](C)C[C@@H]5C)C[C@@H]4C)O3)O2)C[C@H](O)[C@H]1C)[C@H](C)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)OC(C(C)C(=O)O)C(C)C1OC2(CCC(C)(C3CCC(C)(C4OC(C5OC(O)(COC(=O)Nc6ccccc6)C(C)CC5C)CC4C)O3)O2)CC(O)C1C
Yield: 61.1 %

Procedure:
Phenyl isocyanate (2.38 g, 20 mmol) was added to a solution of laidlomycin (14 g, 20 mmol) in 100 ml of pyridine. The mixture was heated in an oil bath at 70° for 30 min. The mixture was cooled, diluted with dichloromethane, washed with 5% aqueous hydrochloric acid and water, and evaporated. The residue was purified by silica gel chromatography (75% ether hexane, 0.01% formic acid eluent) to afford 10 g of laidlomycin phenylcarbamate as an amorphous solid which melted at 88°-90° C. Carbon-13 NMR spectroscopy confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.Cl.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[NH:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC1(C)CN(CC(=O)N[C@H]2CC[C@H](O)CC2)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
[5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid (200 mg, 0.48 mmol), trans-4-aminocyclohexanol hydrochloride (145 mg, 0.96 mmol) and diisopropylethylamine (124 mg, 167 uL, 0.96 mmol) were dissolved in pyridine (4 mL) and stirred at room temperature 10 min. EDC (184 mg) was added and the reaction was stirred at room temperature over night (16 h). Water (2 mL) was added and the resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with 50 mL 1 M aqueous potassium carbonate and extracted with ethyl acetate (75+2×50 mL). The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methanol/methylene chloride gradient) to afford pure 4-[(trans-4-hydroxy-cyclohexylcarbamoyl)-methyl]-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide (148 mg, 59%) as a yellow foam. The bis-HCl salt was prepared by adding 2 equivalents of conc. HCl to an ethanolic solution of the freebase. Concentration, followed by ether trituration afforded the salt as a free-flowing, yellow powder. 1H-NMR (freebase, 300 MHz, CDCl3) δ 11.71 (br s, 1H), 10.21 (s, 1H), 9.06 (s, 1H), 8.45-8.27 (m, 2H), 8.08-7.84 (m, 2H), 6.36 (br s, 1H), 4.13-3.81 (m, 3H), 3.72-3.56 (m, 1H), 3.51-3.37 (m, 2H), 3.03 (d, 1H), 2.79-2.26 (m, 5H), 2.16-1.94 (m, 4H), 1.54-1.30 (m, 5H), 1.22 (s, 3H). MS (NH4OAc standard conditions, ES+) e/z=514 (M+H)+. DAD Rf=1.39 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[N:17]1([C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccc(O)cc2)cc1)N1CCOCC1
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of 4-hydroxy-biphenyl-4′-carboxylic acid (5.35 g, 25.0 mmol), morpholine (2.39 g, 27.5 mmol) and triethylamine (3.5 mL, 25 mmol) in dichloromethane (100 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 16 hours, diluted with aqueous NaH2PO4 and filtered. The solid was washed with 1:2 diethyl ether/water (100 mL) then with water (400 mL). The solid was dried in vacuo to give the titled compound (5.89 g, 83%). MS (DCI) m/z 284 (M+H)+;
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16].[Br:17]N1C(=O)CCC1=O>C([O-])(=O)C.[Na+]>[NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[C:14]([Br:17])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: NC[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a solution of 5'-amino-2',5'-dideoxyuridine (0.113 g 0.5 mmole) in 100 ml of 0.05 M sodium acetate buffer, pH 6.0, is added 0.8 g (2.5 mmole) mercuric acetate. The solution is heated at 60° C for 5 hours and cooled on ice. Chelex 100 resin, 20 g, is added and the slurry stirred for 15 minutes at 0° C. The resin is removed by filtration and 0.177 g (1.0 mmole) of N-bromosuccinimide is added. The solution is stirred at room temperature for 30 minutes. The extent of bromination is followed spectrophotometrically at 300 nm, and the reaction terminated by the addition of aniline-ethanol when the absorbance increase plateaus. The reaction mixture is applied directly to a 2 × 15 cm column of Dowex 50 (H+) resin, the column washed with 200 ml of water, and eluted with 1 molar ammonium hydroxide. The solvent is removed at 40° C under reduced pressure, and the residue crystallized from ethanol-ether to provide 100 mg (69%) of the desired product.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][CH:10]([CH3:25])[CH2:11][N:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[Br:8][C:16]1[CH:15]=[CH:14][C:13]2[N:12]([CH2:11][CH:10]([CH3:25])[CH3:9])[C:24]3[C:19]([C:18]=2[CH:17]=1)=[CH:20][CH:21]=[CH:22][CH:23]=3
Reactant: CC(C)Cn1c2ccccc2c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)Cn1c2ccccc2c2cc(Br)ccc21
Yield: 84 %

Procedure:
The procedure for the synthesis of 2 was followed (1 eq. NBS was used) to prepare 3 from 1 as white crystals in an 84% yield. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.20-8.19 (d, 1H), 8.05-8.03 (d, 1H), 7.53-7.38 (m, 3H), 7.28-7.21 (m, 2H), 4.04-4.02 (d, 2H), 2.32-2.30 (m, 1H), 0.97-0.94 (d, 6H).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([CH:15]([F:17])[F:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:19][C:20]1[C:25]([CH2:26]O)=[CH:24][CH:23]=[C:22]([CH3:28])[N:21]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[F:16][CH:15]([F:17])[C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:2])=[O:18])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([CH3:28])=[CH:23][CH:24]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(C(F)F)c12
Reactant: Cc1ccc(CO)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(COc2cc(C(F)F)c3c(CC(=O)O)csc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
To a mixture of methyl(4-(difluoromethyl)-6-hydroxy-1-benzothiophen-3-yl)acetate (78 mg) and THF (dry) (2 mL) were added (2,6-dimethylpyridin-3-yl)methanol (43.2 mg), tri-n-butylphosphine (0.212 mL) and ADDP (94 mg) at room temperature. The mixture was stirred at room temperature for 2 h. To the mixture were added ADDP (94 mg) and tri-n-butylphosphine (0.212 mL), and the mixture was stirred at room temperature for 30 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by short pad of silica gel (EtOAc/hexane). To a mixture of the residue and THF (2 mL) was added 1N NaOH (1 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative HPLC (C18, H2O/CH3CN (including 10 mM NH4HCO3)). The fraction was extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (29.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][OH:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCC=Cc1ccc(Br)cc1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
Ethyl 4 -bromocinnamate (12.12 g) was dissolved in dry dichloromethane (50 ml) under nitrogen and cooled to -20°. Diisobutylaluminium hydride (100 ml, 1M solution in dichloromethane) (ex Aldrich) was added dropwise. The solution was allowed to warm to 25° then stirred for 18 hours then partitioned between ether and dilute hydrochloric acid. The organic phase was washed with saturated sodium bicarbonate, brine, dried over magnesium sulphate and concentrated under vacuum to give 3-(4-bromophenyl)prop-2-en-1-ol (8.9 g). NMR 1H: 7.28(2H,d), 7.05 (2H,d), 6.45 (1H,d), 6.25 (1H,t), 4.25 (2H,d), 2.0 (1H,s).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>P(Cl)(Cl)(Cl)=O>[CH:2]([C:3]1[O:20][C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:21])[CH3:1]
Reactant: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(C)cc2)oc1C(C)C

Procedure:
13 g of ethyl 4-methyl-2-(4-methylbenzoylamino)-3-oxopentanoate in 80 ml of phosphorus oxychloride are heated to the boil under reflux for 2 h. The phosphorus oxychloride is removed under reduced pressure and the resulting residue is dissolved in 200 ml of dichloromethane, washed three times with saturated NaHCO3 solution and dried over MgSO4, and the solvent is then removed under reduced pressure. This gives 11 g of ethyl 5-isopropyl-2-p-tolyloxazole-4-carboxylate as a brownish solid. C16H19NO3 (273.33), MS(ESI)=292 (M+H+), Rf(n-heptane:ethyl acetate)=2:1)=0.43.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)[CH:6]=1)=[O:4].[OH-].[Na+]>>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:21][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)c2cnn(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2cc(C(=O)O)cc3c2cnn3-c2ccccc2)nc1

Procedure:
4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid methyl ester was treated with NaOH using the procedure of step 3 of Example 1 to afford 4-(5-methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid.
Reaction SMILES: N1C(N[C@H]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Cl)C)=C2C(NC=N2)=NC=1.[NH:31]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:25]1([N:14]2[CH:13]=[CH:22][C:21]3[C:16](=[C:17]([C:33]4[CH:34]=[CH:35][NH:31][N:32]=4)[CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CN1CCCC1=O
Product: O=c1c2c(-c3cc[nH]n3)cccc2ccn1-c1ccccc1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
(S)-3-(14(9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (3) (200 mg, 0.48 mmol) and 1H-pyrazole-4-boronic acid (108 mg, 0.96 mmol) were dissolved in anhydrous NMP (8 mL) and the resulting solution was degassed and back-filled with argon (two cycles). To this mixture, Na2CO3 (152 mg, 1.44 mmol), Pd(OAc)2 (22 mg, 0.096 mmol) and di-(1-adamantyl)-n-butylphosphine (104 mg, 0.288 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon (two cycles) and then stirred at 160° C. under argon for 3 h. The reaction mixture was allowed to cool to RT and then partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was triturated with Et2O to afford the product, (S)-3-(14(9H-purin-6-yl)amino)ethyl)-2-phenyl-8-(1H-pyrazol-3-yl)isoquinolin-1(2H)-one (6) as a yellowish solid. ESI-MS m/z: 449.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:29])([CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[C:15](OS(C(F)(F)F)(=O)=O)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:35][O:34][C:30](=[O:33])[CH:31]=[CH:32][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:29])[CH3:28]
Reactant: CC(C)(Cc1c[nH]c2c(OS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cccc2c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Trifluoro-methanesulfonic acid 3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl ester (200 mg, 0.46 mmol), methyl acrylate (80 mg, 0.92 mmol) and triethylamine (0.40 mL, 3.0 mmol) is stirred in dimethylformamide (2.0 mL) at room temperature for 30 minutes. Dichlorobis(triphenylphosphine)palladium (31 mg, 0.045 mmol) is added, the reaction mixture is heated to 90° C. and allowed to stir overnight. The reaction is cooled to room temperature, poured into a separatory funnel containing ethyl acetate and brine (50 mL each) and the aqeous layer is extracted with ethyl acetate (50 mL). The combined organic layers are washed with brine, dried (Na2SO4) and evaporated. The residue is purified using silica gel chromatography (20% ethyl acetate/hexane) to give 140 mg of 3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylic acid methyl ester (82%). FDMS m/e=372.2 (M++1). The title compound is prepared from 3-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yl]-acrylic acid methyl ester as described for the alternate preparation of Amine 6 (82%). FDMS m/e=277.2 (M++1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:24])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]([O:24][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]/[CH:37]=[CH:36]\[CH2:35]/[CH:34]=[CH:33]\[CH2:32]/[CH:31]=[CH:30]\[CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCO
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCOC(=O)c1cccnc1
Yield: 91 %

Procedure:
1,3-Dicyclohexylcarbodiimide (97 g, 0.49 mol) and 4-(N,N-dimethylamino)pyridine (65 g, 0.53 mol) in methylene chloride (800 ml) were added with stirring to a solution of nicotinic acid (60 g, 0.49 mol) and z,z,z-octadeca-6,9,12-trienol (107 g, 0.41 mol) in methylene chloride (1200 ml). The progress of the reaction was monitored by tlc. On completion, the reaction mixture was filtered and the organic layer washed with 2M hydrochloric acid (500 ml) and water (3×500 ml), dried with magnesium sulphate and concentrated under reduced pressure. Purification by dry column chromatography using a gradient of ethyl acetate in hexane yielded z,z,z-octadeca-6,9,12-trienyl nicotinate as a pale yellow oil in 91% yield.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Yield: 69.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-hydroxy quinoline (0.63 g, 3.0 mmol) and N(3-hydroxypropyl)morpholine (0.54 g, 3.8 mmol) was treated with diethyl azodicarboxylate (1.38 g, 6.0 mmol) and triphenylphosphine (1.57 g, 6.0 mmol) at room temperature for 2 hours. Purification by flash chromatography on silica gel, eluting with 0-20% methanol in 1:1 ethyl acetate/dichloromethane yielded 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)-quinoline (0.70 g, 69% yield) as white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][C:3]=1[F:25].ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:37])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][C:3]=1[F:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (0.81 mmol) of the compound from Example 152 were introduced into 55 ml of dichloromethane at 0° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvents were removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 266 mg (85% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[H][H]>C(O)C.[Pd]>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1

Procedure:
14 g (45 mmol) of methyl 5-[4-(trifluoromethoxy)phenyl]pyridine-3-carboxylate in ethanol (500 ml) were admixed with 17 g of moistened palladium/carbon catalyst (10% palladium, 50% water), and then hydrogenated at 60° C. and a 50 bar hydrogen atmosphere overnight. The reaction solution was filtered, the filter residue was washed with ethanol and the filtrate was concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 600:1→10:1). Yield: 8 g (59% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[C:12]([S:14]C#N)[C:11]([CH:17]([CH3:19])[CH3:18])=[CH:10][C:9]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH3:4])([CH3:3])[CH3:2].S.[Na].[BH4-].[Na+].CO>CC(O)=O.O>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[C:12]([SH:14])[C:11]([CH:17]([CH3:18])[CH3:19])=[CH:10][C:9]=1[NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc1SC#N
Agent: S
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc1S

Procedure:
The title compound was prepared according to General Method 14b using (2-tert-butyoxycarbonylamino-4-isopropyl-5-thiocyanato-phenyl)-carbamic acid tert-butyl ester (prepared in Example SS-1; 9 g, 22 mmol), sodium hydrogen sulfide (3.7 g, 66 mmol), sodium borohydride (5.02 g, 132 mmol), MeOH (20 mL), H2O (5 mL), and AcOH (2 mL). The crude product was used without any purification. MS(APCI): 381 (M−H).