Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, off-white solid (25 mg, 30%), MS (ISP) m/z=415.4 [(M+H)+], mp 146° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:29](#N)[C:30](C)=[O:31]>C1COCC1>[C:30]([CH:15]1[C:14](=[O:20])[CH2:13][CH:12]2[N:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH:16]1[CH2:17][CH2:18][CH2:19]2)(=[O:31])[CH3:29]
Reactant: CC(=O)C#N
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
The ketone (9-[(4-chlorophenyl)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-one, 94 mg, 0.30 mmol) under nitrogen was dissolved in THF (1.5 mL), and with good stirring at room temperature, lithium diisopropylamide (1.0 M in cyclohexane/THF, 1.0 mL, 1.0 mmol) was added all at once by syringe. After stirring for 15 min, pyruvonitrile (140 mg, 2.0 mmol) was added all at once to the reaction mixture and stirred vigorously for 30 min at RT and for 24 h in a 60° C. bath. The reaction mixture was partially evaporated under a stream of nitrogen while being warmed in a 70° C. bath. The black residue was dissolved with water and dichloromethane and acidified with aq NaHSO4. The organic phase was separated and combined with one additional dichloromethane extraction of the aq phase. The organic phase was washed with 0.1 M NaOH (3×), and the basic washes were combined and acidified to pH 1-2 using aq NaHSO4. The acidic phase was extracted with dichloromethane (3×), and the combined dichloromethane extracts were washed with brine (2×), and then dried (Na2SO4) and evaporated to yield the brown solid product. MS (ES) m/e 356.0 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH:34]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:38][CH:37]=3)O)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(#N)C.ClCCl.O>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:36]3[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:40][CH:41]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(OCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
Cool a mixture of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[(4-benzyloxyphenyl)-hydroxy-methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.52 moles; 1.55 kg) in acetonitrile (6.19 L) and dichloromethane (6.19 L) in an brine/ice bath until the internal temperature is −5° C., then add triethylsilane (3.79 moles; 607 mL) over 2 minutes. Add boron trifluoride etherate (3.79 moles; 479 mL) dropwise maintaining the internal temperature below +5° C. Stir the mixture in the ice bath for 30 mins. Carefully add a mixture of NaHCO3 (saturated aqueous solution; 5 L) and water (4 L). Separate the organic phase and wash with water then brine then dry over MgSO4, filter, and concentrate under reduced pressure to afford a mixture of the title compound and compounds with one or more of the acetyl groups missing. Dissolve the residue in dichloromethane (1.86 L) and add acetic acid anhydride (7.58 moles; 716 mL) and N,N-dimethyl-4-pyridinamine, (75.78 mmoles; 9.26 g). Warm the mixture to 40° C. and gently agitate to aid dissolution then stir the mixture for 1 hour at room temperature. Concentrate the mixture under reduced pressure and slurry the residue in MTBE (6 L) overnight. Collect the solid by filtration and dry in an oven at 60° C. under reduced pressure to afford the title compound (692.8 g; 70% yield) mass spectrum (m/z): 658.3 (M+1) and 680.2 (M+23).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>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].C1(C)C=CC=CC=1.C(O)C>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][NH:23]2)=[CH:19][C:18]=1[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: COc1nc(N2CCC(O)C2)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCC(O)C4)nc3OC)cc12
Temperature: 80 °C
Yield: 35.3 %

Procedure:
A vial was charged with 1-(5-bromo-6-methoxypyridin-2-yl)pyrrolidin-3-ol (100.0 mg, 0.37 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (176.4 mg, 0.55 mmol), Pd(dppf)Cl2 (26.8 mg, 0.04 mmol), potassium carbonate (152 mg, 1.10 mmol, 2M/L aqueous) and toluene/ethanol (1.5 mL/0.5 mL). The mixture was purged with nitrogen for 5 minutes and then sealed. The reaction was heated to 80° C. overnight. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×3). The organic layer was dried (sodium sulfate) and concentrated. The resulting residue was purified through prep. TLC (petroleum ether: ethyl acetate, 2:1) to give the title compound (52.5 mg, 35.7%) as an off-white solid. 1H NMR (400 MHz, CDCl3) ppm: 8.62 (br. s), 8.05 (s, 1H), 7.89 (d, 1H), 7.50 (s, 1H), 7.35 (d, 1H), 6.00 (d, 1H), 4.61 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.73-3.57 (m, 4H), 2.24-2.05 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[N+:16]([O-])=O>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[NH2:16]
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)c(OCCCl)cc1N
Reaction time: 12 h
Yield: 99.2 %

Procedure:
To a solution of 4-(2-chloro-ethoxy)-5-methoxy-2-nitro-benzoic acid methyl ester (2.7 g, 9.32 mmol) in ethyl acetate (30 mL) was added 10% Pd/C (405 mg) and the mixture was stirred under H2 for 12 h. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered using a celite pad and was washed with excess ethyl acetate and evaporated to dryness to afford the pure 2-amino-4-(2-chloro-ethoxy)-5-methoxy-benzoic acid methyl ester (2.40 g, 99%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 7.15 (s, 1H), 6.40 (s, 2H), 6.35 (s, 1H), 4.18 (t, 2H), 3.95 (t, 2H), 3.70 s, 3H), 3.65 (s, 3H), LC-MS (ESI) m/z 260 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]([F:20])(S(F)(=O)=O)C(O)=O.C([O-])(O)=O.[Na+]>C(#N)C>[F:11][CH:12]([F:20])[O:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@@H]1CC[C@H]1CO
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H]1CC[C@H]1COC(F)F
Temperature: 60 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
To a solution of (1R,2R)-methyl 2-(hydroxymethyl)cyclobutanecarboxylate (100 mg, 0.694 mmol) in acetonitrile (5 mL) was added CuI(I) (66.1 mg, 0.347 mmol) and the reaction mixture was heated to 60° C. To the stirred solution was added 2,2-difluoro-2-(fluorosulphonyl)acetic acid (124 mg, 0.694 mmol) and the reaction mixture was stirred for an additional 12 h at 60° C. The reaction mixture was cooled to 0° C., a saturated aqueous solution of NaHCO3 was added and extracted with ethyl acetate (3×10 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure to afford Intermediate 241A as a yellow oil (100 mg, 80%). The crude product was used in the next step without further purification. 1H NMR (300 MHz, chloroform-d) δ ppm 5.92-6.56 (m, 1H), 3.86 (d, J=5.29 Hz, 2H), 3.70 (s, 3H), 3.01 (d, J=8.88 Hz, 2H), 2.18 (d, J=10.15 Hz, 2H), 1.68-2.02 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[C:15]([CH3:24])=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[C:15]([CH3:24])=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1
Reactant: COC(=O)c1cc(C)c(Br)cn1
Reactant: COc1ccc(B(O)O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(-c2ccc(OC)cc2F)cn1
Reaction time: 0.03 h

Procedure:
(2-Fluoro-4-methoxyphenyl)boronic acid (177 mg, 1.043 mmol), methyl 5-bromo-4-methylpyridine-2-carboxylate (200 mg, 0.869 mmol), 1,1bis(di-tert-butylphosphino)ferrocene palladium dichloride (89 mg, 0.130 mmol), cesium carbonate (623 mg, 1.913 mmol) and THF (5 mL) were sealed in a microwave vessel and subject to microwave irradiation at 140° C. for 20 min. The reaction crude was combined with the crude from an identical probe reaction (44.3 mg scale). Volatiles were removed under reduced pressure. The resulting pot residue was purified by preparative HPLC (reverse phase, Kromasil® 100-5C18, 100×21.1 mm) eluting with acetonitrile/water+0.1% TFA (30% to 100% organic in 10 min, then to 100% for 2 min, 20 mL/min). Related fractions were pooled and evaporated under reduced pressure to afford a dark solid. This solid was further purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 50 g cartridge). The column was eluted with an EtOAc/hexanes mixture (0% to 100%). Related fractions were pooled and evaporated to afford a light yellow oil as the titled compound. LCMS calc.=275.10. found=276.11 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=2)=[C:9]([C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)CN
Solvent: ClCCl
Product: CC(C)CNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.288 mmol) and isobutylamine (1 mL, 10.06 mmol) was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with dilute aqueous HCl. The DCM extract was dried over MgSO4, filtered, evaporated onto silica gel and chromatographed (0-20% MeOH in DCM). The title compound was obtained as a yellow solid (75 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.40-7.62 (m, 3H), 7.23-7.33 (m, 2H), 7.20 (s, 1H), 7.14 (d, J=7.7 Hz, 2H), 6.00 (br. s., 1H), 2.85-3.11 (m, 2H), 1.67-1.87 (m, 1H), 1.36 (s, 9H), 0.82 (d, J=6.4 Hz, 6H). MS (ESI): 558.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([O:9][C:8]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH3:11])=[O:10])[CH3:20]
Reactant: CCI
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)cc(Cl)nc1Cl
Reaction time: 18 h
Yield: 98.7 %

Procedure:
A mixture of 2,6-dichlor-4-methylpyridin-3-carboxylic acid (100 g, 485 mmol) and potassium carbonate (100 g, 728 mmol) in dimethylformamide (1.25 I) is stirred for 30 h at RT before ethyl iodide (59.5 ml, 728 mmol) is added and stirring is continued for 18 h. After completion of the reaction, water is added and the mixture is extracted with ethyl acetate (3×). The combined organic layers are washed with water (2×) and brine (1×), dried over magnesium sulphate and evaporated to dryness to yield 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid ethyl ester (112 g), which was used without further purification.
Reaction SMILES: N1C=CN=C1.S(Cl)(Cl)=O.[CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]2[CH:23]=[N:22][C:21]([C:29](O)=[O:30])=[C:20]([CH3:32])[C:19]3=2)[CH2:12][CH:11]=1.[C:33](=[N:37]O)([NH2:36])[CH2:34][CH3:35]>O1CCCC1.CN(C)C=O>[CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]2[CH:23]=[N:22][C:21]([C:29]4[O:30][N:37]=[C:33]([CH2:34][CH3:35])[N:36]=4)=[C:20]([CH3:32])[C:19]3=2)[CH2:12][CH:11]=1
Reactant: CCC(N)=NO
Reactant: Cc1c(C(=O)O)ncc2[nH]c3ccc(C4CC=CCC4)cc3c12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCc1noc(-c2ncc3[nH]c4ccc(C5CC=CCC5)cc4c3c2C)n1
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
1.36 g (20 mmol) of imidazole is combined in 15 ml of absolute tetrahydrofuran with 0.36 ml of thionyl chloride in 5 ml of absolute tetrahydrofuran. After 15 minutes of agitation at room temperature, the mixture is suctioned off from the precipitate. The filtrate is added to a solution of 0.33 g (1.08 mmol) of 6-(1-cyclohexen-4-yl)-4-methyl-β-carboline-3-carboxylic acid in 15 ml of absolute dimethylformamide. After agitation for one hour at room temperature, the mixture is combined with 1.15 g (13 mmol) of propionamidoxime, the tetrahydrofuran is distilled off, and the reaction solution is heated for 3 hours under reflux. After the solvent has been removed by distillation, the mixture is distributed in methylene chloride/saturated sodium bicarbonate solution, the organic phase is washed with saturated sodium chloride solution until it is neutral, dried over magnesium sulfate, filtered, and concentrated to dryness. After column chromatography over silica gel with methylene chloride:ethanol=10:1 as the eluent, and recrystallization from ethanol/hexane, the residue yields 194 mg (50% of theory) of 6-(1-cyclohexen-4-yl)-4-methyl-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-β-carboline, mp 247°-248° C.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C)(C)C.C1COCC1.Cl>[OH-].[Na+].O>[C:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][S:17][C:9]1[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Cn1c(SCCNC(=O)OC(C)(C)C)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCSc1nc2ccccc2n1CC(=O)O
Reaction time: 7 h
Yield: 77.2 %

Procedure:
tert-Butyl[2-(2-tert-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor V-02b, 28.5 mg, 0.07 mmol) is suspended in 0.2 M aqueous NaOH (2.1 ml), THF (3.95 ml) is then added and the initially turbid suspension becomes a clear solution. After 7 h, 1M aqueous HCl solution (420 μl) is added. The solution is diluted with water (10 ml) and extracted with dichloromethane (15 ml). The organic phase is dried over MgSO4 filtered over a fritted funnel and the solvents are evaporated in vacuo. Drying of the residue under high vacuum yields the title compound (19 mg) in 77% as a colourless solid: tR=1.74 min (LC-2), ESI-MS (pos.): m/z 352.17 [M+H]+, ESI-MS (neg.): m/z 350.20 [M−H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].[Pd].[Pd]>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([NH2:27])=[CH:29][CH:30]=2)[N:7]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)n1
Yield: 71 %

Procedure:
A mixture of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazine (1.26, 4.2 mmol), sodium carbonate solution (2M, 2 mL), tetrakis palladium triphenylphosphine 70 mg (catalytic amount) and 4-aminophenyl boronic pinacol ester (1.37 g, 6.3 mmoles) in DME (100 mL) was heated to reflux for 24 hours. The solvent was evaporated, the residue was re-dissolved in methylene chloride and filtered through Celite™. The solvent was evaporated and the residue was chromatographed on silica gel eluting with first 26/4 hexanes/ethyl acetate then increased to 1/1 hexanes ethyl acetate to give 1.0 of 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}aniline (71% yield); M+H 357.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]2[CH:20]([CH:21]2[CH2:24][OH:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]2[CH:22]([CH:21]2[CH:24]=[O:25])[CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC2C(CO)C2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2C(C=O)C2C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To a stirring solution of oxalyl chloride (7.8 mL, 89.5 mmol) in 370 mL of anhydrous CH2Cl2 at −78° C., under Nitrogen, was added DMSO (13.8 mL, 193.9 mmol) dropwise. After 10 minutes, 6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.9 gm, 74.5 mmol) in 72 mL anhydrous CH2Cl2 was added. After the mixture stirred 30 minutes, triethylamine (52.0 mL, 372.9 mmol) was added and the mixture was allowed to slowly warm to 0° C. over 1 hour. The mixture was concentrated, the resulting solid was taken up in saturated NaHCO3 and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated to give a quantitative crude yield of 6-Formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.8 gm), which was used in the next step without purification. 400 MHz 1H NMR (CDCl3) δ 9.4 (d, J=4.1 Hz, 1H), 3.6 (dd, J=11.2 Hz, 37.8 Hz, 2H), 3.4 (d, J=9.95, 2H), 2.1 (m, 2H), 1.8-1.7 (q, J=3.32 Hz, 1H), 1.4 (s, 9H); GCMS (M+0) 211.0.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(C(C)C)CC)(C)C.[C:27](Cl)([O:29][CH2:30][CH:31]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28].OS([O-])(=O)=O.[K+]>ClCCl>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:27]([O:29][CH2:30][CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[C:43]1=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:28]
Reactant: CCCCC/C=C/CCCNCC(OC)OC
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C/CCCN(CC(OC)OC)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
2-(trans-Dec-4-en-1-ylamino)acetaldehyde dimethyl acetal (10.5 g, 43.2 mmol) was mixed with dichloromethane (300 mL) and 7.5 mL (43.2 mmol) diisopropylethyl amine and 11.2 g (43.2 mmol) of FMOC-Cl was added portionwise. The reaction was stirred at room temperature for 3 hours and then poured into a solution of 10% KHSO4 (200 mL). The organic layer was washed with water (200 mL), dried over MgSO4, and concentrated under reduced pressure. The resulting oil was chromatographed on silica gel in 10% EtOAc/Hexanes to give 16.1 g (34.6 mmol) of N-Fmoc-2-(trans-dec-4-en-1-ylamino)acetaldehyde dimethyl acetal as a clear oil that was used directly in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)=[O:15]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[CH:20]=[CH:21][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Yield: 75.1 %

Procedure:
Dry air is bubbled through a solution of 4-acetamidophenol (320 mg, 2.1 mmol), copper(II) acetate (384 mg, 2.1 mmol), TEA (1.5 mL, 10.5 mol), (4-methoxycarbonylphenyl)boronic acid (760 mg, 4.2 mmol), and powdered molecular sieves (2 g) in CH2Cl2 (21 mL) for 16 hours at room temperature. The resulting material is concentrated and purified by flash column chromatography (25-50% EtOAc in heptane) to give methyl 4-(4-acetamidophenoxy)benzoate (450 mg, 75%). 1H NMR (300 MHz, DMSO) δ 8.01, 7.54, 7.27, 7.05, 6.98, 3.92, 2.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](O)[N:9]=[C:8]2[CH3:14].O=P(Cl)(Cl)[Cl:17]>O>[Cl:17][C:10]1[N:9]=[C:8]([CH3:14])[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1cccc2c(C)nc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc2c(C)nc(Cl)nc12
Temperature: 100 °C

Procedure:
To 8-methoxy-4-methylquinazolin-2-ol was added POCl3 and the mixture was added heated to 100° C. for 16 h when the reaction went to completion. To the reaction mixture was added ice and water and the precipitated solid was filtered and dried on the high vacuum overnight to give 2-chloro-8-methoxy-4-methylquinazoline. ES/MS m/z 209 (MH+).