Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:37])[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:25]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:22])[CH3:21])[N:16]=1)=[O:13])C1C=CC=CC=1>C1COCC1>[Si:30]([O:29][CH2:28][C@H:27]([CH3:37])[O:26][C:24]1[CH:23]=[C:11]([CH:10]=[C:9]([OH:8])[CH:25]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH:20]([CH3:21])[CH3:22])[N:16]=1)=[O:13])([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)n1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Solvent: C1CCOC1
Product: CC(C)n1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.7 %

Procedure:
A solution of 3-(benzyloxy)-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(1-isopropyl-1H-pyrazol-3-yl)benzamide (1.97 g, 3.77 mmol) and THF (70 mL) was evacuated and purged with, Argon (×3). Palladium on carbon (10% w/w, 400 mg) was added and reaction mixture was evacuated and finally purged with hydrogen gas. Reaction mixture was left to stir at ambient temperature under hydrogen for 16 hours. Pd/C was filtered off and concentrated in vacuo to give the product as a colourless oil (1.58 g, 97%).
Reaction SMILES: [CH3:1][N:2]1[C:6](N)=[CH:5][CH:4]=[N:3]1.[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][N:12]=1)[CH3:9]>>[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([NH:17][C:1]2[N:3]=[CH:4][C:5]3[CH2:5][CH2:6][NH:2][CH2:1][C:6]=3[N:2]=2)[CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: CCOc1cc(N)ccn1
Reactant: Cn1nccc1N
Product: CCOc1cc(Nc2ncc3c(n2)CNCC3)ccn1

Procedure:
N-(2-ethoxypyridin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (186) was prepared in accord with the procedures described in steps 1 to 4 of example 25 except in step 1, 1-methyl-1H-pyrazol-5-amine was replaced with 2-ethoxypyridin-4-amine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]1[CH2:12][O:11][CH2:10]C1>CS(C)=O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:8][C@@H:12]2[CH2:10][O:11]2)[CH:3]=1
Reactant: C1CCOC1
Reactant: Oc1cccnc1
Solvent: CS(C)=O
Product: c1cncc(OC[C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of 11.9 g (0.125 mol) of 3-hydroxypyridine in 50 mL of DMSO at 15° C. was added 120 mL (0.12 mol) of a 1.0 M solution of sodium hexamethyldisilylazide in THF. After the reaction mixture was allowed to stir for 5 min, 25.9 g (0.10 mol) of (2S)-glycidyl 3-nitrobenzene sulfonate was added in one portion. The mixture was cooled with a room temperature water bath for 30 min. It s was then quenched by the addition of 250 mL of water and extracted with three portions of ethyl acetate. The combined aqueous extracts were washed sequentially with water and brine, dried over sodium sulfate, treated with granular charcoal, filtered and concentrated to give 7.7 g (51%) of an orange oil which was used without further purification. An analytical sample was prepared by flash chromatography (silica gel, 80% ethyl acetate/hexane): 1H NMR (400 MHz, CDCl3) a 8.31 (m, 1H), 8.21 (m, 1H), 7.20-7.22 (m, 2H), 4.29 (dd, 1H, J=1,6 Hz), 3.95 (m, 1H), 3.34 (m, 1H), 2.90 (t, 1H, J=3Hz), 2.75 (m, 1H).
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[CH:4]([OH:8])[CH2:5][CH2:6][OH:7])#[N:2].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]([CH:4]1[CH2:5][CH2:6][O:7][C:11]([CH3:16])([CH3:12])[O:8]1)([CH3:10])[CH3:9])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C#N)C(O)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)OCCC(C(C)(C)C#N)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol (500 mg) was dissolved in acetone (5 mL) and p-toluenesulfonic acid (50 mg) and powder molecular sieve 4A (100 mg) were added. The mixture was stirred at room temperature for 1 hr. Thereto was added a powder of potassium carbonate to neutralize the reaction mixture, which was filtrated and concentrated under reduced pressure to give optically active 4-(1-cyano-1-methylethyl)-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[C:25]([F:26])=[CH:24][C:23]([O:27]C)=[CH:22][C:21]=4[F:29])=[CH:15][C:14]=3[Cl:30])[C:8]2=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[C:25]([F:26])=[CH:24][C:23]([OH:27])=[CH:22][C:21]=4[F:29])=[CH:15][C:14]=3[Cl:30])[C:8]2=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(F)c(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C(Cc2c(Cl)cc(-c3c(F)cc(O)cc3F)cc2Cl)CCN1C1CCCCC1
Temperature: 0 °C
Yield: 94 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (500 mg, 1.0 mmol) and 2,6-difluoro-4-methoxyphenylboronic acid (590 mg, 3.2 mmol) affords 494 mg (100%) of 1-Cyclohexyl-3-(3,5-dichloro-2′,6′-difluoro-4′-methoxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one. Charge a flask with 1-cyclohexyl-3-(3,5-dichloro-2′,6′-difluoro-4′-methoxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (500 mg, 1.1 mmol), dissolve in dry methylene chloride (10 mL) and cool to 0° C. under nitrogen. Add BBr3 (0.25 mL, 2.7 mmol) and stir at 0° C. for 1.5 hours. Pour into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate in vacuo to yield 470 mg (97%) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:29][NH2:30]>O>[CH3:29][NH:30][C:19](=[O:21])[CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)NC
Temperature: 80 °C

Procedure:
A mixture of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.24 g, 16.5 mmol, prepared in Parts A and B of Example 16), THF (15 mL), and methylamine (available as a 40% solution in water, 8 mL) was scaled in a high-pressure vessel, heated at 80° C. overnight, and concentrated under reduced pressure to provide 4.7 g of N-methyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3cccs3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNC(=O)c1ncc2c(-c3cccs3)noc2c1O
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Ethyl 7-hydroxy-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (0.11 g, 0.38 mmol) was dissolved in 10 mL of DMF. Glycine (0.569 g, 7.59 mmol) and sodium ethoxide (0.387 g, 5.69 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 92 mg of the title compound. MS: (+) m/z 320.37 (M+1).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1.O1CCCC1>CCOCC>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC(O)(c2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Phenylmagnesium bromide in ether (3.00M, 0.400 mL) was added to a solution of 1-tert-butyl 2-methyl(2S)-4-oxopyrrolidine-1,2-dicarboxylate (243.0 mg, 0.0009989 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) at −40° C. The reaction mixture was stirred at between −40° C. and −10° C. for 2 h and then was quenched with amonium chloride solution (5 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[Cl:23][C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:19]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (4.50 g, 17.1 mmol, Preparation #5, Step A) in DCM (40 mL) at ambient temperature was added oxalyl chloride (3.00 mL, 34.2 mmol) followed by DMF (0.10 mL, 1.3 mmol). After about 3 h, the reaction was concentrated under reduced pressure to constant weight to afford benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate as a yellow oil (3.88 g, 81%): 1H NMR (CDCl3) δ 7.44-7.35 (m, 5H), 5.16 (s, 2H), 4.20-4.10 (m, 2H), 3.03-2.89 (m, 3H), 2.15-2.05 (m, 2H), 1.81-1.76 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH:16]C(OCC2C=CC=CC=2)=O)[C:13]2[C:8](=[CH:9][C:10]([O:29][CH3:30])=[C:11]([O:27][CH3:28])[CH:12]=2)[N:7]1[C:31]([O:33][CH:34]([CH2:36][CH3:37])[CH3:35])=[O:32])=[O:5])[CH3:2]>[Pd].C(O)C.C1CCCCC=1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([O:29][CH3:30])=[C:11]([O:27][CH3:28])[CH:12]=2)[N:7]1[C:31]([O:33][CH:34]([CH2:36][CH3:37])[CH3:35])=[O:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)[C@H]1C[C@@H](N)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Temperature: 70 °C
Yield: 84.5 %

Procedure:
cis-4-Benzyloxycarbonylamino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 2) (800 mg), 10% palladium on carbon (800 mg), and a mixture of ethanol-cyclohexene (2:1, 60 mL) was heated to 70° C. for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using to 5% methanol/ethyl acetate afforded the title compound (500 mg). 1H NMR (CDCl3) δ 0.9 (t, 3H), 1.4 (m, 5H), 2.5 (m, 1H), 3.9 (d, 6H), 6.9 (s, 1H), 7.2 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)(=[O:38])=[O:37])[C:26]([Cl:44])=[CH:25][N:24]=1>>[Cl:44][C:26]1[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)(=[O:38])=[O:37])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.072 g, 61%). MP: 68-88° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.42 (s, 1H), 8.54 (d, 1H, J=8.3 Hz), 8.13 (s, 1H), 7.97 (s, 1H), 7.93 (d, 1H, J=7.8 Hz), 7.55 (t, 1H, J=7.7 Hz), 7.47 (s, 1H), 7.21 (t, 1H, J=7.7 Hz), 6.65 (s, 1H), 3.86 (s, 3H), 3.58-3.50 (m, 2H), 3.48-3.40 (m, 2H), 3.33 (s, 6H), 3.29-3.23 (m, 4H), 3.07-2.98 (m, 1H), 2.87-2.75 (m, 6H), 2.74-2.68 (m, 2H). MS: 631.25 (MH)+.
Reaction SMILES: CO[C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])[CH3:17]>C(#N)C.C(N(CC)CC)C>[NH2:14][C:13]1[C:10]([C:11]#[N:12])=[C:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:22]([CH2:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])[C:20]=1[C:19]([O:18][CH3:16])=[O:23]
Reactant: COC(=C(C#N)C#N)c1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCn1c(C(=O)OC)c(N)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After dissolving (methoxyphenylmethylene)methane-1,1-dicarbonitrile (15.10 g) and β-alanine ethyl ester hydrochloride (15.11 g) in acetonitrile (300 mL), triethylamine (23.00 mL) was added and the mixture was stirred for 10 minutes at room temperature. After confirming complete consumption of the (methoxyphenyl-methylene)methane-1,1-dicarbonitrile by thin-layer chromatography (hexane/ethyl acetate=3/1), the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. Acetonitrile (700 mL) and anhydrous cesium carbonate (53.65 g) were added to the residue. Methyl bromoacetate (16.00 mL) was added thereto and the mixture was heated to reflux for 40 minutes. After cooling the mixture to room temperature, it was allowed to stand, the supernatant was separated by decantation, and the solvent was distilled off under reduced pressure. The residue was combined with the solid portion remaining after decantation, ethyl acetate and water were added, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was passed through a chromatography column packed with a small amount of silica gel (elution with dichloromethane), for removal of the highly polar impurities, to obtain the title compound as a crude product (35.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][O:6][CH:7]([CH3:9])[CH3:8])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Solvent: CC(C)O
Product: Cc1c(COC(C)C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate with isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-isopropoxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.32 ppm (d, 1H), 5.22 ppm (m, 1H), 4.45 ppm (d, 1H), 4.34 ppm (d, 1H), 3.69 ppm (m, 1H), 3.48 ppm (s, 3H), 2.44 ppm (s, 3H), 1.35 ppm (d, 6H), 1.21 ppm (d, 6H).
Reaction SMILES: [CH:1]12[CH2:18][CH:8]([CH2:9][N:10]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:11]1)[C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[F:14][C:13]([F:15])([F:16])[C:12]([N:10]1[CH2:11][CH:1]2[CH2:18][CH:8]([C:7]3[CH:6]=[CH:5][C:4]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:3][C:2]=32)[CH2:9]1)=[O:17]
Reactant: O=C(N1CC2CC(C1)c1ccccc12)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(N1CC2CC(C1)c1cc(S(=O)(=O)Cl)ccc12)C(F)(F)F
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (530 mg, 2.1 mmol) was added to chlorosulfonic acid (2 mL, 30 mmol) and stirred for 5 minutes. The mixture was quenched with ice, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated to provide an oil (640 mg, 87%). (TLC 30% ethyl acetate/hexanes Rf 0.15).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].CN(C=O)C.[H-].[Na+].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[N:20]=1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([NH:25][C:21]2[N:20]=[CH:19][N:24]=[C:23]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]=3[OH:10])[N:22]=2)[CH:27]=[C:28]([O:36][CH3:37])[C:29]=1[O:34][CH3:35]
Reactant: O=C1Cc2ccccc2N1
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(Nc2ncnc(-c3c(O)[nH]c4ccccc34)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxindole (176 mg, 1.32 mmol) was dissolved in a 1:1 mixture of THF:DMF (4 mL), under N2, at RT. NaH (53 mg of a 60% suspension in mineral oil, 1.32 mmol) was added, which produced a vigorous gas evolution. This mixture was stirred for 30 min at RT, then (4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (156 mg, 0.53 mmol) was added and the reaction was heated to 80° C. for 2 h. The reaction was cooled to RT, partially concentrated under reduced pressure, diluted with EtOAc, then extracted with water. The water extract was back extracted two times with fresh EtOAc. All of the EtOAc extracts were washed with brine, combined, dried over NaSO4, filtered and concentrated. The recovered material was purified by preparative HPLC (5 to 100% CH3CN:H2O (0.1% TFA buffer) over 10 min at 20 mL/min) Crystals formed in the recovered eluant, which were recovered by vacuum filtration, washed with water, and dried under high vacuum giving 3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-1H-indol-2-ol as a yellow solid: MS m/z=394 [M+H]+. Calc'd for C20H19N5O4: 393.14.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:16][CH2:17][CH2:18][S:19][C:20]1[N:24]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:16][CH2:17][CH2:18][S:19][C:20]1[N:24]([CH2:25][C:26]([OH:28])=[O:27])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1c2ccccc2c(=O)n1CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)n1c2ccccc2c(=O)n1CCCSc1nc2ccccc2n1CC(=O)O
Yield: 13.2 %

Procedure:
tert-Butyl {2-[3-(2,3-dihydro-1-ethyloxycarbonyl-3-oxo-indazol-2-yl)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor G-01b, 63.8 mg, 0.1 mmol) is stirred in TFA/dichloromethane (1:1, 2 ml) at rt overnight. The solvents are removed in vacuo. The crude is taken up in chloroform (1 ml) and filtered over cotton wool. The solvent is removed in vacuuo and the residue is dried under high vacuum. This yields the title compound (6 mg) in 11% as a colourless oil: tR=2.24 min (LC-2), ESI-MS (pos.): m/z 455.11 [M+H]+, ESI-MS (neg.): m/z 453.22 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.31 (t, 3H, CH3), 2.03 (quint., 2H, CH2CH2N), 3.18 (m, 2H, SCH2), 4.23 (t, 2H, CH2N), 4.36 (q, 2H, OCH2), 4.94 (s, 2H, CH2CO2), 7.10-7.15 (m, 2H, m), 7.39 (t, 1 Harom), 7.46 (m, 2Harom), 7.70-7.78 (m, 2Harom), 7.87 (d, 1Harom)
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].S(C1C=CC(C)=CC=1)(O[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)(=O)=O>CS(C)=O>[CH:27]1([N:12]2[C:13]3[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=3)[C:10]([C:15]3[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=3)=[CH:11]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2cn(C3CCCC3)c3cc([N+](=O)[O-])ccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Method M Add KOH pellets (200 mg, 3.42 mmol) to a solution of 4-(6-nitro-1H-indol-3-yl)-benzonitrile, 9, (150 mg, 0.57 mmol) in DMSO (10 mL). After the KOH pellets dissolve, add cyclopenyl tosylate (210 mg, 0.85 mmol) in DMSO (3 mL). Allow the reaction mixture to stir overnight at ambient temperature. Add additional cyclopentyl tosylate (210 mg, 0.85) and allow the reaction mixture to stir for another 6 h. Add still more cyclopentyl tosylate (210 mg, 0.85 mmol) and allow the reaction mixture to stir overnight at ambient temperature. Quench the resulting reaction mixture with 5N HCl/ice. Extract the quenched reaction mixture with EtOAc. Wash the EtOAc extracts with brine. Dry the organic layer over MgSO4, filter, and remove the solvent from the filtrate to provide a solid. Purify by silica gel column chromatography (0-100% EtOAc/hexanes gradient) and collect the fractions and remove the solvent to afford 110 mg (58%) of the title compound. LRMS (API ES+)=332.2 (M+H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].N1C(C)=CC=CC=1C.[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[N:20]>>[C:18]([C:19]1[O:3][C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])=[CH:4][N:20]=1)([CH3:22])([CH3:21])[CH3:17]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(C)(C)C#N
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1cnc(C(C)(C)C)o1
Temperature: 25 °C
Yield: 29 %

Procedure:
A solution of ethyl pyruvate (2.0 g, 17.2 mmol) and HDNIB (9.7 g, 20.7 mmol) in trimethylacetonitrile (15 mL) was heated to reflux for 3 hours. After the reaction mixture was cooled to RT, 2,6-lutidine (0.2 mL, 1.7 mmol) was added. The reaction mixture was refluxed for an additional 8 hours. The reaction was checked by LC-MS and the solvent was removed. The residue was dissolved in CH2Cl2C washed with water and brine, dried (Na2SO4), concentrated in vacuo and purified via silica gel column chromatography (EtOAc/hexane) to obtain ethyl 2-tert-butyloxazole-5-carboxylate (1.0 g, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.89 (s, 1H), 4.42 (d, J=7.2 Hz, 2H), 1.49 (s, 9H), 1.43 (d, J=7.2 Hz, 3H); MS (ESI) m/z: 198.1 (M+H+).