Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][P:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13])C1C=CC=CC=1.C>CO.C1C=CC=CC=1.[Pd]>[ClH:1].[NH2:9][CH2:10][P:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13]
Reactant: COP(=O)(CNCc1ccccc1)OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: COP(=O)(CN)OC

Procedure:
Dimethyl N-benzyl-aminomethylphosphonate hydrochloride (80.0 g) in methanol (800 ml) is hydrogenated at 40 psi with 10% palladium on powdered charcoal (4.0 g). The catalyst is removed by filtration through a pad of super cel. Evaporation of the methanolic filtrate gives a clear residue which is taken up in benzene. Removal of the benzene in vacuo affords crystalline dimethyl aminomethylphosphonate hydrochloride.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:19]>[OH-].[Na+].O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:19])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: COc1cccc(-c2nsc(S)n2)c1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2nsc(SN)n2)c1
Reaction time: 0.25 h

Procedure:
A solution of 2.2 g of 5-mercapto-3-(3-methoxyphenyl)-1,2,4-thiadiazole in 35 ml of 5% sodium hydroxide and a solution prepared by diluting 22 ml of 5.25% NaOCl solution to 35 ml with water were added dropwise simultaneously to 95 ml of ammonium hydroxide solution while maintaining the mixture at 0°. The resulting mixture was stirred for 15 minutes and the precipitated solid was collected, washed with water and dried (P2O5 /high vacuum) to give 1.76 g of solid, m.p. 157°-160° C. dec.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH:3]([NH:15][C:16](=O)[CH3:17])[C:4]1[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:16]([NH:15][CH:3]([C:4]1[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1)[CH:2]([CH3:19])[CH3:1])[CH3:17]
Reactant: CC(=O)NC(c1nc(-c2ccccc2)c[nH]1)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNC(c1nc(-c2ccccc2)c[nH]1)C(C)C
Temperature: 25 °C

Procedure:
A solution of N-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-acetamide (0.077 g, 0.30 mmol) in THF (2.0 mL) was added dropwise over 10 min to a refluxing 1.0 M solution of LiAlH4 in THF (3.0 mL). The reaction was maintained at reflux for 11 h, cooled to rt, and quenched by sequential treatment with 0.11 mL of cold water (5° C.), 0.11 mL of 15% NaOH in aqueous solution, and 0.33 mL of cold water (5° C.). The resultant solid was removed by suction filtration and the filtrate (pH 8-9) was extracted three times with EtOAc. The combined organic fractions were dried over MgSO4, filtered, and concentrated to afford 0.069 g of a 5:1 mixture (determined by 1H NMR) of ethyl-[2-methyl-1-(4-phenyl-1H-imidazol-2-yl)-propyl]-amine and recovered Cpd 2c as a colorless oil (HPLC: peaks overlap). 1H NMR (300 MHz, CDCl3): δ 7.67 (2H, br s), 7.35 (2H, t, J=7.6 Hz), 7.26-7.17 (2H, m), 3.72 (1H, d, J=6.0 Hz), 2.56 (2H, dq, J=13.0, 7.1 Hz), 2.05 (1H, m), 1.08 (3H, t, J=7.1 Hz), 0.97 (3H, d, J=6.7 Hz), 0.89 (3H, d, J=6.7 Hz); MS (ES+) (relative intensity): 244.2 (100) (M+1). This sample was of sufficient quality to use in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[N:6][C:7]=1[NH:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:17](OC)(OC)OC>>[CH3:15][C:9]1([N:8]2[C:7]3=[N:6][C:5]([OH:16])=[CH:4][CH:3]=[C:2]3[N:1]=[CH:17]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(Nc2nc(O)ccc2N)CCCCC1
Reactant: COC(OC)OC
Product: CC1(n2cnc3ccc(O)nc32)CCCCC1

Procedure:
From 5-amino-6-(1-methylcyclohexylamino)pyridin-2-ol and trimethyl orthoformate, prepared in a similar manner as the one described in Example 1.127, Step D, the title compound was obtained. LCMS m/z=232.20 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ ppm 1.54-1.67 (m, 4H), 1.68-1.76 (m, 2H), 1.83 (s, 3H), 2.22-2.30 (m, 2H), 2.59-2.68 (m, 2H), 6.94 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 9.17 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][OH:18])[C:10]2[C:15](F)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[O:18][N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=C(Nc1cccc(Cl)c1)c1ncccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(Nc2noc3cccnc23)c1

Procedure:
A solution of N-(3-chlorophenyl)-3-fluoro-N′-hydroxypicolinimidamide, 3, (7.73 mmol) in DMF (50 mL) was added at 0° C. to a mixture of NaH (1.2 g, 31 mmol, 60% oil dispersion) in DMF (20 mL). After addition was complete, the ice bath was removed. An additional 12 h passed and the r×n was added to EtOAc:H2CO (1:1). The organic layer was separated and washed with H2CO, brine, dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the residue was purified by reverse phase liquid column chromatography (50-75% acetonitrile: water with 0.1% trifluoroacetic acid) to yield N-(3-chlorophenyl)isoxazolo[4,5-b]pyridin-3-amine as a pale yellow solid (0.52 g, 24% over two steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[Br:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (10.0 g, 43.61 mmol) was dissolved in dry methylene chloride (62 mL) and dry pyridine (9.0 mL). To the reaction mixture was then added thionyl chloride (6.23 g, 52.34 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added successively, under nitrogen atmosphere, 2-bromo-aniline (8.25 g, 47.98 mmol), dry triethylamine (15.45 g, 0.152 mol), dry methylene chloride (76 mL), 4-(dimethylamino)pyridine (0.53 g, 4.36 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned with aqueous 2N HCl and tert-butyl methyl ether. The organic layer was washed with aqueous 2N HCl, aqueous NaHCO3, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was recrystallized from ethyl acetate to yield the title compound as a solid.
Reaction SMILES: [CH:1]([C:4]1[N:26]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([O:23]CC)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[CH:1]([C:4]1[N:26]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(C(C)C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
A mixture of ethyl 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (330 mg, 926 μmol) and lithium hydroxide monohydrate (155 mg, 3.7 mmol) in methanol (6 ml) and water (2 ml) is stirred for 18 hours at 25° C. The solvents are evaporated, the white residue is dissolved in water and acidified with 37% aqueous hydrochloric acid. The precipitated white solid is collected by filtration, washed with water and dried affording 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (285 mg, 93.7%) as a white solid. Mp.: >250° C. MS: m/z=327.3 (M−H+).
Reaction SMILES: N[C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cu][C:16]#[N:17].[C-]#N.[K+].C(Cl)Cl>O.Cl>[C:16]([C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1)#[N:17]
Reactant: COc1cc(C(C)=O)cc(N)c1OC
Reactant: N#C[Cu]
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(C)=O)cc(C#N)c1OC
Reaction time: 3 h

Procedure:
A solution of 5.2 g of sodium nitrile in 20 ml of water is added dropwise at 0° within 20 minutes to 14.0 g of 5'-amino-3',4'-dimethoxyacetophenone dissolved in 155 ml of 1N hydrochloric acid. After stirring at -2° for 30 minutes the cold diazonium salt solution is added dropwise within 30 minutes at 5°-10° to a solution of 8.7 g of copper(I) cyanide and 5.45 g of potassium cyanide in 60 ml of water. After completion of the addition 200 ml of methylene chloride are added, and the reaction mixture is stirred at 23° for 3 hours and then filtered. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. There is obtained 5'-cyano-3',4'-dimethoxyacetophenone of m.p. 125°-126°.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:28](C)[C@@H:27]2[C@@:5]([C:31]([OH:33])=[O:32])([CH2:6][CH2:7][C@@:8]3([CH3:30])[C@:13]4([CH3:26])[CH2:14][CH2:15][C@H:16]5[C:21]([CH3:23])([CH3:22])[C@@H:20]([OH:24])[CH2:19][CH2:18][C@:17]5([CH3:25])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[CH3:34][O-].[Na+:36]>CO.C(Cl)(Cl)Cl>[CH3:25][C@@:17]12[C@H:12]3[CH2:11][CH:10]=[C:9]4[C@@H:27]5[CH2:28][C:2]([CH3:34])([CH3:1])[CH2:3][CH2:4][C@:5]5([C:31]([O-:33])=[O:32])[CH2:6][CH2:7][C@@:8]4([CH3:30])[C@:13]3([CH3:26])[CH2:14][CH2:15][C@H:16]1[C:21]([CH3:22])([CH3:23])[C@@H:20]([OH:24])[CH2:19][CH2:18]2.[Na+:36]
Reactant: C[O-]
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1(C)CC[C@]2(C(=O)[O-])CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]2C1
Reaction time: 0.5 h

Procedure:
30 mg of 3-O-(α-L-arabopyranosyl) ursolic acid was dissolved in methanol/chloroform (4 ml, 3/1), added with 5 mg of NaOMe, then stirred at room tempreature for 30 min and filtered to separate out a white solid. The solid was washed with methanol and dried to obtain 3-O-(α-L-arabopyranosyl) ursolic acid sodium salt.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C@@H:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=2)[CH:15]=[C:14]1[C:27](OCC)=[O:28])[CH3:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl.C(O)C>[CH3:12][C@@H:11]1[N:13]2[C:21]3[CH:20]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:17][C:16]=3[CH:15]=[C:14]2[C:27](=[O:28])[NH:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@@H](C)CCNC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc3n(c2c1)[C@@H](C)CCNC3=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of diethyl 1-{(2S)-4-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H-indole-2,6-dicarboxylate (891 mg, 2.1 mmol) in CH2Cl2 (4 mL) is added TFA (3 mL). The mixture is stirred at room temperature for 1 h then the solvent is evaporated. To a solution of the residue in ethanol (10 mL) is added K2CO3 (854 mg, 6.2 mmol). The reaction mixture is refluxed for 4 h with vigorous stifling. EtOAc is added and the organic layer is washed with water, brine, dried (MgSO4) and concentrated to afford crude compound which is purified by flash column chromatography using EtOAc in hexanes then methanol in CH2Cl2 to afford the title compound (269 mg, 46%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH2:40][CH3:41])([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH3:39])[CH:33]=3)[CH2:30][CH3:31])=[CH:25][C:24]=2[CH3:42])=[CH:21][CH:22]=1)=[O:17].C(OCC)C>CN(C)C=O>[CH3:14][O:15][C:16]([C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:34]([CH3:39])[CH:33]=3)([CH2:30][CH3:31])[CH2:40][CH3:41])=[CH:25][C:24]=2[CH3:42])=[CH:21][CH:22]=1)=[O:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2ccc(C(=O)OC)o2)c(C)c1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(=O)OC)o2)c(C)c1
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 86 %

Procedure:
t-Butyldimethylsilyl chloride (42.24 mg, 0.28 mmol) and imidazole (47.7 mg, 0.701 mmol) were added to a solution of 5-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenyl}-furan-2-carboxylic acid methyl ester (Example 19-(1); 55 mg, 0.14 mmol) in N,N-dimethylformamide (0.2 mL) at room temperature, and the mixture was stirred at room temperature for 0.2 hour. Diethyl ether was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=95/5 to ethyl acetate only) to give the title compound (61 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][S:18]([CH3:17])(=[O:20])=[O:19])=[C:4]([F:10])[CH:3]=1
Reactant: Cc1cc(N)c(F)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NS(C)(=O)=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylaniline (2.04 g, 10.0 mmol) in anhydrous CH2Cl2 (20 ml) and pyridine (3.23 ml, 40.0 mmol) was added methanesulfonyl chloride (0.86 ml, 11.0 mmol) and the resulting mixture was stirred at room temperature for 2 h. Solvent was removed in vacuo, and the residue was partitioned between EtOAc and 1M aq. HCl. The organic layer was washed with saturated aqueous NaHCO3, brine and then dried over Na2SO4. The drying agent was filtered off, and the filtrate was concentrated to give the title compound as a solid (2.80 g, 99%).
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:50]=[CH:49][C:41]2[N:42]([CH2:46][CH2:47][OH:48])[C:43](=[O:45])[S:44][C:40]=2[CH:39]=1>>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:50]=[CH:49][C:41]3[N:42]([CH2:46][CH2:47][OH:48])[C:43](=[O:45])[S:44][C:40]=3[CH:39]=2)=[CH:7][CH:6]=1
Reactant: O=c1sc2cc(Br)ccc2n1CCO
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc3c(c2)sc(=O)n3CCO)cc1)C(N)=O

Procedure:
The subtitle compound was prepared by the method of Example 96 step (a) using (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate and 6-bromo-3-(2-hydroxyethyl)benzo[d]thiazol-2(3H)-one.
Reaction SMILES: [CH2:1]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([N:29]([CH2:34][CH2:35][CH3:36])[S:30]([CH3:33])(=[O:32])=[O:31])[CH:23]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH2:1]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][O:10][CH2:21][C:22]1[CH:23]=[C:24]([N:29]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:34][CH2:35][CH3:36])[N:25]=[C:26]([Cl:28])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(c1cc(CBr)cc(Cl)n1)S(C)(=O)=O
Reactant: CC(CO)(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (1-benzyl-2-hydroxy-1-methylethyl)carbamate (250 mg, 0.94 mmol, intermediate IV) and N-[4-(bromomethyl)-6-chloropyridin-2-yl]-N-propylmethanesulfonamide (290 mg, 0.85 mmol) in dichloromethane (20 mL) was added silver triflate (290 mg, 1.13 mmol) and 2,6-ditertbutylpyridine polymer bound (1.84 g, 2.83 mmol, Aldrich 37, 782-1). The reaction mixture was stirred at 50° C. in an oil bath for 16 h and then irradiated under microwave (Smith Synthesizer) at 90° C. for 45, 60 and 90 min intervals (3 runs, with addition of additional silver triflate and 2,6-ditertbutylpyridine polymer bound before 2nd and 3rd run). The reaction mixture was filtered on celite, rinsed with dichloromethane, concentrated in vacuo and purified by flash chromatography (silica, 0-30% EtOAc/hexanes) to provide tert-butyl [1-benzyl-2-({2-chloro-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate. 1H NMR (400 MHz, CDCl3) δ 7.34-7.16 (m, 7H), 4.56 (s, 2H), 4.50 (s, 1H), 3.83 (t, J=6.8 Hz, 2H), 3.66 (A of AB, d, J=9.2 Hz, 1H), 3.54 (B of AB, d, J=9.2 Hz, 1H), 3.15 (A of AB, d, J=13.2 Hz, 1H), 3.03 (s, 3H), 2.90 (B of AB, d, J=13.2 Hz, 1H), 1.64-1.50 (m, 2H), 1.47 (s, 9H), 1.26 (s, 3H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][CH:12]=[O:13])[S:9][CH:10]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:43]=[N+:44]=[N-:45])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[N:43]([CH:5]([C:6]1[N:7]=[C:8]([NH:11][CH:12]=[O:13])[S:9][CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[N+:44]=[N-:45]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CCOC(=O)Cc1csc(NC=O)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(N=[N+]=[N-])c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
A solution of ethyl[2-(N-formylamino)thiazol-4-yl]acetate (1 g, 0.0047 mol) in THF (10 mL) was stirred under argon at −78° C. and potassium bis(trimethylsilyl)amide (2.8 g, 0.014 mol) in THF (10 mL) was added. After stirring for 30 minutes, 2,4,6-triisopropylbenzenesulfonyl azide (3.6 g, 0.012 mol) was added as a solid in one portion. After 5 minutes, acetic acid (1.4 mL, 0.018 mol) was added and the mixture warmed to room temperature. The reaction mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), separated and the organic layer dried (MgSO4). Evaporation of the solvent and purification of the residue by silica gel chromotography afforded the azide (0.95 g, 80%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[C:7](=[O:19])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([OH:17])[C:10]=2[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:5][C:6]1[C:7](=[O:19])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:3][CH:2]=[CH2:1])[C:10]=2[CH3:18]
Reactant: C=CCBr
Reactant: Cc1c(F)c(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(C)c(F)c(=O)oc2c1C
Temperature: 25 °C
Reaction time: 28 h
Yield: 77.6 %

Procedure:
Allyl bromide (1.08 mL, 12.48 mmoles) was added to a mixture of 3-fluoro-4,8-dimethyl-7-hydroxycoumarin (1.73 g, 8.31 mmoles), ca. 5 g of potassium carbonate and 45 mL of dry acetone. The reaction mixture was stirred under an inert atmosphere at room temperature for 28 hours. During this time, excess allyl bromide (1.44 mL, 16.64 mmoles) was added in two portions. The carbonate salt was removed by suction filtration washed with acetone and the solvent evaporated under reduced pressure yielding a solid, which was purified by recrystallisation from a mixture of methanol:water. Thus, 1.60 g (78% yield) of 3-fluoro-4,8-dimethyl-7-allyloxycoumarin was obtained as a white solid: mp 117° C.
Reaction SMILES: N12CCCN=C1CCCCC2.[N+:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[C-:13].[N+]([C:23](=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])([O-])=O>O1CCCC1.C(O)(C)C>[CH3:24][C:23]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:12][CH:13]=1
Reactant: CC(=Cc1ccccc1)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (3.70 g, 24.6 mmol) was added dropwise to a stirred solution of ethyl isocyanoacetate (1.50 g, 13.3 mmol) and 2-nitro-3-phenyl-2-propene (2.0 g, 12.3 mmol) in a mixture of tetrahydrofuran (15 mL) and iso-propanol (5 mL) at between 10 and 20° C. The reaction mixture was stirred at room temperature for 4 h. Excess tetrahydrofuran was removed in vacuo, water (15 mL) was added to the residue and the mixture was extracted with diethyl ether (3×25 mL). The combined organic phases were washed with brine (2×15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford ethyl 4-methyl-3-phenyl-1H-pyrrole-2-carboxylate (2.5 g, 90%) as an oil.
Reaction SMILES: C(O[C:4](OCC)([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)[C:5](=[O:7])[CH3:6])C.Cl.C1C[O:30]CC1>>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:4][C:5](=[O:7])[CH:6]=[O:30])[CH:12]=[C:13]([O:21][CH3:22])[C:14]=1[O:19][CH3:20]
Reactant: C1CCOC1
Reactant: CCOC(CCCc1cc(OC)c(OC)c(OC)c1)(OCC)C(C)=O
Agent: Cl
Product: COc1cc(CCCCC(=O)C=O)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution 1.8 g of 6-(3,4,5-trimethoxyphenyl)-2-keto-3-hexanal-diethylacetal in 15 ml of THF was added sufficient 6N HCl so that the pH<1. this mixture was refluxed for 18 hours. the mixture was cooled to room temperature and the solvent evaporated. the residue was triturated with 50 ml of ethyl acetate, the ethyl acetate solution dried with sodium sulfate (Na2SO4) and evaporated. the residue was chromatographed on 30 g of silica using CHCl3 as the elutant. Appropriate fractions were combined and evaporated to yield 0.8 g of 6-(3,4,5-trimethoxyphenyl)-2-keto-hexanal as an oil. 1H NMR: (CDCl3) δ 9.15 (s, 1 H), 6.40 (s, 2 H), 3.80 (s, 6 H), 3.76 (s, 3 H), 2.50 (m, 4 H), 1.60 (m, 4 H).
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)[C:20]([CH3:31])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl>O1CCOCC1>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=5)[C:20]([CH3:31])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ncc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide (126 mg, 0.286 mmol) in 1,4-dioxane (1.50 mL), 4 M aqueous HCl (775 μL, 3.10 mmol) was added and stirred at 90° C. for one hour. The reaction was cooled to room temperature, quenched with Et3N and concentrated. The resulting mixture was dissolved in EtOAc and filtered. The solid was dissolved in water and the product was extracted using ethyl acetate (×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered and purified by reverse phase preparative HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 426.11, found 427.3 (M+1)+. Retention time 1.34 minutes.