Azzindani/Open_Reaction_Data huggingface dataset:
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].[I:11]N1C(=O)CCC1=O.O>C(O)(=O)C>[I:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1Cc2ccccc2N1
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2cc(I)ccc2N1
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A solution of 2-indolinone (2.66 g, 20 mmol) in acetic acid (20 ml) was stirred at room temperature in the presence of N-iodosuccinimide (5.4 g, 24 mmol) for 2 hours. H2O (150 ml) was then added. The precipitate was filtered, washed with H2O, and dried. The resulting solid was refluxed in ethyl acetate (50 ml), cooled to 0° C., filtered, washed with ethylacetate and ether and dried to provide 5-iodo-1,3-dihydro-indol-2-one (3.62 g. 70%) as a beige solid, m.p. 190-192° C. and MS: m/e=259 (M+).
Reaction SMILES: C(OC(=O)C)(=O)C.[OH:8][CH:9](CCCCCCCC)/[CH:10]=[CH:11]/[CH:12]=[CH:13]/C1C=CC=CC=1CCCCCO.[C:34]1([Si:40]([O:51][Si:52]([C:65]([CH3:68])([CH3:67])[CH3:66])([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:41]([CH3:44])([CH3:43])[CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH2:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH3:13].[C:59]1([Si:52]([O:51][Si:40]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:65]([CH3:68])([CH3:67])[CH3:66])[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: CCCCCCCCC(O)/C=C/C=C/c1ccccc1CCCCCO
Agent: CC(C)(C)[Si](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
For acetylation, 0.5 ml of acetic anhydride is added to a solution of 310 mg of the above-described alcohol in 2 ml of pyridine and stirred for 16 hours at 25° C. Then, it is concentrated by evaporation with adding toluene in a vacuum and the residue is chromatographed on silica gel. With hexane/1-5% of methyl-tert-butyl ether, 265 mg of 5-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-phenyl]-pentan-1-ol-diphenyl-tert-butylsilyl ether is obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([C:18]2[S:22][CH:21]=[N:20][CH:19]=2)[CH:17]=1)[NH2:14].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>>[F:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH:14][C:13]2[CH:15]=[C:16]([C:18]3[S:22][CH:21]=[N:20][CH:19]=3)[CH:17]=[C:11]([CH3:10])[CH:12]=2)=[N:3][CH:4]=1
Reactant: Cc1nc(Cl)ncc1F
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(Nc2ncc(F)c(C)n2)cc(-c2cncs2)c1
Temperature: 100 °C
Yield: 57.4 %

Procedure:
2-Chloro-5-fluoro-4-methylpyrimidine (500 mg, 3.41 mmol), 3-methyl-5-(1,3-thiazol-5-yl)aniline (649 mg, 3.41 mmol), PdOAc2 (77 mg, 0.341 mmol), Xantphos (296 mg, 0.512 mmol), and cesium carbonate (2223 mg, 6.82 mmol) were combined in a flask and degassed with Argon. Dioxane (12 mL) was added and the solution was degassed with Argon for 5 min. The mixture was heated to 100° C. for 2 h and then allowed to cool to room temperature. The mixture was diluted with Brine and EtOAc. The layers were separated and the aqueous portion was re-extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification via silica gel flash chromatography (0-40% EtOAc:CH2Cl2) afforded 5-fluoro-4-methyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (588 mg, 57%) as a beige solid. MS ESI: [M+H]+ m/z 301. 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 8.33 (s, 2H), 8.09 (s, 1H), 7.74 (s, 1H), 7.33 (s, 1H), 7.08 (s, 1H), 2.40 (s, 3H). rhSYK activity=+++.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[C:30]([Cl:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1N=C2C=CC=CC2=N1>CN(C)C=O.C(N(CC)CC)C>[NH2:21][C:22]1[C:30]([Cl:31])=[CH:29][C:25]([C:26]([NH:20][CH2:19][CH:16]2[CH2:17][CH2:18][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:8]([CH3:9])[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:15]2)=[O:27])=[C:24]([O:32][CH3:33])[CH:23]=1
Reactant: CN(CCCCN1CCC(CN)C1)Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nc2ccccc2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN(C)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.8 %

Procedure:
A suspension of N-benzyl-N-methyl-4-(3-aminomethylpyrrolidin-1-yl)-butylamine (1.06 g), 4-amino-5-chloro-2-methoxybenzoic acid (0.78 g), dicyclohexylcarbodiimide (0.79 g), 2-hydroxybenzotriazole (0.52 g) and triethylamine (1.1 ml) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 12 hr. The solvent was evaporated, and water was added to the residue, which was followed by extraction with chloroform. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.19 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-(N-methyl-N-benzylamino)butyl)pyrrolidin-3-yl)methyl)-benzamide.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:6]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1cccc(C(Br)c2cccc(C(F)(F)F)c2)c1
Product: CCOP(=O)(OCC)C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1

Procedure:
A solution containing 3,3'-bis(trifluoromethyl)benzhydryl bromide (29.8 g, 77.6 mmol), prepared according to methods in Example 3 and triethyl phosphite (21.6 mL, 126 mmol), was heated at 155°-160° C. for 16 hours, under N2. The reaction mixture was cooled and washed with H2O (2×150 mL) to remove the excess triethyl phosphite. The non-aqueous portion was added to CH2Cl2 (150 mL), dried (MgSO4), filtered, and concentrated in volume to give a pale yellow oil, 30.1 g. The crude product was chromatographed on a silica gel column. Elution with ethyl acetate/hexane (1:1) afforded analytically pure product as a white solid, 10.7 g, (31.2%), mp 82°-85° C. 300MHz 1H NMR (CDCl3): δ,4.54 (d,1H, J=25.3 Hz, PCH). MS: 441 (M+1).
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[C:4]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:5]=2[S:6][C:7]=1[C:8](Cl)=[O:9]>O1CCOCC1>[Cl:2][C:3]1[C:4]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:5]=2[S:6][C:7]=1[C:8]([OH:1])=[O:9]
Reactant: O
Reactant: COc1cc2sc(C(=O)Cl)c(Cl)c2cc1OC
Solvent: C1COCCO1
Product: COc1cc2sc(C(=O)O)c(Cl)c2cc1OC

Procedure:
40 ml of water are added to a solution of 70 mmol of the compound of Step A in 250 ml of dioxane. After 20 hours' reflux and then return to room temperature, a precipitate forms. After filtration and rinsing with water until neutral, the precipitate is dried over P2O5 under reduced pressure. 18.6 g of the expected product are thus isolated.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH:17][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COCCCN
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Product: COCCCNc1ccc(S(N)(=O)=O)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture of 6-chloropyridine-3-sulfonamide (5 g, 0.025 mol) and 3-methoxy propylamine (50 ml) is stirred at 100° C. for 12 h. The mixture is cooled and excess reagent is removed by distillation. The residue is suspended in DCM (25 ml) and cooled. The precipitate is filtered, washed with cold ammonium hydroxide (2×50 ml) and dried under vacuum to afford 5 g (78%) of the titled compound as a white solid. mp: 129-132° C., LC/MS: (ES+) 246.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: COc1ccc(CO)cc1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(Cl)nc(SC)n2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 658.1 %

Procedure:
To a solution of 4,6-dichloro-2-(methyl thio)pyrimidine (75 g, 38.4 mmol, Sigma-Aldrich) in DMF (750 mL) was added p-methoxybenzyl alcohol (58.38 g, 42.1 mmol) and K2CO3 (212.3 g, 1538 mmol). The reaction was stirred at 60° C. for 12 h, then cooled to RT. Water (500 mL) was added to the mixture and the resulting suspension was filtered. The solid was dried and triturated with Hexanes to give 4-Chloro-6-(4-methoxy-benzyloxy)-2-methylsulfanyl-pyrimidine (75 g, 66.4% yield) as a white solid. MS (ESI, pos. ion) m/z: 297.0 (M+1); 1H NMR (400 MHz, CDCl3): δ 7.30-7.37 (m, 3H), 6.89-6.93 (m, 2H), 5.36 (s, 2H), 3.82 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[CH:7][C:6]=1[O:15][CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[CH3:16][O:15][C:6]1[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[C:3]1[N:17]=[C:18]([NH2:20])[S:19][CH:2]=1
Reactant: NC(N)=S
Reactant: COc1cc(OC)c(C(=O)CBr)c(OC)c1
Solvent: CCO
Product: COc1cc(OC)c(-c2csc(N)n2)c(OC)c1
Yield: 76.4 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-trimethoxyphenyl)ethanone (2.49 g, 8.6 mmol) and thiourea (0.67 g, 8.7 mmol) in 95% EtOH (16 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4,6-trimethoxyphenyl)thiazol-2-amine (1.75 g) as yellow solids in >99% yield: 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 2 H), 6.78 (s, 1 H), 6.36 (s, 2 H), 3.84 (s, 3 H), 3.79 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([NH2:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH2:14](C(CC)(CC)C([O-])([O-])[O-])[CH3:15]>>[Cl:1][C:2]1[C:7]2[N:6]([C:14]([CH3:15])=[N:9][N:8]=2)[C:5]([NH2:10])=[C:4]([N+:11]([O-:13])=[O:12])[N:3]=1
Reactant: NNc1nc(N)c([N+](=O)[O-])nc1Cl
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nnc2c(Cl)nc([N+](=O)[O-])c(N)n12
Yield: 75 %

Procedure:
To 5.0 g (0.024 m) 5-chloro-6-hydrazino-3-nitropyrazinamine was added 50 ml of triethylorthoacetate and the resulting suspension was heated at 100° for 2.5 hours. The reaction mixture was cooled, filtered and the resulting dark brown solid washed with chloroform to give 4.1 g (75%) of the titled product as a brown solid, m.p. 220°; H' nmr (DMSO-d6): 9.60 (2H, broad singlet), 3.40 (3H, s); ms:m/e 228.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[N:14]([CH3:27])[S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C([O-])([O-])=O.[K+].[K+].[C:34]([N:41](N)[CH2:42][CH:43]=O)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH2:7]([N:5]1[CH2:4][C@@H:3]([N:14]([CH2:27][CH2:7][CH:8]([CH3:13])[CH3:9])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C@H:2]([NH:1][CH2:43][CH2:42][NH:41][C:34](=[O:35])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN([C@@H]1CN(Cc2ccccc2)C[C@H]1N)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N(N)CC=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CC(C)CCN([C@@H]1CN(Cc2ccccc2)C[C@H]1NCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(3R,4R)-4-amino-1-benzylpyrrolidin-3-yl]-N-methyl-4-nitrobenzenesulfonamide (692 mg, 1.5 mmol) in MeOH was added K2CO3 (405 mg, 3 mmol) and the mixture was stirred for 0.5 hour at room temperature. To this mixture, Boc-amino glycinal (1.8 mmol) was added following by addition of a solution of NaBH3CN (111 mg, 1.8 mmol) and ZnCl2 (0.6 eq) in MeOH at room temperature. The reaction mixture was stirred at room temperature overnight, quenched with 1N aqueous NaOH, extracted with CHCl3, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 2-5% MeOH in CHCl3 giving the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[C:3]([NH:35][CH2:34][CH2:33][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: NCCN1CCOCC1
Product: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1NCCN1CCOCC1
Temperature: 180 °C
Yield: 41.1 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.010 g, 0.025 mmol) was dissolved in 2-morpholin-4-ylethanamine (1 ml, 8 mmol) and heated in a sealed vial at 180° C. for 40 min. The excess amine was removed under reduced pressure, and the solid residue was washed with methanol, giving the title product (0.005 g, 41%).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:27])=[C:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:9]([O:16][CH2:17][CH3:18])=[N:10]2.CO.[OH-].[Li+]>O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:8]2[C:9]([O:16][CH2:17][CH3:18])=[N:10][C:11]3[C:6]([C:7]=2[CH3:27])=[C:5]([CH2:4][C:3]([OH:28])=[O:2])[CH:14]=[C:13]([CH3:15])[CH:12]=3)=[CH:25][CH:24]=1
Reactant: CCOc1nc2cc(C)cc(CC(=O)OC)c2c(C)c1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1nc2cc(C)cc(CC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorobenzyl)-2-ethoxy-4,7-dimethylquinolin-5-yl]acetic acid methyl ester (0.10 g), methanol (2.0 mL), saturated aqueous lithium hydroxide solution (0.20 mL) and water (0.4 mL) was stirred at 50° C. for 5 hours. The methanol was removed under reduced pressure and the residue acidified by the addition of trifluoroacetic acid. The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a white solid, 0.095 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15].[C:16]1([CH:23]=CC(O)=[CH:19][CH:18]=1)O.C=CC=C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:19][CH2:18][CH2:16][CH2:23][C@H:10]2[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15]
Reactant: Oc1ccc(O)cc1
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Agent: C=CC=C
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H]2CCCC[C@H]2[N+](=O)[O-])cc1OC
Temperature: 160 °C
Reaction time: 144 h

Procedure:
50.0 g of 3,4-dimethoxy-ω-nitrostyrene and 1.0 g (9.1 mmol) of hydroquinone are suspended in 200 ml of abs. toluene and, at −70° C., admixed with 55.0 g (1.02 mol) of liquid 1,3-butadiene. The mixture is stirred in an autoclave at 160° C. for 6 days and then cooled. Some of the solvent is removed using a rotary evaporator, and the resulting precipitate is filtered off with suction and recrystallized from ethanol. M.p.: 113.5-115.5° C.; Yield 76.3% of Th.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH:4]=[C:5]([CH3:7])[CH3:6].[CH3:10][C:11]([CH3:15])=[CH:12]CO.[N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O>>[CH3:1][O:2][CH:3]([O:8][CH2:9][CH:10]=[C:11]([CH3:15])[CH3:12])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: CC(C)=CCO
Reactant: COC(C=C(C)C)OC
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Product: COC(C=C(C)C)OCC=C(C)C
Temperature: 25 °C
Reaction time: 76 h

Procedure:
In a 50 ml. one-neck flask was placed 5.5 g. (0.0422 mol.) of 1,1-dimethoxy-3-methyl-2-butene and 10.0 g. (0.116 mol.) of prenol and 0.40 g. (0.002 mol.) of 2,4-dinitrophenol. The resulting solution was degassed with nitrogen and sealed with a serum cap and stirred at room temperature for 76 hours. The reaction solution was then diluted with 100 ml. of hexane and washed with 3 × 100 ml. of 1.0 N aqueous NaOH solution and 2 × 100 ml. of saturated aqueous NaCl solution. The combined water washings were back with extracted 1 × 50 ml. of hexane. The combined hexane solutions were dried (Na2SO4) and concentrated to give 9.0 g. of crude product. Distillation of 8.3 g. at 20 mmHg and a bath temperature of 55°-60° gave 1.48 g. of prenol. Continued distillation initially at 0.20 mmHg gave 2.43 g. of 1-methoxy-1-(3-methylbut-2-enoxy)-3-methyl-2-butene (b.p. 40°-45° at 0.20 mmHg) and finally at 0.050 mmHg gave 3.29 g. of 1,1-bis-(3-methylbut-2-enoxy)-3-methylbut-2-ene (b.p. 70°-75° at 0.050 mmHg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][C@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH:9]([O:8][C:4]1[CH:3]=[C:2](/[CH:16]=[CH:15]/[CH2:14][C@@H:13]([OH:17])[CH3:12])[CH:7]=[N:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: C=CC[C@H](C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Oc1cncc(/C=C/C[C@H](C)O)c1
Temperature: 135 °C
Yield: 60.7 %

Procedure:
A mixture of 5-bromo-3-isopropoxypyridine (12.56 g, 58.13 mmol), (2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (130 mg, 0.58 mmol), tri-o-tolylphosphine (706 mg, 2.32 mmol), triethylamine (35 mL, 252 mmol) and acetonitrile (35 mL) were heated in a sealed glass tube at 130-140° C. for 8 h. The reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure on a rotary evaporator. Water (50 mL) was added and the mixture was extracted with chloroform (3×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over silica gel, eluting with chloroform-acetone (95:5, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing 7.80 g (60.7%) of a pale-yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:6]=2[O:5]1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:6]2[O:5][CH:4]([CH2:3][N:2]([CH3:1])[C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CNCC1Cc2cccc(-c3ccccc3C)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cccc2c1OC(CN(C)C(=O)OCc1ccccc1)C2
Yield: 64.3 %

Procedure:
Treatment of (±)-[(N-methyl-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.67 g, 32.64 mmol) with diisopropylethylamine (0.512 g, 3.97 mmol) and benzyl chloroformate (0.605 g, 3.17 mmol) generally according to the procedure described for Intermediate 12 provided 0.790 g (77%) of (±)-benzyl {[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:26][C:34](=[O:35])[NH:28][N:27]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Yield: 53.7 %

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (350 mg, 0.862 mmol) in dioxane (8 mL) was added CDI (210 mg, 1.293 mmol). The reaction mixture was heated to reflux for 2 hours and was subsequently concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (200 mg, 57%).
Reaction SMILES: [OH:1][C:2]1[C:15]([CH3:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[Na+].Cl>O.CN(C=O)C>[CH3:16][C:15]1[C:2]([O:1][CH2:25][C:26]([OH:28])=[O:27])=[CH:3][C:4]2[C:5](=[O:17])[C:6]3[C:11]([O:12][C:13]=2[CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)CBr
Reactant: Cc1cc2oc3ccccc3c(=O)c2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2oc3ccccc3c(=O)c2cc1OCC(=O)O
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A mixture of 2-hydroxy-3-methyl-9-oxo-9H-xanthene (1.1 g), potassium carbonate (1.4 g), ethyl bromoacetate (1.7 g) and DMF (20 ml) was stirred at 60°-70° C. for 3 hours. After cooling the mixture, sodium hydroxide (4 g) and water (100 ml) were added and the resulting mixture was stirred at 90°-100° C. for 1 hour. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from DMF gave 1.3 g of 3-methyl-9-oxo-9H-xanthene-2-yloxyacetic acid. m.p. 225°-227° C. This compound showed a mass spectrum having a molecular ion peak at m/e 284.
Reaction SMILES: [OH-].[NH4+].[NH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].[Br:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13]>C(#N)C>[Br:10][CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([NH:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6])=[O:13]
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(Cl)C(Br)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(NC(=O)C(Br)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Ammonium hydroxide (1.6 g) aqueous solution (40 mL) was added to aminoisobutyric acid (2.1 g). The solution was cooled to 0° C., to which a solution of a-bromophenylacetyl chloride (6 g) in acetonitrile (5 mL) was slowly added dropwise. After the addition was completed, the mixture was warmed to room temperature and stirred overnight. The precipitate was filtered off and washed with water to give 3.4 g of 2-(α-bromophenylacetylamino)isobutyric acid.