Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)CCC.C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:11]([C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[N:6][C:5]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2oc(Cl)nc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2oc(-c3cccs3)nc2c1
Temperature: 100 °C
Yield: 0.6 %

Procedure:
A mixture of 2-chloro-5-nitrobenzo[d]oxazole (404 mg, 2.04 mmol), 2-(tributylstannyl)-thiophene (648 μL, 2.04 mmol) and tetrakis(triphenylphosphine)palladium (0) (40.8 mg) in dioxane (12.2 mL) was heated at 100° C. for 16 h under nitrogen. Ethyl acetate was added, the organic layer was washed with water, dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 10:90 v/v, and then purified by reverse phase HPLC to afford 3 mg (2%) of the title product (LCMS RT=6.95 min)
Reaction SMILES: CC1(C)OC(=O)[CH:5]([C:9]([CH3:26])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[CH2:10][CH3:11])[C:4](=[O:27])[O:3]1>CN(C=O)C.O.Cl>[CH3:26][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1)([CH2:10][CH3:11])[CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCC(C)(c1cccc(OCc2ccccc2)c1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(CC(=O)O)c1cccc(OCc2ccccc2)c1
Yield: 65.3 %

Procedure:
A solution of 5-(2-(3-(benzyloxy)phenyl)butan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione 103.C (209 mg, 546 μmol) in DMF (2 mL) and H2O (0.2 mL) was heated to 90° C. overnight. The reaction was then diluted with 0.2N HCl, extracted with EtOAc, dried over MgSO4, filtered, stripped, and purified by silica gel chromatography to afford 3-(3-(benzyloxy)phenyl)-3-methylpentanoic acid 103.D (106.4 mg, 65.3% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[N:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:24])[C:22]=3[CH2:23][CH:15]2[C:14]2[N:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:13]=2[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[N:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:24])[C:22]=3[CH:23]=[C:15]2[C:14]2[N:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:13]=2[O:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc2c1CC1c3nc(Cl)ccc3OC(CCOCc3ccccc3)N21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Fc1cccc2c1cc1n2C(CCOCc2ccccc2)Oc2ccc(Cl)nc2-1
Temperature: 80 °C
Reaction time: 2 h
Yield: 8.8 %

Procedure:
To a solution of 6-(2-(benzyloxy)ethyl)-2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (500 mg, 1.22 mmol) in toluene (7 mL) was added DDQ (552 mg, 2.43 mmol). The mixture was stirred at 80° C. for 2 hours. Then it was concentrated in vacuo, the resulting residue was purified using prep-HPLC to provide 6-(2-(benzyloxy)ethyl)-2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (44 mg, yield: 9%). 1H-NMR (CDCl3, 400 MHz) δ 7.32˜7.43 (m, 5H), 7.22˜7.28 (m, 1H), 7.11˜7.20 (m, 3H), 6.80˜6.86 (m, 1H), 6.65 (t, J=6.4 Hz, 1H), 4.48 (dd, J=8.0 Hz, 1H), 4.51 (d, J=12.0 Hz, 1H), 4.46 (d, J=12.0 Hz, 1H), 3.55˜3.62 (m, 1H), 3.25˜3.33 (m, 1H), 2.15˜2.23 (m, 1H), 2.02˜2.12 (m, 1H). MS (M+H)+: 409.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:3]1>[Pd]>[OH:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=2)[CH2:5]1
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Agent: [Pd]
Product: Nc1ccc(N2CC(O)C2)nc1
Yield: 96.7 %

Procedure:
The process is carried out according to the method described in step 5.2, using 5.5 g (28.18 mmol) of 2-(3-hydroxyazetidin-1-yl)-5-nitropyridine, prepared in step 10.1, and 0.5 g of 10% palladium-on-charcoal. 4.5 g of the expected product are thus obtained in the form of violet crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[CH:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16]>>[CH3:16][C:10]1[CH:9]=[C:14]([CH:13]=[CH:12][CH:11]=1)[O:15][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3]
Reactant: Cc1cccc(O)c1
Reactant: CC(C)N1CC(O)C1
Product: Cc1cccc(OCC(O)CNC(C)C)c1
Yield: 81 %

Procedure:
1-(iso-propyl)-3-azetidinol and m-cresol were reacted in the same manner as in Example 6 to yield 1-(3'-methylphenoxy)-3-(iso-propylamino)-2-propanol melting at 80°-82° C. The yield was 81%.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.C(=O)([O-])[O-].[Na+].[Na+].[C:27]1(C)C=CC=C[CH:28]=1>C(O)C.S(=O)(=O)(O)O>[CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([O:19][CH2:27][CH3:28])=[O:18])[CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CN1c2ccccc2Sc2ccc(CC(=O)O)cc21
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc2c(c1)N(C)c1ccccc1S2

Procedure:
18.0 g of (10-methyl-10H-phenothiazin-2-yl)acetic acid are dissolved in a mixture of 400 ml of toluene and 200 ml of ethanol, and 5 ml of concentrated sulfuric acid are added. In a water separator filled with molecular sieve, the reaction mixture is heated at the boil under reflux for twelve hours. The reaction mixture is then cooled in an ice bath, and 200 ml of water are added. The mixture is then neutralized by addition of solid sodium carbonate. The product is then extracted five times with in each case 250 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane=>n-heptane:ethyl acetate=10:1. This gives 17.0 g of ethyl (10-methyl-10H-phenothiazin-2-yl)acetate as a yellow oil. C17H17NO2S (299.39), LCMS (ESI): 300.1 (M+H+), Rf (n-heptane:ethyl acetate=3:1)=0.34.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:8]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=2[N:7]=1.[I:28]N1C(C)(C)C(=O)N(I)C1=O.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([I:28])=[C:9]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:8]([CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:6]=2[N:7]=1
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Reactant: CCOC(OCC)c1cc2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(OCC)c1c(I)c2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
To 0.1 g (0.00025 mole) of tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate in acetonitrile (2 mL) was added 1,3-Diiodo-5,5-dimethylhydantoin (95 mg, 1 eq), and solid NaHCO3 (63 mg, 3 eq). Stir at room temperature for 16 hrs. Filter, concentrate and then column with hexane/ethylacetate (0-50%) to afford tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate as a pale yellow solid 0.03 g. LCMS (ESI) 525 (M+H).
Reaction SMILES: [CH3:1][C@H:2]1[CH:11]=[CH:10][C:9]2[C@H:4]([C@@H:5]([O:13][C:14](=[O:19])[C@@H:15]([CH3:18])[CH2:16][CH3:17])[CH2:6][C@@H:7]([CH3:12])[CH:8]=2)[C@H:3]1[CH2:20][CH2:21][C:22](=[O:38])[CH2:23][C@@H:24]([O:30][Si](C(C)(C)C)(C)C)[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>O1CCCC1>[CH3:1][C@H:2]1[CH:11]=[CH:10][C:9]2[C@H:4]([C@@H:5]([O:13][C:14](=[O:19])[C@@H:15]([CH3:18])[CH2:16][CH3:17])[CH2:6][C@@H:7]([CH3:12])[CH:8]=2)[C@H:3]1[CH2:20][CH2:21][C:22](=[O:38])[CH2:23][C@@H:24]([OH:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CCC(=O)C[C@H](CC(=O)OC)O[Si](C)(C)C(C)(C)C)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(=O)OC)[C@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
The silyl ether from Step C (230 mg, 0.00024 mol) was dissolved in 5 ml of tetrahydrofuran (THF) and treated with 54 μl, (0.057 g, 0.00095 mol) of acetic acid and 710 μl (1M in THF, 0.00071 mol) of tetrabutylammonium fluoride (Bu4N F) and the mixture was stirred overnight at room temperature. Another 57 μl of acetic acid and 710 μl of Bu4N F were added and stirring was continued an additional 24 hours. The mixture was poured into 100 ml of ether and washed with 1×5 ml of 1N hydrochloric acid, 1×10 ml of saturated aqueous sodium bicarbonate and 2×10 ml of brine and dried (MgS04) Concentration to dryness gave 120 mg of an oil. The oil was chromatographed on a "Still" column of silica gel (1.5×17.7 cm, 230-400 mesh) by elution with 5% acetone in methylene chloride (v/v) collecting 5 ml fractions. Fractions 12-20 containing the product were combined and concentrated to dryness to give 53 mg of solid (m.p. 64°-66° C.). Recrystallization of a sample from hexane gave material with m.p. 67°-68° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[N:7]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:12][CH2:11][C:10]2([NH:17][CH2:16][CH2:15][N:14]3[CH:18]=[CH:19][CH:20]=[C:13]23)[CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:10]12([CH2:11][CH2:12][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][CH2:9]1)[N:17]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:16][CH2:15][N:14]1[CH:18]=[CH:19][CH:20]=[C:13]21
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NCCn1cccc12
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
Ethyl chloroformate (328.2 μL, 3.43 mmol) was added to a solution of tert-butyl spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (500 mg, 1.72 mmol) and K2CO3 (474.3 mg, 3.43 mmol) in acetonitrile (5.0 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered using acetonitrile and the solvent was evaporated under reduced pressure. The compound was dissolved in ethyl acetate and washed with 1N hydrochloric acid and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 1-tert-butyl 2′-ethyl 3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate (395 mg, 63%) as an amber oil that was used in the next step without further purification. ESI-MS m/z calc. 363.2, found 364.3 (M+1)+; Retention time: 1.78 minutes (3 minute run).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[N:9]=[C:10]([CH3:23])[N:11]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:6][CH:5]=1)(=[O:3])N.S(=O)(=O)(O)[OH:26]>O>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:24])[N:9]=[C:10]([CH3:23])[N:11]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:6][CH:5]=1)([OH:3])=[O:26]
Reactant: Cc1nc(=O)c2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1nc(=O)c2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
7-Carbamoyl-1-(2,4-dichlorobenzyl)-2-methyl-4(1H)-quinazolinone (1.40 g) in a mixture of concentrated sulfuric acid (6 ml) and water (6 ml) was heated at 100° C. for 1 hr. After cooling, the precipitated solid was collected by filtration, washed with water, dried and concentrated to give the object compound (1.46 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:7]=1>C1COCC1.CO.[Pt]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:7]=1
Reactant: COC(=O)/C=C/c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of unsaturated ester 6 (0.31 g, 0.65 mmol) and 5% Pt/C (0.01 g) in THF (6 mL) and MeOH (12 mL), previously purged with nitrogen, was stirred under a hydrogen atmosphere (balloon) at RT overnight. The platinum was removed by filtration through Hyflo and the filtrate was evaporated to dryness to afford the saturated ester 7, 0.31 g (99%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[OH:16][CH2:17][C:18]1[C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=[C:20]([CH3:29])[N:19]=1>>[F:15][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][NH:2][C:26](=[O:27])[CH2:25][O:24][C:23]1[C:18]([CH2:17][OH:16])=[N:19][C:20]([CH3:29])=[CH:21][CH:22]=1
Reactant: Cc1ccc(OCC(=O)O)c(CO)n1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Product: Cc1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(CO)n1
Yield: 88.1 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (270 mg, 1.00 mmol) was reacted with (2-hydroxymethyl-6-methyl-pyridin-3-yloxy)-acetic acid (200 mg) to give N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-(2-hydroxymethyl-6-methyl-pyridin-3-yloxy)-acetamide (350 mg, 88%) after purification by column chromatography (Hex/EtOAc=10/1).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[CH:3]=[O:4].[O:15]=[CH:16][C:17](=C)C.C(OC(=O)C)(=O)C>>[C:16]([O:4][CH:3]=[C:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:15])[CH3:17]
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Reactant: C=C(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
The production process (B) comprises the step (3) of reacting 1,2-methylenedioxybenzene [formula (1)], methacrolein and acetic anhydride with each other to produce 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene [formula (3)]; and the step (2) of subjecting the obtained 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene [formula (3)] to hydrolysis reaction or to transesterification reaction with an alcohol, followed by subjecting the resulting reaction mixture to distillative purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:23])[CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([O:19][CH3:20])[CH3:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:24]O>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:23][CH3:24])[CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])([CH3:21])[CH3:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: COC(C)(C)CCCC(C)CCC(O)c1ccc(C(C)C)cc1
Product: COC(CCC(C)CCCC(C)(C)OC)c1ccc(C(C)C)cc1

Procedure:
Crude 1-(p-isopropylphenyl)-4,8-dimethyl-8-methoxy-1-nonanol (1.1 g) and "Amberlyst A-15" resin (50 mg) in methanol (20 ml), as the acidic lower alkanol, was refluxed for 2 days. GC analysis showed the consumption of the alcohol and appearance of the dimethoxy compound. Material was recovered quantitatively. "Amberlyst A-15" resin used in this methoxylation reaction is a commercially available solid acidic ion exchange resin with pendant sulfonic acid groups.
Reaction SMILES: C(C1C=CC(N[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([NH:23]CCCNC(=O)OC(C)(C)C)=[O:22])=[CH:13][N:12]=2)=CC=1)(=O)N>C(Cl)(Cl)Cl.CO.FC(F)(F)C(O)=O>[CH2:18]([NH:17][C:15]1[C:14]([C:21]([NH2:23])=[O:22])=[CH:13][N:12]=[CH:11][N:16]=1)[CH2:19][CH3:20]
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCNc1ncncc1C(N)=O
Reaction time: 0.5 h
Yield: 385.6 %

Procedure:
To a suspension of tert-butyl (3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D2, 190 mg) in chloroform (8 mL) and methanol (2 mL), trifluoroacetic acid (1 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The solvent was evaporated under reduced pressure to obtain N-(3-aminopropyl)-2-(4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamide (D3) trifluoroacetate (280 mg).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[CH2:27][CH2:28][CH3:29]>O1CCOCC1.C(O)C>[CH3:29][CH2:28][C:27]([C:18]1[C:17]([O:16][CH3:15])=[CH:22][C:21]([O:23][CH3:24])=[C:20]([O:25][CH3:26])[CH:19]=1)=[O:6]
Reactant: CCCc1cc(OC)c(OC)cc1OC
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCO
Product: CCC(=O)c1cc(OC)c(OC)cc1OC
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of DDQ (3.06-4.09 g) in dioxane (40 mL) was added dropwise over a period of 10 min to a ice cold and well stirred solution of 2,4,5-trimethoxyphenylpropane (1.89 g, 0.009 mol) in wet dioxane or ethanol (55 mL) and the resulting mixture was stirred at room temperature for over night. The precipitate was filtered and further washed twice with dioxane. The combined dioxane layer was evaporated and mixture was poured into water and extracted with dichloromethane (3×70 mL). The combined organic layer were washed with brine (3×15 mL) and dried over sodium sulphate. The residue obtained on evaporation of the solvents was chromatographed on silica gel column using hexane-ethyl acetate mixture with increasing proportion of ethyl acetate upto 40% to afford viscous liquid which was crystallized from ethylacetate/hexane to afford 1.19 g (59%) of white crystals of isoacoramone. The spectral data was found similar as mentioned above in Example III.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:33])[C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)[O:17][NH2:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=O)[C:41]([OH:43])=[O:42])[N:39]=1.O.Cl>CN(C)C=O>[NH2:34][C:35]1[S:36][CH:37]=[C:38](/[C:40](=[N:18]/[O:17][C@H:16]([C:15]([O:14][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:33])[C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:28])[CH3:27])=[C:21]([O:29][C:30](=[O:32])[CH3:31])[CH:20]=2)/[C:41]([OH:43])=[O:42])[N:39]=1
Reactant: CC(=O)Oc1ccc([C@H](ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc([C@H](O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To an ice-cooled solution of the product obtained in Step 4 (20.3 g) in dimethylformamide (60 ml) was added 2-(2-amino-4-thiazolyl)glyoxylic acid (7.8 g). The mixture was allowed to stand until it reached room temperature, and stirred overnight. The reaction mixture was then poured into ice-cooled water (400 ml), and the pH of the resulting mixture was adjusted to 2.0 with 1N hydrochloric acid. The mixture was extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with brine (200 ml) and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure and the residue was dissolved in a small amount of chloroform. This solution was added dropwise to ether. The formed crystals were collected by filtration and washed with ether, giving 22.3 g of the objective compound as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:25]C3CCCCO3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].[N-:38]=[N+:39]=[N-:40].[Na+].Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.[Br-].[Zn+2].[Br-].C(O)(C)C>[OH:37][C:5]1[C:6]([CH2:34][CH2:35][CH3:36])=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:25])[C:17]3[CH:24]=[CH:23][CH:22]=[C:19]([C:20]4[N:38]=[N:39][NH:40][N:21]=4)[CH:18]=3)=[CH:14][CH:15]=2)[CH:32]=[CH:33][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CC(C)O
Product: CCCc1c(OCc2ccc(C(O)c3cccc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Yield: 94.5 %

Procedure:
Bring to a heavy reflux, a mixture of 3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (3.0 g, 6 mmol), zinc (II) bromide (4.1 g, 18 mmol), sodium azide (2.34 g, 36 mmol), water (20 mL) and isopropyl alcohol (20 mL) for 18 hours. Cool and dilute the reaction mixture with water (100 mL) and adjust the pH to 2 with 1M hydrochloric acid. Extract the product with ethyl acetate (2×150 mL), combine the extracts and wash with water (100 mL), brine (100 mL), dry over magnesium sulfate, filter, and concentrate. Stir the residue in methanol (50 mL), and add p-toluenesulfonic acid mono hydrate (4 g, 21 mmol) and stir at room temperature for an hour. Concentrate the mixture and dilute with water (100 mL). Extract the product with ethyl acetate (2×100 mL). Wash the combined extracts with water (2×100 mL), brine (100 mL), dry over magnesium sulfate, filter, and concentrate. Purify the resulting residue via silica chromatography eluting with 1:1 hexanes:ethyl acetate to 1:1 ethyl acetate:acetone to acetone to give the title compound (2.6 g, 95%) as a tan solid. 1H NMR (DMSO-d6) δ 12.86 (s, 1H), 8.12 (s, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.39-7.55 (m, 6H), 6.72 (d, 1H), 6.11 (d, 1H), 5.82 (d, 1H), 5.23 (s, 2H), 2.56 (s, 3H), 2.57-2.60 (m, 2H), 1.44-1.52 (m, 2H), 0.87 (t, 3H). LCMS (m/z) 457 M−1.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:22])[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:25][N:26]1[C:30]([CH2:31]Cl)=[N:29][CH:28]=[N:27]1.O>CN(C=O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([O:22][CH2:31][C:30]4[N:26]([CH3:25])[N:27]=[CH:28][N:29]=4)=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=[C:10]3[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ncnc1CCl
Reactant: O=c1[nH]c2c(cc1-c1ccccc1)nnn2-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccccc1)nnn2-c1ccccc1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
A mixture of 3,6-diphenyl-5-oxo-4H-1,2,3-triazolo[4,5-b]pyridine (0.03 g, 0.10 mmol) and sodium hydride (55% in oil, 0.006 g, 0.12 mmol) in dry DMF (2 ml) was stirred at room temperature under nitrogen until all effervescence had ceased. A solution of 2-methyl-3-chloromethyl-1,2,4-triazole (0.025 g, 0.20 mmol) in dry DMF (0.5 ml) was added and the mixture was stirred for 4 days. Water (20 ml) was added and the aqueous solution was extracted with 10% methanol-dichloromethane (20 ml). The extract was dried (Na2SO4), filtered and concentrated. Preparative thin-layer chromatography on silica gel, eluting with 5% methanol-dichloromethane, gave the alkylation product which was recrystallised from ethyl acetate-hexane to give 3,6-diphenyl-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine (0.004 g, 10%) as a white, crystalline solid, m.p. 153-156° C. δH (360 MHz; CDCl3) 3.71 (3H, s), 5.69 (2H, s), 7.42-7.54 (6H, m), 7.63 (2H, dd, J=8 and 8), 7.86 (1H, s), 8.24 (2H, d, J=8) and 8.32 (1H, s); m/z (ES+) 383 (M+H+).