Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([CH:12]=[CH:13][CH:14](O)[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:17]([O-])(=[O:19])C.[Na+]>CN(C)C=O.O>[C:6]1([CH:12]=[CH:13][CH:14]=[CH:15][CH:17]=[O:19])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(O)C=Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CC=CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
Dimethylformamide (DMF, anhydrous, 14 mL) was cooled to 0–5° C. and phosphorus oxychloride (8.2 mL) was added dropwise over a period of 40 minutes. The resulting solution was added dropwise to a cooled (0–5° C.) solution of 4-phenyl-3-buten-2-ol (10 g) in 32 mL of anhydrous DMF over a period of all hour. The reaction mixture was warmed to room temperature over a 35-minute period and then gradually heated up to 80° C. over a period of 45 minutes. The reaction was stirred at 80° C. for three hours and then cooled to 0–5° C. To the cooled reaction solution was added dropwise a solution of sodium acetate (40 g) in deionized water (100 mL) over a period of one hour. The mixture was then reheated to 80° C., stirred at 80° C. for an additional 10 minutes, cooled down to room temperature and extracted with ether (100 mL) twice. The combined extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to yield 8.78 g of the desired 5-phenyl-2,4-pentadienal as a liquid which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz), δ(ppm) 7.51 (m, 2H), 7.37 (m, 3H), 7.26 (m, 1H), 7.01 (m, 2H), 6.26 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[S-2].[Li+].[Li+].Cl.[C:21]([O:24]CC)(=[O:23])[CH3:22]>CS(C)=O>[C:21]([O-:24])(=[O:23])[CH3:22].[F:1][C:2]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(C)=O
Agent: Cl
Agent: O=C(c1ccccc1)c1cc(F)ccc1F
Agent: [Li+]
Solvent: CS(C)=O
Product: CC(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 g (91.6 mmol) of 2,5-difluorobenzophenone 1 (Fluka) was dissolved in 400 ml of DMSO. 7.0 g (150 mmol) of lithium sulfide (Fluka) was added under argon. After three hours at 120° C., the mixture was allowed to cool to room temperature. It was shaken with 200 ml of 2 M HCl aq. and 500 ml of ethyl acetate. The organic phase was washed twice with NaCl solution, dried over MgSO4, filtered, and concentrated. 24 g of crude product 2 was obtained as a reddish oil. TLC (n-heptanelethyl acetate 3:1) gave Rf=0.3 (starting material 1 Rf=0.4). C13H9FOS (232.28). MS (M+H)+=233.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1)[CH3:2].Cl>O1CCOCC1>[O:13]=[C:12]1[C:11]2([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][N:8]1[CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32]
Reactant: CCOC(=O)CCCN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CCCN1CN(c2ccccc2)C2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(4-ethoxy-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.09 g, 0.2 mmol) was added 4M solution of HCl in dioxane (2 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain ethyl 4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)butanoate as a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1([CH2:17][C:18](O)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:18](=[O:19])[CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)c1ccccc1NC(=O)Cc1ccccc1
Reaction time: 4 h

Procedure:
A mixture of o-aminoacetophenone (25 g.) and phenylacetic acid (25 g.) in anhydrous methylene dichloride (200 ml.) was prepared. To that mixture was added dicyclohexylcarbodiimide (40 g.) in portions of approx. 10 g. every 5 min. at ambient temperature. When the addition was completed the mixture was stirred for 4 hr. at ambient temperature. The mixture was then filtered, and the filtrate was evaporated in vacuo to dryness. The residue was crystallised from cyclohexane to give o-acetyl-N-(phenylacetyl)aniline, m.p. 78°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C)C=O.C(O)(C)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([O:20][CH3:22])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Yield: 86 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 200 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, and to the resulting solution were added 110 mg of potassium carbonate and 93 mg of dimethyl sulfate at room temperature, after which the resulting mixture was subjected to reaction at the same temperature for 2 hours. Subsequently, 20 ml of water and 20 ml of ethyl acetate were added to the reaction mixture, and the organic layer was then separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution, and thereafter dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 5 ml of isopropyl alcohol, after which crystals were collected by filtration to obtain 180 mg (yield 86.0%) of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinate. The physical properties of this compound were identical with those of the compound obtained in Example 2.
Reaction SMILES: [NH2:1][C:2]([O:9][CH2:10][CH3:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(OCC)C.[O:17]([C:24]([N:26]=[C:27]=[S:28])=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OO>C(O)C>[CH2:10]([O:9][C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:27]([NH:26][C:24](=[O:25])[O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:28][N:1]=1)[CH3:11]
Reactant: O=C(N=C=S)Oc1ccccc1
Reactant: CCOC(=O)C=C(N)OCC
Agent: OO
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1c(OCC)nsc1NC(=O)Oc1ccccc1
Yield: 38.8 %

Procedure:
A mixture of 66.1 g of ethyl 3-amino-3-ethoxyacrylate and 300 ml of diethyl ether was stirred in a 500 ml flask during the addition of 60.5 g of phenoxycarbonylisothiocyanate. A solution of 38.3 ml of 33% hydrogen peroxide (11.5 g of active H2O2) in 300 ml of ethanol was added to the reaction mixture at a rate sufficient to maintain uniform reflux. The reaction mixture was allowed to stand at ambient temperature over a weekend. The precipitate was collected by filtration and dried. The filter cake was recrystallized from 1400 ml of 1:1 acetonitrile:water to yield 44.1 g of phenyl (3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)carbamate, mp 130° (decomposes). The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[Cl:15]N1C(=O)CCC1=O>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:15])=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
This compound was prepared as reported by K. S. Gudmundsson et al, Synthetic Communications 1997, 27 (5), 861-870: To a stirred solution of 4-chloro-2-trimethylacetamido-pyridine (0.870 g, 4.07 mmol) in anhydrous acetonitrile (11 ml) was added N-chlorosuccinimide (2.72 g, 20.37 mmol). The reaction mixture was heated at 100° C. for 3 h then more N-chlorosuccinimide (0.600 g) was added and stirring was continued at this temperature for 2 h. The mixture was then allowed to cool to room temperature, the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (170 ml) and 10% aqueous NaOH (60 ml). The organic layer was washed with 10% aqueous NaOH (60 ml), water (60 ml), saturated brine (60 ml), dried (Na2SO4), and concentrated in vacuo. The residue was absorbed on silica gel (2.3 g) and the free running powder was placed on a 50 g isolute silica column. Elution with 15% ethyl acetate in hexanes and 20% ethyl acetate in hexanes afforded the title compound as a white solid (0.500 g, 50%); 1H-NMR (250 Mz, CDCl3) 1.35 (s, 9H, C(CH3)3), 8.05 (br s, 1H, CONH), 8.28 (s, 1H), 8.52 (s, 1H) (3-H, 6-H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([NH2:14])=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[NH2:14][C:4]1[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]=1[NH:13][C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Reactant: CCOC(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
An ice-cold solution of 3,5-bis(trifluoromethyl)-1,2-phenylenediamine (880 mg, 3.6 mmol) and pyridine (104 mg, 1.3 mmol) in methylene chloride (20 mL) was treated with ethyl 3-chloro-3-oxopropionate (181 mg, 1.2 mmol). The mixture was stirred at 0° C. for 3 h, then allowed to warm to room temperature and stirred for four days. The solution was diluted to 100 mL with methylene chloride, washed with saturated NH4Cl (3×20 mL), water (20 mL), and brine (20 mL), then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over silica gel, eluting with 20%-30%-40% EtOAc/heptane, to yield 330 mg of a white solid as product. 1H NMR (500 MHz, DMSO) δ ppm 1.22 (t, J=7.15 Hz, 3 H) 3.52 (s, 2 H) 4.14 (q, J=7.15 Hz, 2 H) 6.16 (s, 2 H) 7.54 (s, 1 H) 7.71 (m, 1 H) 9.60 (s, 1 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:19]=[CH:18][N:8]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:7](=[O:20])[N:6]=1)(=[O:3])[CH3:2].[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([NH:4][C:5]1[CH:19]=[CH:18][N:8]([C@@H:9]2[O:17][C@H:14]([CH2:15][O:16][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:7](=[O:20])[N:6]=1)(=[O:3])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Product: CC(=O)Nc1ccn([C@@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 79.8 %

Procedure:
N-Acetylcytidine (see D. M. Brown et al., J. Chem. Soc. 1956, 2384) (1.000 g, 3.5057 mmol), trityl chloride (1.0751 g, 3.8563 mmol) and a small stirring bar were placed in a dry round-bottomed flask fused onto a reflux condenser. The flask was closed with a septum and flushed with argon. Pyridine (10.2 mL) was injected and the mixture was stirred at room temperature for 36 h. The mixture was evaporated, diluted with CH2Cl2, and again evaporated. The gummy residue was washed with water and the residue was dissolved in acetone. The solution was dried (MgSO4) and evaporated. Flash chromatography of the residue over silica gel (4.5×30 cm), using 7% MeOH in CH2Cl2, gave the product (1.4752 g, 80%). (Cf. H. U. Blank et al., Justus Liebigs Ann. Chem. 1970, 742, 16).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O)(=O)=O>CSC.O>[C:1]([S:5][CH2:6][C:7]1([C:17]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:18])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: CSC
Product: CC(C)[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-valine, benzyl ester (256 mg, 0.547 mmol) in dimethylsulfide (3 mL) and add trifluoromethanesulfonic acid (0.2 mL). Stir at room temperature under an argon atmosphere for 6 hours. Dilute with water and extract into ethyl ether. Wash with water, then brine and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: CC(Cl)Cl
Product: O=C(CCc1ccccc1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 70.9 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), hydrocinnamoyl chloride (0.10 mL, 0.69 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-3-phenylpropanamide (0.17 g). MS (ESI) m/z 348 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([S:6][N:7]([CH3:11])[C:8]([F:10])=[O:9])[C:3](F)=[O:4].[C:12]1([OH:22])[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:12]1([O:22][C:3](=[O:4])[N:2]([CH3:1])[S:6][N:7]([CH3:11])[C:8]([F:10])=[O:9])[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(SN(C)C(=O)F)C(=O)F
Reactant: Oc1cccc2c1CCCC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(SN(C)C(=O)Oc1cccc2c1CCCC2)C(=O)F

Procedure:
5,6,7,8-Tetrahydronaphthyl-N-methyl-N-(N'-methyl-N'-fluoroformylaminosulfenyl)carbamate was prepared by the procedure of Example IX by reacting 9.21 g of bis-(N-methyl-N-fluorocarbonylamino)sulfide with 7.41 g of 5,6,7,8-tetrahydro-1-naphthol in 300 ml of toluene with 5.05 g of triethylamine as acid acceptor to yield 9.5 g of an oil.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[N:15]([CH2:27][C:28]#[CH:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([C:14]1[N:15]([CH2:27][C:28]#[CH:29])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:19]([O-:6])=[CH:18][C:17]=2[N:26]=1)[CH3:13]
Reactant: C#CCn1c(CC)nc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: C#CCn1c(CC)nc2c[n+]([O-])c3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.4 %

Procedure:
3-Chloroperoxybenzoic acid (1.21 g of 77%, 1.15 eq.) was added in a single portion to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline (1.00 g, 4.25 mmol, 1.0 eq) in chloroform (42 mL). The reaction mixture was stirred at ambient temperature for 1 hour at which time analysis by thin layer chromatography (TLC) indicated that the reaction was complete. The reaction mixture was diluted with chloroform (150 mL) and washed with aqueous saturated sodium bicarbonate (2×50 mL). The combined aqueous layers were back extracted with chloroform (3×30 mL). The combined organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 1.19 g of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinoline 5-oxide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[OH:9][C:10]([CH3:25])([CH3:24])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[O:22][CH3:23].N1C=CC=CC=1.CO>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]([OH:9])([CH3:25])[CH3:24])=[C:14]([O:22][CH3:23])[CH:15]=2)[C:4](=[O:8])[CH:3]=1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Reactant: O=c1cc(Cl)nc[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 21 h
Yield: 46 %

Procedure:
A mixture of 6-chloropyrimidin-4(3H)-one (50 mg, 0.383 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (184 mg, 0.766 mmol), copper (II) acetate, monohydrate (84 mg, 0.421 mmol), and pyridine (1.5 mL, 19.15 mmol) in DCM (4 mL) was stirred at RT under the presence of air overnight (21 hours). Pyridine (0.5 mL) and MeOH (0.5 mL) were added and continued to stir for 2 hours. The reaction was diluted with DCM, washed with 1N HCl, sat NaHCO3, dried (Na2SO4), and concentrated to afford crude product. The crude was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to afford the desired product 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-pyrimidin-4(3H)-one 11A (57.4 mg, 0.177 mmol, 46% yield) as a light brown solid.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:10]2[C:6](=[C:7]([CH3:11])[CH2:8][CH2:9]2)[C@H:5](/[CH:12]=[C:13](/[C:15]([OH:17])=[O:16])\[CH3:14])[CH2:4][CH2:3]1.C([N:20](CC)CC)C.ClC(OC)=O.N>C1COCC1>[CH3:1][C@H:2]1[C@@H:10]2[C:6](=[C:7]([CH3:11])[CH2:8][CH2:9]2)[C@H:5](/[CH:12]=[C:13](/[C:15]([OH:17])=[O:16])\[CH3:14])[CH2:4][CH2:3]1.[CH3:1][C@H:2]1[C@@H:10]2[C:6](=[C:7]([CH3:11])[CH2:8][CH2:9]2)[C@H:5](/[CH:12]=[C:13](/[C:15]([NH2:20])=[O:17])\[CH3:14])[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Agent: CC1=C2[C@H](/C=C(\C)C(=O)O)CC[C@@H](C)[C@H]2CC1
Agent: COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC1=C2[C@H](/C=C(\C)C(N)=O)CC[C@@H](C)[C@H]2CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Valerenic acid (18.9 mg, 0.0807 mmol) was dissolved in THF (3 mL) and cooled to 0° C. Triethylamin (12.0 μL, 8.76 mg, 0.0866 mmol) and methyl chloroformate (97%, 8.5 μL, 9.36 mg, 0.0862 mmol) were added. After stirring for 1 hour the resulting solution was treated with aqueous ammonia (25% 25 μL, 5.5 mg, 0.3230 mmol). After 30 minutes the reaction mixture was warmed to room temperature and stirred for an additional hour. Then the mixture was filtrated and the filtrate concentrated in vacuo. Purification by chromatography (pure diethylether to diethylether/EtOAc 1/1) provided 6.6 mg Valerenic acid and 11.2 mg of Valerenic acid amide as white solid with 92% yield based on recovered starting material.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[F:13]>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:13]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(N)cc1F
Yield: 91.5 %

Procedure:
A mixture of N-Methyl-2-fluoro-4-nitrobenzamide (Formula 38) (0.18 g, 0.91 mmol) and iron (0.31 g, 5.60 mmol) in ethyl acetate (5 mL) and acetic acid (5 mL) was refluxed for 1 h. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and the residue was purified with SiO2 column chromatography (dichloromethane:acetone, 95:5) to give N-Methyl-2-fluoro-4-aminobenzamide (Formula 39) (0.14 g, 92%) as an off-white solid. 1H NMR (acetone-d6) δ 2.86 (d, 3H, J=4.3), 5.50 (br s, 2H), 6.37 (dd, 1H, J=14.7 and 2.1), 6.50 (dd, 1H, J=8.6 and 2.1), 7.06 (br s, 1H), 7.68 (dd, 1H, J=8.8 and 8.8).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:7]2=[O:14].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:6]2[CH2:5][CH2:4][C:3]3[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[N:11][CH:10]=[C:9]([O:12][CH3:13])[C:8]=3[C:7]2=[O:14])=[CH:21][CH:20]=1
Reactant: COc1cnc(N)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cnc(NS(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 25 °C

Procedure:
To a solution of 5-amino-2-(4-fluorobenzyl)-8-methoxy-3,4-dihydro-2,6-naphthyridin-1(2H)-one (0.889 g, 2.95 mmol) in pyridine (5 mL) was added dropwise methanesulfonyl chloride (0.575 g, 5.016 mmol). After stirring for an hour at room temperature, the product mixture was quenched with pH 7 buffer, then concentrated under vacuum. The residue was dissolved in CHCl3 and pH 7 buffer, the pH of the aqueous layer was adjusted to pH 5 with 1N NaOH and the layers separated. Several more extractions with CHCl3 were performed. The organic extracts were dried with Na2SO4, filtered, and concentrated under vacuum, then dissolved in toluene and CHCl3 and evaporated to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=1.[Na+].[Cl-]>CN(C=O)C.O>[CH:1]1([CH2:4][O:5][C:11]2[N:10]=[C:9]([NH2:8])[CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Nc1ccnc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccnc(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (724 mg) was dissolved in DMF (4 mL) and treated with sodium hydride (401 mg, 60% in mineral oil) at 0° C. for 30 minutes. Then, a solution of 4-amino-2-chloro-pyrimidine (260 mg, CAS 7461-50-9 or made according to J. Am. Chem. Soc. 1930, 52, 1152-1157) in DMF (4 mL) was added drop by drop. The mixture was stirred at room temperature for 1 hour and then allowed to stir at 50° C. over night. The mixture was poured into water and the mixture was saturated with NaCl. The aqueous solution was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane as an eluant. The desired product was obtained as a light yellow oil (169 mg). MS (EI): 166.2 (M+H+).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[C:37]1([S:43]([C:45]2[CH:50]=[CH:49][C:48]([N:51]([CH3:53])[CH3:52])=[C:47]([N+:54]([O-])=O)[CH:46]=2)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:37]1([S:43]([C:45]2[CH:50]=[CH:49][C:48]([N:51]([CH3:52])[CH3:53])=[C:47]([NH2:54])[CH:46]=2)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CN(C)c1ccc(S(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: CN(C)c1ccc(S(=O)c2ccccc2)cc1N
Yield: 90 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of phenyl-(4-dimethylamino-3-nitrophenyl) sulfoxide, the title compound is obtained.