Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:16].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](=[NH:29])OCC>C(O)C>[ClH:16].[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: CCOC(=N)Cc1ccccc1C
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1CC(=N)Nc1ncccc1OCc1ccccc1
Yield: 16.3 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (4.0 g, 20 mmol) and ethyl 2-methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 1 hour. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol 10:1). The product was obtained as a white crystalline solid (1.2 g), m.p. 119°-120° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8]
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.4 %

Procedure:
6-Bromohexanoyl chloride (16.2 g) was dissolved in methylene chloride (50 ml), and aluminum chloride (10.6 g) was added, which was followed by stirring at room temperature for 30 min. The reaction mixture was ice-cooled, and benzene (5.0 g) was dropwise added, which was followed by stirring for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. 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 (hexane:ethyl acetate=3:1) to give 18.2 g of 6-bromo-1-phenyl-1-hexanone.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH2:38])(=[O:37])=[O:36])[C:31]([CH3:34])=[CH:32][CH:33]=1>>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[CH:29][C:30]=1[S:35](=[O:36])(=[O:37])[NH2:38]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-6-methyl-benzenesulfonamide [CAS-No. 6973-09-7] according to general procedure II. Yellow solid. MS (ISP) 544.0 [(M+H+]; mp 297° C.
Reaction SMILES: [NH2:1][C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([CH2:32][C:33](Cl)=[O:34])[CH:31]=1>ClCCl>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([CH2:32][C:33]([NH:1][C:2]2([C:14]([O:16][CH3:17])=[O:15])[CH2:3][CH2:4][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:6][CH2:7]2)=[O:34])[CH:31]=1
Reactant: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1
Reactant: Cc1ccc(Br)cc1CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC(OC)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.00 g (11.75 mmol) of methyl 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 22A) and 1.19 g (11.75 mmol) of triethylamine were dissolved in 40 ml of dichloromethane. 2.65 g (10.69 mmol) of (5-bromo-2-methylphenyl)acetyl chloride (Example 3A), dissolved in 40 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution and with aqueous 1% strength citric acid. After drying over sodium sulphate, the organic phase was concentrated and the product was dried. This gave 4.79 g (87% of theory) of the title compound as a beige powder.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.O.[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)NCc1ccccc1)c1ccc(O)cc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CNCc1ccccc1)c1ccc(O)cc1
Yield: 52.3 %

Procedure:
Dissolve N-benzyl-2-(4-hydroxy-phenyl)-propionamide (13.25 g, 51.9 mmol) in anhydrous tetrahydrofuran (100 mL) and add via a cannula to borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 300 mL, 300 mmol) under nitrogen. Heat the reaction to reflux for 18 h under nitrogen. Cool the reaction to 0° C. and quench with 6 M hydrochloric acid. Concentrate the tetrahydrofuran on a rotary evaporator to give the crude product. Add water (50 mL) and tetrahydrofuran (30 mL) to the crude product and heat the reaction to reflux for 1 h. Cool the reaction to room temperature and adjust the pH to pH=8 with 5 N sodium hydroxide. Add brine (200 mL) and extract with ethyl acetate (3×200 mL). Dry the ethyl acetate extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 0.7% concentrated ammonium hydroxide/7% ethanol/chloroform to yield 6.55 g (52%) of 4-(2-benzylamino-1-methyl-ethyl)-phenol: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 3.08 minutes, Purity: 99.6%; mass spectrum (ion spray): m/z=242.1 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:14][CH2:13]1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4].S(OC)(O[CH3:35])(=O)=O.[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>CN(C=O)C.C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:14][CH2:13]1)[C:3](=[N:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[S:4][CH3:35]
Reactant: Cc1ccc(OCCCCN2CCC(N(C)C(=S)Nc3ccccc3)CC2)cc1C
Reactant: COS(=O)(=O)OC
Agent: O=C(O)/C=C/C(=O)O
Solvent: CN(C)C=O
Solvent: CCO
Product: CSC(=Nc1ccccc1)N(C)C1CCN(CCCCOc2ccc(C)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g (2.35 mmol) of the preceding thiourea (10.2) in 10 ml of DMF is treated at 25° C. with 245 μl of dimethyl sulfate, stirred overnight at 25° C. and then heated for 1 h at 60° C. The mixture is evaporated to dryness and the residue is recovered in the usual way and purified by flash chromatography to give 325 mg (Yd: 32%) of a light yellow oil. This oil is taken up in ethanol and salified with a solution of 80 mg of fumaric acid in the same solvent to give 340 mg (Yd: 26%) of compound of formula:
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][N:24]([CH2:26][C:27]([N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)=[O:28])[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]([N:29]([C:30]1[CH:31]=[CH:32][C:33]([NH:36]/[C:3](=[C:10]2\[C:11](=[O:22])[NH:12][C:13]3[C:18]\2=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=3)/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:34][CH:35]=1)[CH3:37])=[O:28])[CH3:23]
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Product: CN(C)CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3cc4c(cc32)OCO4)c2ccccc2)cc1

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine
Reaction SMILES: [Na].[CH3:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[C:3]([CH2:2][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCCC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCCCCC(=O)CC(=O)C(=O)OCC
Temperature: 0 °C
Yield: 101.3 %

Procedure:
4.7 g of sodium metal was dissolved in 92 ml of ethanol. A mixture of 20 g of 2-heptanone and 26 g of diethyl oxalate was dropwise added thereto at 0° C. After the removing the ice bath, the reaction mixture was stirred at room temperature for 3 hours. After evaporation of the reaction mixture, 200 ml of water was added to the resulting syrup, and then an aqueous 10% hydrochloric acid was added with ice-cooling, the pH being adjusted to 1. After extraction with benzene (300 ml×3), the organic layer was washed with 100 ml of water, dried with Glauber's salt (Na2SO4). And concentrated to give ethyl hexanoylpyruvate as a liquid (38 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A solution of 2-fluoro-5-nitrobenzonitrile (500 mg, 3.0 mmol) in ethanol (35 mL) was treated with potassium carbonate (420 mg, 3.0 mmol) and piperazine-1-carboxylic acid tert-butyl ester (560 mg, 3.0 mmol). The reaction mixture was stirred at 80° C. for 1 h, then cooled and partitioned between ethyl acetate and water. The organic layer was then collected, dried over sodium sulfate, filtered and evaporated to a yellow residue. Purification using flash chromatography yielded 4-(2-cyano-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (590 mg, 59% yield) as a bright yellow solid. HRMS calcd for C16H20N4O4 (M+Na) 355.1377, obsd 355.1376.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: NCc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(CNCc2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 48 h
Yield: 97.6 %

Procedure:
4-Phenoxybenzaldehyde (1.0 g, 5.0 mmol) and 4-fluorobenzylamine (631 mg, 5.0 mmol) were dissolved in methanol (17 mL) under a nitrogen at room temperature. Sodium cyanoborohydride (317 mg, 5.0 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 1.5 g (97%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.55 (s, 1H), 3.76 (s, 2H), 3.78 (s, 2H), 6.95-7.15 (m, 7H), 7.25-7.40 (m, 6H). MS (DCl/N H3) m/e 308 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:16][S-:17].[Na+]>C1COCC1.CCOCC>[CH3:16][S:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C[S-]
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc2nc(SC)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (4.8 g, 16.8 mmol) from Step 1 of Example 2 in THF (100 mL) was added sodium thiomethoxide (1.74 g, 25.2 mmol) slowly at 0° C. The reaction mixture was stirred at rt overnight. The mixture was diluted with Et2O (200 mL) and washed with saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate as a white solid (4.18 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J=1.5 Hz, 1H), 8.11 (dd, J=1.6, 8.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.82 (s, 3H), 1.42 (t, J=7.1 Hz, 3H) LCMS (ESI) m/z 254 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=2)=O)=[N:5][N:4]=[N:3]1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][N:21]=[C:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: Cn1nnnc1C(=O)c1cccc(OC(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NO)c1cccc(OC(F)(F)F)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a stirred solution of (1-methyl-1H-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methanone (5.12 g, 16.2 mmol) in dry pyridine (25 mL) was added hydroxylamine hydrochloride (2.81 g, 40.4 mmol). The mixture was stirred at 70° C. for 3 h, then left to stand overnight. After concentration of the reaction mixture in vacuo, the residue was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL), the combined organic layers dried (MgSO4), concentrated in vacuo and dissolved in toluene. A crystalline precipitate appeared, which was filtered off to afford N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-[3-(trifluoromethoxy)phenyl]methanimine as a white solid [4.33 g, yield 92%; HPLC/MS:m/z=288 (M+H); log P(HCOOH)=2.37].
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.O.[NH2:14]N.Cl.NN>>[CH3:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[S:9][C:8]([NH:10][NH2:14])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1cc2nc(N)sc2cc1C
Reactant: NN
Agent: Cl
Solvent: O
Product: Cc1cc2nc(NN)sc2cc1C
Yield: 82 %

Procedure:
5,6-Dimethyl-2-aminobenzothiazole (5.0 g., 0.028 mole), 85% hydrazine hydrate (3.49 g.; 0.056 mole) and hydrazine monohydrochloride (1.99 g.; 0.028 mole) were reacted in the procedures of Example 1. 5,6-Dimethyl-2-hydrazinobenzothiazole was obtained in 82% yield, m.p. 223°-228°C. Assay (titration) 97.2%. Recrystallization from ethanol gave material melting 235°-237°C. (dec.).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=O.Cl.[NH2:37][CH2:38][CH2:39][N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42].C[O-].[Na+]>CCO>[CH3:44][S:41]([N:40]([CH3:45])[CH2:39][CH2:38][NH:37][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[CH:8]2)=[O:2])(=[O:43])=[O:42]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: COC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 49 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3,8-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (39 mg, 0.084 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (80 mg, 0.42 mmol), and NaOMe (23 mg, 0.42 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was washed with brine and dried over MgSO4. After evaporating the solvent, the residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+2% AcOH) to give 24 mg of the title compound as a light yellow solid. MS: (+) m/z 583.32 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:14][N:15]=[C:16]=[O:17]>C(OCC)(=O)C>[CH3:14][NH:15][C:16](=[O:17])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CN=C=O
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NC)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 10 g of ethyl 2-aminothiazol-4-ylglyoxylate. 7 g of methyl isocyanate and 200 ml of ethyl acetate. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:17])[CH3:16].NC1C=CC(C2C=CC=C(Cl)C=2)=CC=1[C:39](=[O:41])C.C([Mg]Br)C1C=CC=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:18]([C:15]1([CH3:16])[O:17][C:39](=[O:41])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)=[CH:4][C:3]1=2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: CC(O)(Cc1ccccc1)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: Br[Mg]Cc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Yield: 30 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-benzyl-ethanol (prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to procedure described previously, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. THF was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as an off-white solid: mp 187-188° C.; 1H-NMR (DMSO-d6) δ 10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3 Hz), 3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H); MS (ESI) m/z 364 ([M+H]+, 100%); Anal. Calcd. For C22H18ClNO2: C, 72.63; H, 4.99; N, 3.85. Found: C, 71.82; H, 5.09; N, 3.58.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([O:41]CC=C)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33]CC4C=CC=CC=4)[C@@H:21]([O:22]CC4C=CC=CC=4)[C@@H:12]3[O:13]CC3C=CC=CC=3)[C:6]=2[N:7]=1.COC(O)C.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:21]([OH:22])[C@@H:12]3[OH:13])[C:6]=2[N:7]=1
Reactant: [H][H]
Reactant: C=CCOc1nc(N)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Product: Nc1nc2c(ccn2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1

Procedure:
A mixture of 8.0 g of 2-amino-4-allyloxy-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, 1.5 g of 20% palladium on charcoal, 6.7 ml of acetic acid, and 150 ml of methoxy ethanol is hydrogenated at 50° C. and approximately 3 atmospheres until the uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, dissolved in water, and treated with 60 ml of wet IR-45 ion exchange resin. The filtrate is concentrated to dryness in vacuo and the residue is recrystallized from water to provide pure 2-amino-7-β-D-arabinofuranosyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one.
Reaction SMILES: C=C.[C:3](=[O:6])([OH:5])[OH:4].[CH:7]([CH:9]=[CH2:10])=[CH2:8]>>[CH2:7]=[CH2:8].[C:3]1(=[O:5])[O:4][CH2:10][CH:9]([CH:7]=[CH2:8])[O:6]1
Reactant: C=CC=C
Reactant: O=C(O)O
Agent: C=C
Product: C=CC1COC(=O)O1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
Upon removal from the glove box, the flask was evacuated and backfilled with ethylene. The catalyst was dissolved in CH2Cl2 (25 mL) and immediately treated with vinyl ethylene carbonate (5 mL). The resulting orange solution was stirred at 23° C. under an ethylene atmosphere (1 atm) for 20 hours. A small amount of polymer had precipitated out of solution. The polymerization was quenched with MeOH and acetone leaving gray oil adhering to the walls of the flask. The polymer was washed several times with acetone and MeOH to remove any remaining monomer. The polymer was dissolved in CH2Cl2 and transferred to a storage jar. The solvent was left to evaporate and the resulting oily polymer was dried in vacuo at ~80° C. for 3 days to afford a tacky solid (2.15 g, 1100 TO). 1H NMR was consistent with a copolymer containing approximately 96.5 weight % ethylene and 3.5 weight % vinyl ethylene carbonate monomer units.; Mn 40,000 g /mol ; Mw 92,000 g /mol ; DSC Tg -68° C., Tm -38° C.
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:3]=1[C:4]([OH:14])([C:9]#[C:10][CH:11]1[CH2:13][CH2:12]1)[C:5]([F:8])([F:7])[F:6].C(N(CC)CC)C.[C:28](Cl)(Cl)=[O:29]>C1(C)C=CC=CC=1>[Cl:20][C:16]1[CH:17]=[C:18]([F:19])[C:2]2[NH:1][C:28](=[O:29])[O:14][C:4]([C:9]#[C:10][CH:11]3[CH2:13][CH2:12]3)([C:5]([F:6])([F:7])[F:8])[C:3]=2[CH:15]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(F)cc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1Nc2c(F)cc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a stirred, cooled (−25° C.) solution of 144 mg (0.47 mmol) of (+/−)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL(1.2 mmol) of a 1.93 M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at −25° C. after which time it was warmed to ambient temperatue and quenched with 0.5 N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO3, water, and brine. The solution was dried (MgSO4), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (+/−)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. 1H NMR (300 MHz, CDCl3) δ7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). 19F NMR (282 MHz, CDCl3) δ−132.5(s, 1F), −81.1(s, 3F). High resolution mass spec: calculated for C14H9NO2ClF4(M+H)+: 334.0258, found: 334.0244.