Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH3:12])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]1[NH:20][C:21]([NH:23][C:24]([O:26][CH3:27])=[O:25])=[S:22].[OH-].[Na+].[CH3:30]I>CC(C)=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH3:12])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]1[NH:20][C:21](=[N:23][C:24]([O:26][CH3:27])=[O:25])[S:22][CH3:30]
Reactant: CCCSC1(C)C=CC(=N)C(NC(=S)NC(=O)OC)=C1Cc1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCSC1(C)C=CC(=N)C(NC(=NC(=O)OC)SC)=C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a suspension of 1-imino(4-methyl)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.02 g; 0.01 mole) in acetone (60 ml) and water (20 ml) there is added 50% aqueous sodium hydroxide (0.8 g; 0.01 mole). The solution that forms within 10 min. is stirred at room temperature for 50 min. and to it there is added methyl iodide (1.42 g; 0.01 mole). The suspension that forms is stirred at room temperature for 1 hr. and is vacuum filtered. The filter cake is air dried to afford 1-imino(4-methyl)phenylmethyl-2-(3-carbomethoxy-S-methyl isothioureido)-4-propylthiobenzene (3.6 g; 86.6%), m.p. 113°-115° C.
Reaction SMILES: C(N[CH:4]([OH:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)C.[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19]N=C1)=[O:15]>O1CCCC1>[CH2:20]([N:16]1[CH:5]([CH2:6][C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[CH2:4][O:13][C:14]1=[O:15])[CH3:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNC(O)CCc1ccncc1
Solvent: C1CCOC1
Product: CCN1C(=O)OCC1Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
Crude α-(ethylamino)-4-pyridinepropanol (2.07 g, 0.0122 mol) is stirred in dry tetrahydrofuran (20 mL) with activated 3Å sieves for about 10 minutes. Carbonyldiimidazole (2.26 g, 0.0139 mol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and Kugelrohr distilled at 80-100° C. and 2 mm Hg to remove excess imidazole. The residue is chromatographed on silica gel eluting with 10:1 chloroform:methanol to afford 1.7 g of the title compound as an amber oil.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:27])([F:26])[C:16]([NH:18][C@@H:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17]>>[CH:8]1([CH2:7][N:6]2[C:2]([N:22]3[CH2:23][CH2:24][CH2:25][C@@H:19]([NH:18][C:16](=[O:17])[C:15]([F:26])([F:14])[F:27])[CH2:20][CH2:21]3)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cnn(CC2CC2)c1Cl
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC2CC2)CC1)C(F)(F)F
Yield: 55 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (R)—N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.98 g, 55%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 6.42-6.39 (m, 1H), 4.22-4.14 (m, 1H), 4.00-3.85 (m, 2H), 3.44-3.32 (m, 1H), 3.30-3.15 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.30-1.20 (m, 1H), 0.70-0.62 (m, 2H), 0.50-0.35 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CO>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:3]1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In methanol (30 ml), 3-aminopyrrolidine (0.54 g) was dissolved under ice cooling, followed by the addition of diisopropylethylamine (720 μl) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.84 g). The resulting mixture was gradually heated to room temperature and stirred for 11 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜5% methanol-dichloromethane), whereby the title compound (0.59 g, 94%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([F:16])[CH:5]=1)(=O)[CH3:2].[CH2:17]([O:19]C(=O)/C=C(/OCC)\C)[CH3:18].Cl.[C:29](=O)=O>CN(C)C=O>[F:16][C:6]1[CH:5]=[C:4](/[C:1](/[CH3:29])=[CH:2]/[C:17](=[O:19])[CH3:18])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)c(F)c1
Reactant: O=C=O
Reactant: CCOC(=O)/C=C(\C)OCC
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)/C=C(\C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
72.8 Gm (0.649 mol) of potassium tert.butylate were added all at once to a slution of 97.0 gm (0.453 mol) of 4-acetyl-2-fluoro-biphenyl and 103.0 gm (0.651 mol) of (E)-3-ethoxy-crotonic acid ethyl ester in 1 liter of anhydrous dimethylformamide, whereby the temperature of the mixture rose spontaneously from 20°C to 38°C and its color turned intensely red. The reaction mixture was stirred for one hour while maintaining an internal temperature of 32° to 35°C, and then, while the mixture was still warm, 200 ml of concentrated hydrochloric acid were added dropwise thereto, and the resulting mixture was heated for 30 minutes at 90°-100°C. After the evolution of carbon dioxide had ceased, the cooled mixture was stirred into one liter of ice water, and the yellowish precipitate formed thereby was filtered off, thoroughly washed with water and recrystallized, in the presence of activated charcoal, once from methanol and twice from diisopropyl ether. 75.0 gm (65% of theory) of the fallow crystalline compound, m.p. 103°C, of the formula ##SPC21##
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.Cl.N>O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)[OH:8])=[CH:17][CH:18]=1
Reactant: Clc1ccc(Br)cc1
Reactant: O=C(c1ccccc1)c1ncc[nH]1
Agent: Cl
Agent: N
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccc(Cl)cc1)c1ncc[nH]1

Procedure:
A solution of 17.2 g. of 2-benzoylimidazole (A. Sonn and P. Greif, Ber. 66 (1933), 1900) in 100 ml. of anhydrous tetrahydrofuran was added drop-wise to a Grignard reagent prepared from 5.8 g. of magnesium and 45.9 g. of 1-bromo-4-chlorobenzene in 150 ml. of anhydrous tetrahydrofuran. The reaction mixture was boiled under reflux for half an hour, cooled and poured onto a mixture of ice and hydrochloric acid. The solution was neutralized with concentrated ammonia solution and extracted with tetrahydrofuran. The organic solvents layer was dried and concentrated; the residue was crystallised from isopropyl alcohol. Melting point of the product was 162°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.Cl.[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:21])=[CH:23][CH:24]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:25])[C:6]=2[CH:26]=1
Reactant: Cc1c(C(CC(C)C)Nc2ccc(C(=O)O)cc2)oc2ccc(Cl)cc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2oc3ccc(Cl)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 86 %

Procedure:
To a mixture of 4-{[1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl]amino}benzoic acid (180 mg) synthesized above, β-alanine ethyl ester hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (111 mg), triethylamine (202 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg) and the mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (196 mg, 86%) as a colorless oil.
Reaction SMILES: [Si:1]([C:8]#[CH:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N)CC.[Cl:14]/[CH:15]=[CH:16]\Cl>CCOCC.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14]/[CH:15]=[CH:16]\[C:9]#[C:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C(C)(C)C
Reactant: Cl/C=C\Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOCC
Solvent: CCCN
Product: CC(C)(C)[Si](C)(C)C#C/C=C\Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A solution of tert-butyldimethylsilylacetylene (14.5 g, 103 mmol, 1 equiv), n-propyl amine (42.5 ml,, 517 mmol, 5.00 equiv), and (Z)-1,2-dichloroethene (32.5 mL, 413 mmol, 4.00 equiv) in ether (150 mL) was deoxygenated at -78° C. by alternately evacuating the reaction vessel and flushing with argon (8×). The deoxygenated solution was transferred to an ice bath and copper iodide (2.95 g, 15.5 mmol, 0.15 equiv) was added. The mixture was cooled to -78° C. and was deoxygenated as above. In a similar fashion, bis(triphenylphosphine)palladium(II) chloride (3.64 g, 5.17 mmol, 0.05 equiv) was added at 0° C. and the reaction solution was deoxygenated at -78° C. The deoxygenated reaction mixture was warmed to 23° C. and was stirred at that temperature for 3 h. The product solution was washed with 1:1 saturated aqueous potassium carbonate solution:saturated aqueous ammonium chloride solution (3×150 mL), was dried over sodium sulfate, and was concentrated. The residue was purified by distillation under reduced pressure (bp 60°-65° C., mmHg) to afford (Z)-1-chloro-4-(tert-butyldimethylsilyl)-1-buten-3-yne as a clear oil (12.5 g, 60%). ##STR28##
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][NH:10]2)=[CH:4][N:3]=1.[H-].[Na+].Cl[CH2:18][CH:19]1[C:23]([CH3:24])=[CH:22][O:21][N:20]1C.[CH3:26]N(C=O)C>>[Cl:1][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][N:10]2[CH2:24][C:23]1[C:19]([CH3:18])=[N:20][O:21][C:22]=1[CH3:26]
Reactant: CN(C)C=O
Reactant: CC1=CON(C)C1CCl
Reactant: CN1C(=O)CCNc2nc(Cl)ncc21
Agent: [H-]
Agent: [Na+]
Product: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C

Procedure:
To a stirred solution of 10-chloro-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 100; 64 mg, 0.3 mmol) in DMF (2 mL) was added sodium hydride (60% mineral oil dispersion; 18 mg, 0.36 mmol) and the solution stirred at room temperature until effervescence had ceased. 3 chloromethyl-2,4-dimethylisoxazole (Aldrich; 52 mg, 0.36 mmol) was added and the reaction heated at 50° C. with stirring overnight. The solvent was evaporated and residue dissolved in methanol, transferred to an SCX cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated to yield the title compound as an off white solid (82 mg, 85%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([Si](C)(C)C)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)c1[nH]c2c([N+](=O)[O-])cc(Cl)cc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)cc2c(-c3ccccc3)c[nH]c12
Yield: 101.2 %

Procedure:
5-Chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.5 g, 4.35 mmol) prepared in Step A was dissolved in tetrahydrofuran (30 mL), and tetrabutylammonium fluoride 1M solution (5.2 mL, 5.2 mmol) was added in drops thereto at 0° C. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (1.2 g, Yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:22])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=1[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:22][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([F:23])=[C:25]([CH3:33])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CCC(Oc2ccc(N)cc2-c2c(Cl)cnn2C)CC1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(OC3CCN(C)CC3)c(-c3c(Cl)cnn3C)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenylamine (0.040 g, 0.12 mmol), 4-fluoro-3-methylbenzoyl chloride (0.026 g, 0.12 mmol) and triethylamine (0.016 mL, 0.13 mmol)) in methylene chloride (1.5 mL) was stirred at room temperature overnight and concentrated to give a crude product that was subjected to a purification by prep HPLC. The corresponding fractions were collected and lyophilized to give a TFA-salt of Compound 745 as a white solid in 57.0% yield. LCMS m/z (%)=457.4 (M+H, 100).
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1)#[N:7].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:21])[N:11]=[CH:10][N:9]=[C:8]2[C:6]1[NH:24][N:23]=[N:22][N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2ncnc(C#N)c2cc1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(-c3nnn[nH]3)c2cc1OC
Temperature: 30 °C
Reaction time: 0.29 h
Yield: 59.16 %

Procedure:
Experimental Procedure: 400.0 ml of dimethyl formamide and 20.0 g (0.09 mol) of 4-cyano-6,7-dimethoxy-quinazoline were charged into a 1.0 L 4necked round bottom flask, connected to a mechanical stirrer, thermometer socket and condenser under nitrogen atmosphere. 6.80 g (0.10 mol) of Sodium azide and 5.50 g (0.10 mol) of ammonium chloride were charged at 25-35° C. Stirred the mass for 15-20 min at 25-35° C. Stirred the mass for 15-20 min at 25-35° C. Reaction mass temperature was raised to 110-115° C. Maintained the mass temperature at 110-115° C. for 8-9 hours. Inorganic solid was filtered at 110-115° C. and the filtrate was collected into a conical flask. Cooled the filtrate to 25-30° C. 4000.0 ml of ethyl acetate was charged into a 5.0 L 4necked round bottom flask, connected to a mechanical stirrer, thermometer socket and addition flask. Reaction mass of dimethyl formamide solution was added to ethyl acetate solution under stirring. Maintained the mass temperature at 25-30° C. for 60-90 min. Cooled the mass temperature to 0-5° C. Maintained the mass temperature at 0-5° C. for 150-180 min. Filtered the solid and solid was washed with 100.0 ml of ethyl acetate. Compound was dried at 25-30° C. under vacuum. Obtained 14.20 g (yield is 59.16% by theory) of product Melting range 207.2° C.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4](C)C.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].C[CH:33]([OH:35])C>CCOC(C)=O>[Br:10][C:11]1[C:12]([N:3]2[CH2:4][CH:9]([CH2:33][OH:35])[CH2:7]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
DIPEA (0.115 mL, 0.660 mmol) was added to a solution of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 119 mg, 0.3 mmol) and azetidin-3-yl-methanol, HCl salt (44.5 mg, 0.36 mmol) in iPrOH (0.3 mL) in a vial, which was sealed and the RM mixture stirred at 140° C. for 5 h. After cooling at RT, the RM was dissolved in EtOAc, washed with 0.5 M HCl and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, n-hexane/EtOAc from 50% to 100% EtOAc) and crystallized from n-pentane/EtOAc to afford the title product as white crystals. HPLC (Condition 4) tR=5.33 min, UPLC-MS (Condition 3) tR=1.06 min, m/z=446.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:25]=[C:26]([SH:31])[CH:27]=[CH:28][C:29]=1[Cl:30]>CS(C)=O>[Cl:1][C:2]1[C:3]([S:31][C:26]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Sc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 160, 416 mg, 1.68 mmol) was added to a mixture of potassium carbonate (694 mg, 5.02 mmol), 3,4-dichlorothiophenol (300 mg, 1.77 mmol) in DMSO (16.7 mL) and the reaction stirred at room temperature for 18 hours. The reaction was quenched by addition of 0.5 N aqueous NaOH (20 mL) and EtOAc (30 mL) and the mixture partitioned. The aqueous was further extracted with EtOAc (3×10 mL), the organics combined, washed with brine (10 mL), dried (MgSO4), filtered and evaporated to give a yellow solid. Silica gel column chromatography eluting with 9:1 DCM:heptanes resulted in isolation of the title compound as a white solid (571 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][CH2:37][C@H:38]([OH:40])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][CH2:37][C@H:38]([OH:40])[CH3:39])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol using methods similar to Example 563 to provide a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (t, J=6.63 Hz, 3 H), 1.66-1.80 (m, 6 H), 2.19 (t, J=5.79 Hz, 2 H), 3.16-3.25 (m, 4 H), 3.34-3.48 (m, 2 H), 3.73-3.87 (m, 1 H), 4.17-4.24 (m, 4 H), 4.96 (d, J=4.63 Hz, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.00 (s, 1 H), 8.56 (s, 1 H), 10.43 (s, 1 H), 16.84 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cccc(-n2cnnn2)c1
Reactant: O=[N+]([O-])O
Product: Cc1cc(-n2cnnn2)ccc1[N+](=O)[O-]

Procedure:
1-(3-Methylphenyl)tetrazole (11.3 g) was cautiously added at 0° to fuming nitric acid (100 cm3) with stirring and the solution was then warmed on a steam bath for 5 minutes. The cooled solution was poured onto ice (200 g), and the solid material was filtered off, washed with water (100 cm3) and dried. Recrystallisation from ethyl acetate afforded 1-(3-methyl-4-nitrophenyl)tetrazole, m.p. 166°-168° (9.4 g).
Reaction SMILES: NC1C=CC(C)=CC=1[C:4](O)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]([NH:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1)=[O:5])=[O:21]
Reactant: Nc1nccs1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: COc1ccccc1C(=O)c1cc(C)ccc1N
Product: COc1ccccc1C(=O)c1cc(C)ccc1NC(=O)Nc1nccs1
Yield: 72 %

Procedure:
(2-Amino-5-methyl-phenyl)-(2-methoxy-phenyl)-methanone (843 g, 35%) was prepared from 2-amino-5-methyl-benzoic acid (1.51 g, 0.1 mol) following the general procedure S. 1-[2-(2-methoxy-benzoyl)-4-methyl-phenyl]-3-thiazol-2-yl-urea (132 mg, 72%) was prepared from (2-amino-5-methyl-phenyl)-(2-methoxy-phenyl)-methanone (121 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[CH2:14][CH2:15][OH:16].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[S]>C(O)(C)C.O>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[CH2:14][CH2:15][OH:16]
Reactant: Nc1c(CCO)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Agent: [S]
Solvent: CC(C)O
Solvent: O
Product: Nc1cc([N+](=O)[O-])cc(CCO)c1N

Procedure:
To a suspension of 0.119 mole (27 g) of 2-(2-amino-3,5-dinitrophenyl)ethanol obtained in Example 1 in 67.5 ml of isopropanol to which an equal volume of water has been added, a solutionof 38.4 g of sodium sulphide nonahydrate and 5.4 g of sulphur in 10 ml of water is added dropwise at 60°-65° C. Heating is maintained for 20 minutes after the addition is complete. When the mixture is cooled, a precipitate of the expected product is obtained, and this is drained, made into a paste in water and then recrystallized from 96° strength alcohol. It melts at 172° C.
Reaction SMILES: C(OC(=O)[N:7]([CH:10]([CH3:33])[CH2:11][C:12]1[CH:32]=[CH:31][C:15]2[O:16][CH:17]([CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[O:18][C:14]=2[CH:13]=1)[CH2:8][CH3:9])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH2:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH:17]1[O:16][C:15]2[CH:31]=[CH:32][C:12]([CH2:11][CH:10]([NH:7][CH2:8][CH3:9])[CH3:33])=[CH:13][C:14]=2[O:18]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN(C(=O)OC(C)(C)C)C(C)Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(C)Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.58 g (3.3 mmol) of 2G in 10 mL of dichloromethane (distilled over CaH2) was added trifluoroacetic acid at room temperature, and the mixture was allowed to stir at room temperature for 30 minutes. The resulting reaction mixture was concentrated under reduced pressure to dryness and purified by silica gel column chromatography to give 1.6 g (3.3 mmol, 98%) of 2H as a colorless gum (M+H, 371).