Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH3:11][C:12]1[C:21]([C:22](OCC)=[O:23])=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[N:14]2[N:13]=1>C1C=CC=CC=1>[CH3:11][C:12]1[C:21]([C:22]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:23])=[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[N:14]2[N:13]=1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)c1c(C)nn2c(C)cccc12
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1nn2c(C)cccc2c1C(=O)OC1CN2CCC1CC2
Reaction time: 3 h
Yield: 21.7 %

Procedure:
After a suspension of 350 mg (2.76 mmol) of 3-quinuclidinol in 30 ml of benzene was refluxed for 1.0 hours by using a Dean-Stark apparatus, 0.1 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 3 hours. Unreacted sodium was removed and 200 mg (0.92 mmol) of ethyl 2,7-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 60 mg (0.20 mmol) of the title compound were obtained as white crystals (yield: 22%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C[Si]([C:14]#[CH:15])(C)C.C(N(CC)CC)C>CN(C)C=O>[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])#[CH:15]
Reactant: COc1ccccc1I
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccccc1OC
Yield: 50.9 %

Procedure:
2-Iodoanisole (10.5 g) and trimethylsilylacetylene (10.3 g) were reacted in dimethylformamide (50 ml), in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml) in nitrogen atmosphere at 50° C. for 12 hr. The resulting reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was dissolved in methanol (100 ml), a 5N aqueous solution of sodium hydroxide (20 ml) was added thereto, and then reacted at 60° C. for 1 hr. The reaction solution was evaporated, and to the resulting residue were added ether and water. The resulting ether layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow oil (3.02 g, yield; 51%).
Reaction SMILES: [C:1]1([C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[C:1]1([C:7](=[O:12])[CH:8]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: c1ccccc1
Product: CC(=O)C(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(=O)c1ccccc1

Procedure:
Reaction of equimolar amounts of 1-phenyl-1,3-butanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 1-PHENYL-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-BUTANEDIONE, m.p. 113.5°-116.5° C. (corr.).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])([CH3:15])[CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C>CO.[OH-].[Na+]>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([C:5]([CH3:15])([CH2:6][CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([OH:27])=[O:3])(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)(CC=Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(C)(CC=Cc2ccccc2)C(=O)O)cc1

Procedure:
2-(4Methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid ethyl ester (3.0 g, 11 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.9 g, 68%; yellowish oil; MS: 361 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2.[CH:19]([C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=1)=[O:20].C1CCN2C(=NCCC2)CC1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[C:5]2[CH:19]([OH:20])[C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc2[nH]c(-c3ccccc3)cc2cc1F
Reactant: COC(=O)c1cccc(C=O)n1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cccc(C(O)c2c(-c3ccccc3)[nH]c3cc(OC)c(F)cc23)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.8 %

Procedure:
To a suspension of 5-fluoro-6-methoxy-2-phenyl-1H-indole (176 mg) and methyl 6-formylpyridine-2-carboxylate (133 mg) in dichloromethane (3.6 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.011 mL), and this mixture was stirred at room temperature for 20 hours. The reaction mixture was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (210 mg). 1H-NMR (CDCl3) δ ppm: 3.88 (3H, s), 4.05 (3H, s), 5.31 (1H, d, J=2.8 Hz), 6.10-6.16 (1H, m), 6.81 (1H, d, J=11.8 Hz), 6.91 (1H, d, J=7.0 Hz), 7.23-7.29 (1H, m), 7.38-7.54 (3H, m), 7.66-7.75 (3H, m), 8.00-8.06 (1H, m), 8.12 (1H, br s).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:36])=O>ClCCl.CN(C)C=O>[O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([C:28]([Cl:36])=[O:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(=O)O)C3)c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(=O)Cl)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a cooled solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carboxylic acid (120 mg, 0.26 mmol) in dichloromethane (20 mL) was added two drops of N,N-dimethylformamide followed by oxalyl chloride (30.6 μL, 0.39 mmol) at 0° C. After being stirred for 16 hours at room temperature, the reaction mixture was concentrated in vacuo to afford 100 mg of the crude product which was used for the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:8][C:9]#[C:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:3](OCC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]([CH3:18])([CH2:8][C:9]#[C:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)CC#CCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)CC#CCN1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of ethyl 2,2-dimethyl-6-morpholin-4-ylhex-4-ynoate (380 mg; 1.50 mmol) in THF (5 mL) at 0° C. was added LiAlH4 (2.25 mL; solution 1.00 M in THF; 2.25 mmol). The mixture was stirred at 0° C. for 1 h and quenched with water (80 μL), 80 μL NaOH 15% (80 μL) and water (3×80 μL). The suspension thus obtained was then filtrated through a celite pad and rinsed several times with EtOAc. The filtrate was concentrated under reduced pressure to give 302 mg of the title compound as an orange oil (307 mg, 97% yield). GC/MS, m/z: 211, Rt: 4.13 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[NH:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[S:14](Cl)(=[O:16])=[O:15].[OH:18][CH2:19][C@:20]([OH:37])([CH3:36])[C:21](=[O:35])[C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH:24]([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[NH:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[S:14]([O:18][CH2:19][C@:20]([OH:37])([CH3:36])[C:21](=[O:35])[C@@H:22]([NH:27][C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:15])=[O:16]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)[C@](C)(O)CO
Reactant: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
2-Fluoro-5-(prop-2-yn-1-ylcarbamoyl)benzene-1-sulfonyl chloride (3, 2.52 g, 9.14 mmol) was added dropwise to tert-butyl ((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)carbamate (2.65 g, 9.14 mmol), DIEA (1.91 mL, 10 mmol) and DMAP (0.1 g, 0.914 mmol) in DCM (30 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was washed with 2N HCl and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (3.62 g, 75%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]5=[O:32])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)nc2)CC1
Yield: 69 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (525 mg) described in Preparation Example 106 and 5,5-dimethyloxazolidin-2-one (242 mg) described in Preparation Example 43, the title compound (393 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:16]([CH3:18])[CH3:17].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Br
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
2-Bromophenol (500 mg, 2.9 mmol) was dissolved in dry dimethylformamide (5 mL) under a dry nitrogen atmosphere. Powdered dry cesium carbonate (1.41. g, 4.34 mmol) was added, followed by the addition of 2-bromopropane (404 μL, 4.05 mmol) over a 2 min period. The mixture was stirred at room temperature overnight. Water (50 mL) was added and the mixture extracted with ethyl acetate (2×50 mL). The combined extracts were successively washed with water (25 mL) and saturated salt solution (25 mL) and dried over anhydrous magnesium sulfate. The dried solution was filtered and the solvents removed rotoevaporation to yield the title compound as an oil (522 mg, 84% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[S:9][CH:8]=1)[C:4](O)=[O:5].C(Cl)(=O)C([Cl:20])=O>C1C=CC=CC=1.CN(C)C=O>[CH3:1][O:2][CH:3]([C:7]1[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[S:9][CH:8]=1)[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(C(=O)O)c1csc2cc(F)ccc12
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(C(=O)Cl)c1csc2cc(F)ccc12

Procedure:
A solution of 2.70 g (10.7 mM) of α-methoxy-α-(6-fluoro-3-benzothienyl)acetic acid (from Preparation 1) in 60 ml of benzene containing 2.8 ml of oxalyl chloride and 4 drops of N,N-dimethylformamide was stirred under nitrogen at 25° C. for two hours. The solvent was then removed by evaporation under reduced pressure to give α-methoxy-α-(6-fluoro-3-benzothienyl)acetyl chloride. The acid chloride was dissolved in 60 ml of acetone and added dropwise over five minutes to a stirred cold (5° C.) solution of 2.41 g (11.3 mM) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 60 ml of acetone and 120 ml of water containing 2.84 g (33.8 mM) of sodium bicarbonate. The reaction mixture was stirred for two hours at 5° C. and then warmed to 25° C. and stirred for an additional two hours. The reaction mixture was diluted with 1N hydrochloric acid to pH 7.5 and stored at 0° C. for twelve hours. Following removal of acetone from the reaction mixture by evaporation, the aqueous mixture was acidified to pH 2 with 1N hydrochloric acid, and the aqueous acid layer was extracted several times with dichloromethane. The organic extracts were combined, washed with brine, dried, and the solvent was removed by evaporation under reduced pressure to provide 5.02 g (100%) of 7-[α-methoxyimino-α-(6-fluoro-3-benzothienyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. NMR (CDCl3): δ2.24 (s, 3H); δ4.04 and 4.15 (two singlets, 3H); δ5.08 and 5.11 (two dd, 1H).
Reaction SMILES: [C:1]([S:4][C:5]1[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][CH:6]=1)(=O)[CH3:2].CC(C)([O-])C.[K+].ClCC1[O:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][N:26]=1>C1COCC1>[C:27]([C:24]1[O:23][C:2]([CH2:1][S:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][CH:6]=2)=[N:26][CH:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(=O)Nc1ncc(SC(C)=O)s1
Reactant: CC(C)(C)c1cnc(CCl)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(SCc2ncc(C(C)(C)C)o2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To a solution of 50 mg (0.23 mmol, Applied Chemical Laboratory) of N-[5-(acetylthio)-2-thiazolyl]acetamide in 10 mL of THF was added 0.25 mL of potassium tert-butoxide solution (1 M solution, 0.25 mmol) at rt under argon. The resulting suspension was stirred for 15 min at rt, then a solution of 59 mg of 2-(chloromethyl)-5-t-butyloxazole (0.34 mmol) in 1 mL of THF was added. The resulting mixture was stirred at rt for 16 h, concentrated under reduced pressure and purified by flash column chromatography (silica gel, 25×200 mm, 1:1 EtOAc/hexanes followed by 100% EtOAc) to give 44 mg (0.14 mmol, 61%) of N-[5-[[(5-t-butyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([OH:25])=O)[C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH2:26]([N:28]([CH2:49][CH3:50])[CH2:29][CH2:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>ClCCl>[CH2:49]([N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:43][CH:44]=2)=[CH:35][CH:34]=1)[C:23](=[O:25])[CH2:22][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:21])[CH:20]=[C:11]1[CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:50]
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)cc(=O)c2ccccc21
Reactant: CCN(CC)CCNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCN(CC)CCN(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)Cn1c(CCc2cccc(F)c2F)cc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A mixture of 2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-quinolin-1-yl]-acetic acid (Int. E2) (0.26 g, 1 equiv), N,N-diethyl-N′-(4′-trifluoromethylbiphenyl-4-ylmethyl)ethane-1,2-diamine (Int. A2) (0.265 g, 1 equiv), HATU (0.28 g, 1.2 equiv) and diisopropylamine (0.32 ml, 2.4 equiv) in dichloromethane (15 ml) was stirred at room temperature overnight, then washed with aqueous ammonium chloride and aqueous sodium bicarbonate. The organic layer was dried and evaporated, and the product purified by column chromatography (silica, 2% [2M ammonia in methanol] in dichloromethane). Product fractions were evaporated to an off-white foam (0.201 g). Trituration with ether gave the title compound as a white solid (0.476 g). 1H-NMR (d6-DMSO, ca 2:1 rotamer mixture) δ 0.93 (6H, 2×t), 2.38–2.80 (4H, m), 2.90–3.05 (4H, m), 3.45 (2H, m), 4.30–4.95 (4H, m), 5.23–5.58 (2H, m), 6.06 (1H, 2×s), 7.14–7.38 (7H, m), 7.50–7.95 (7H, m), 8.16 (1H, m); MS (APCI+) found (M+1)=676. C39H38F5N3O2 requires 675.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH2:12][CH3:13])[C:10]([CH3:14])=[N:9][CH:8]=1)=O.C(=O)(O)O.[C:20]1([NH:26][C:27]([NH2:29])=[NH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[O-].[Na+].O>CC(N(C)C)=O>[NH:26]([C:27]1[N:29]=[C:5]([C:7]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:14])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCn1c(C(=O)C=CN(C)C)cnc1C
Reactant: N=C(N)Nc1ccccc1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C
Temperature: 110 °C
Yield: 52.5 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-ethyl-2-methylimidazole (Method 23; 2.10 g, 10.1 mmol), phenylguanidine hydrogen carbonate (2.2 g, 11.1 mmol) and sodium methoxide (1.2 g, 22.2 mmol) were suspended in anhydrous DMA (15 ml) and the mixture heated at 110° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature and poured into water (50 ml). The solution was extracted EtOAc (2×50 ml). The combined extracts were washed with water (2×50 ml) and then brine (2×50 ml), dried and the volatiles removed by evaporation. The residue was triturated with ether, collected by filtration and air dried to give the title compound (1.48 g, 53%) as a reddish brown solid. NMR 1.17 (t, 3H), 2.38 (s, 3H), 4.52 (q, 2H), 6.93 (t, 1H), 7.08 (d, 1H), 7.27 (t, 2H), 7.60 (s, 1H),7.62 (d, 2H), 8.35 (d, 1H), 9.35 (s, 1H); m/z 280.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:25])[CH2:23]Cl)=[CH:17][CH:16]=2)([OH:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C@H:27]1[O:32][C@@H:31]([CH3:33])[CH2:30][NH:29][CH2:28]1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:25])[CH2:23][N:29]3[CH2:28][C@H:27]([CH3:26])[O:32][C@H:31]([CH3:33])[CH2:30]3)=[CH:17][CH:16]=2)([OH:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CCl)Cc1ccc(C(C)(O)Cc2ccc(C(C)(C)C)cc2)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(C(C)(O)Cc2ccc(C(C)(C)C)cc2)cc1)CN1C[C@@H](C)O[C@@H](C)C1
Temperature: 150 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
A mixture of 164 g of (VI) and 159 g of 2,6-cis-dimethylmorpholine was stirred for 6 hours at 150° C. The crude product was dissolved in CHCl3, and the solution was washed with dilute aqueous NaOH and then with water, dried over Na2SO4 and concentrated. Distillation of the residue gave a yield of 147 g of (VII) of boiling point 214°-218° C./0.3 mbar.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[CH3:7][O:8][C:9]1[C:10]([OH:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[OH-].[K+]>O1CCCC1.O>[CH3:1][N:2]([CH3:6])[C:3]([O:17][C:10]1[C:9]([O:8][CH3:7])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])=[S:4]
Reactant: CN(C)C(=S)Cl
Reactant: COc1cccc(C=O)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C=O)c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
A solution of N,N-dimethylthiocarbamoyl chloride (10 g) in tetrahydrofuran (40 ml) was added dropwise at <12° C. over 30 minutes to a stirred solution of 3-methoxy-2-hydroxybenzaldehyde (12.3 g) and potassium hydroxide (4.6 g) in water (105 ml) then the mixture was stirred at ambient temperature for 15 minutes. 10% Aqueous potassium hydroxide solution (30 ml) was added, then the product was extracted into toluene (3×150 ml). The combined extracts were washed with water (150 ml) then dried (MgSO4). The solvents were removed in vacuo and the residue was crystallised from methanol to give 2-(N,N-dimethylthiocarbamoyloxy)-3-methoxybenzaldehyde (10.5 g) as a yellow solid which was used without further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])=[N+:17]=[N-:18]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2)nc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
To a solution of 4-chloromethyl-5-methyl-2-phenyl-1H-imidazole hydrochloride (4.86 g) [CAS 58731-95-6] in DMF (50 ml) was added sodium azide (7.79 g). The reaction mixture was stirred at room temperature for 18 h under argon and concentrated without heating under high vacuum. To the residue was added ice/1 molar K2CO3 solution, and the mixture was extracted with ethyl acetate. The organic phase washed with brine, dried over magnesium sulphate and concentrated. The residue was purified by chromatography on silica gel using methylene chloride/methanol 2% as eluent to obtain 4-azidomethyl-5-methyl-2-phenyl-1H-imidazole (3.70 g) as a light yellow amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([NH:10][CH:11]=[C:12]2[C:17](=[O:18])OC(C)(C)OC2=O)=[CH:8][CH:9]=1)=[O:4]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[NH:10][CH:11]=[CH:12][C:17](=[O:18])[C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)o1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1cc2c(=O)cc[nH]c2o1
Temperature: 200 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
After adding 5-[(2,2-dimethyl-4,6-dioxo-[1.3]dioxan-5-ylidenemethyl)amino]furan-2-carboxylic acid methyl ester (4.0 g) to Dowtherm A (30 ml), the mixture was heated and stirred at 200° C. for 1 hour. After cooling, the precipitated crystals were filtered out and washed with diethyl ether to obtain the title compound (2.0 g).
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[C:9]([O:17][C:18]([F:21])([F:20])[F:19])[CH:8]=2)[NH:3]1.CO.[ClH:24]>O1CCOCC1>[ClH:24].[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[NH:3][C:2](=[O:1])[O:6][N:5]=2)=[CH:8][C:9]=1[O:17][C:18]([F:19])([F:21])[F:20]
Reactant: CC(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc(-c2noc(=O)[nH]2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture consisting of 200 mg of N-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-2-trifluoromethoxyphenyl]acetamide, 10 ml of methanol and 0.5 ml of a 4M solution of hydrochloric acid in dioxane was stirred at room temperature for 15 hours. After concentrating the volatile fractions on a rotary evaporator, a yellowish oil remains.