Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(=O)=O.[CH3:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>C(OCC)(=O)C>[CH3:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CS(=O)(=O)OCCCN1CCOCC1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 42.5 %

Procedure:
A flask was charged with 3-morpholinopropyl methanesulfonate (1.5 g, 6.9 mmol), 3-methyl-4-nitrophenol (0.96 g, 6.3 mmol), cesium carbonate (4.0 g, 12 mmol) and DMA (100 mL), and the reaction mixture was heated to 90° C. for 15 hours. Ethyl acetate (200 ml) was added to the cooled reaction mixture, and the mixture was extracted with water (2×100 ml), 1N sodium hydroxide (2×50 ml) and aqueous 5% lithium chloride (2×50 ml). The organic solvent was removed on a rotary evaporator under reduced pressure. Purification of the crude product by silica column chromatography using 50:50 ethyl acetate:hexanes as eluant gave 0.75 g of 4-(3-(3-methyl-4-nitrophenoxy)propyl)morpholine. (39% yield). MS (EI): 281 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.S(Cl)(Cl)=O.[CH3:14][C:15]([CH3:20])=[CH:16][C:17](O)=[O:18]>ClCCl>[N:1]1([C:17](=[O:18])[CH:16]=[C:15]([CH3:20])[CH3:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(C)=CC(=O)O
Reactant: c1ccc2[nH]nnc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)=CC(=O)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
1H-Benzotriazole (2.14 g, 18.0 mmol, 4 equiv.) was dissolved in dichloromethane (25 ml) and thionyl chloride (330 μl, 4.5 mmol, 1 equiv.) was added at room temperature. (450 mg, 4.5 mmol) 3-Methyl-but-2-enoic acid [CAS 541-47-9] was added and the mixture was stirred for 2 hours at room temperature. The suspension was filtered and the filtrate was extracted once with 2N NaOH solution and twice with dichloromethane. The organic extracts were combined, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:cyclohexane gradient 0:100 to 50:50. The desired 1-benzotriazol-1-yl-3-methyl-but-2-en-1-one (810 mg, 90% yield) was obtained as a light yellow solid, MS: m/e=202.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH3:30])[CH:11]([C:17]1[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:22]=1)[C:12](OCC)=[O:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[CH:11]([C:17]2[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=2)[CH:10]([CH3:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(c1nc(N2CCOCC2)cc(=O)[nH]1)C(C)C
Product: CC(C)C(C(=O)Nc1ccc(F)cc1)c1nc(N2CCOCC2)cc(=O)[nH]1

Procedure:
The product is prepared according to the procedure described in example 70, using 0.023 ml of 4-fluoroaniline and 36 mg of ethyl 3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanoate in place of the ethyl [1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate. After purification by silica column chromatography, eluent: 940303 CH2Cl2/CH3CN/MeOH, 15 mg of N-(4-fluorophenyl)-3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[Br:34]N1C(=O)CCC1=O.ClC1C=CC=CC=1>O>[Br:34][CH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: Cc1c(Br)cccc1-n1nnn(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Clc1ccccc1
Solvent: O
Product: Cn1nnn(-c2cccc(Br)c2CBr)c1=O
Yield: 68.7 %

Procedure:
A mixture of 1-(2-methyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 10) 8.47 g, 1,1′-azobis(cyclohexane-1-carbonitrile) 1.54 g, N-bromosuccinimide 6.44 g and chlorobenzene 125 ml was stirred with heating under reflux for five hours. After cooling the mixture, to the reaction solutions was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-bromomethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 7.52 g.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[N:10]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]>C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]([C:14]1[C:9]([Cl:8])=[N:10][C:11]([Cl:15])=[CH:12][CH:13]=1)=[O:21]
Reactant: Clc1cccc(Cl)n1
Reactant: O=Cc1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(c1cccc(Cl)c1)c1ccc(Cl)nc1Cl

Procedure:
A THF solution of diisopropylamine was treated with 1.6M butyl]ithium/hexane solution. Thereafter, 2,6-dichloropyridine was added dropwise thereto together with THF and reacted, and then 3-chlorobenzaldehyde was further added dropwise. The reaction mixture was worked up and purified in a usual manner and the resulting compound was reacted with manganese dioxide in toluene under heating. The reaction mixture was worked up and purified in a usual manner to obtain 3-(3-chlorobenzoyl)-2,6-dichloropyridine. MS: 286.
Reaction SMILES: [SH:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:13][N:5]1[C:4](=[O:14])[C:3]2[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][S:1][C:2]=2[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]1=[O:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)Cn1c(S)cc(=O)n(C)c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-Mercapto-3-methyl-1-(isobutyl)-pyrimidine-2,4(1H,3H)-dione (49.5 g) was dissolved in dry DMF (900 ml) and ethyl bromopyruvate (30 ml) was added, and then with stirring anhydrous potassium carbonate (15.95 g) was also added. The mixture was stirred at room temperature for 5 h, and then poured into water (5 L). The aqueous solution was acidified with dil hydrochloric acid, and then extracted thoroughly with ethyl acetate. The organic extract was dried (MgSO4) and evaporated at high vacuum to leave a semisolid mass. A portion of this semisolid mass (24 g) was dissolved in methylene chloride (500 ml) and cooled in an ice-bath under an atmosphere of nitrogen. With efficient stirring titanium tetrachloride (13.5 ml) was slowly added. The reaction mixture was stirred 1 hr in the ice-bath and then 3 hr at room temperature. The reaction mixture was poured slowly into vigorously stirred ice-water (1.5 L), and then the resulting suspension was extracted into methylene chloride. After drying the organic solvent was removed in vacuo, and the residue was chromatographed (SiO2/1:1 ethyl acetate-isohexane) to afford the sub-title compound as a pale yellow solid 15 g. δ 1HCDCl3 1.0 (6H, d), 1.4 (3H, t), 2.31-2.45 (1H, m), 3.4 (3H, s), 3.8 (2H, d), 4.4 (2H, q), 7.28 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:21])=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=O)[N:6]=1.[NH2:22][C@@H:23]1[C:41](=[O:42])[N:25]2[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][O:31][C:32](=[O:37])[CH2:33][C:34](=[O:36])[CH3:35])[CH2:28][S:29][C@H:24]12>>[NH2:1][C:2]1[S:3][C:4]([Br:21])=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([NH:22][C@@H:23]2[C:41](=[O:42])[N:25]3[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][O:31][C:32](=[O:37])[CH2:33][C:34](=[O:36])[CH3:35])[CH2:28][S:29][C@H:24]23)=[O:10])[N:6]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1nc(N)sc1Br
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)OC(C)(C)C)c3nc(N)sc3Br)[C@H]2SC1
Yield: 99 %

Procedure:
2-(2-Amino-5-bromothiazol-4-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid are reacted and worked up in the manner Reference Example 40 to give the above-identified compound (99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[C:34]1([S:40]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([N:17]4[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]5[CH2:25][CH2:26][CH2:27][CH:18]45)(=[O:16])=[O:15])=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(O)C1CC2CCCC2N1S(=O)(=O)c1ccc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.5 mmol of benzenesulfonyl chloride in 6 ml of DMF were added. The reaction solution was then stirred at RT for a further 12 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3F)c(F)ccc2c1N
Yield: 66.3 %

Procedure:
Using method A, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (250.0 mg, 0.67 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (227.1 mg, 1.336 mmol) were reacted to afford the title compound (165.4 mg, 67% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.51 (bs, 1H), 7.90 (d×d, J=5.5 Hz, J=9.2 Hz, 1H), 7.53 (apparent triplet, J=8.9 Hz, 1H), 7.41 (t, J=8.5 Hz, 1H), 6.86 (d×d, J=2.4 Hz, J=8.5 Hz, 1H), 6.80 (d×d, J=2.4 Hz, J=11.6 Hz, 1H), 3.87 (s, 3H), 3.44 (q, J=6.7 Hz, J=12.8 Hz, 2H), 1.65 (apparent sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.3 Hz, 3H). MS APCI, m/z=373 (M+H) HPLC 2.78 min.
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:26])[CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:32]([C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1.[Cl-].[Na+].O>[CH3:2][N:3]([CH3:26])[CH2:4][CH2:5][CH:6]=[C:32]([C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=CCCN(C)C)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
2.97 g (6.93 mmol) of (3-dimethylaminopropyl) triphenylphophonium bromide was dissolved in 25 ml of tetrahydrofuran and 4.77 ml (7.63 mmol) of 1.6 M n-butyl lithium was added dropwise thereto under cooling in a dry ice-acetone bath. The mixture was stirred for 30 minutes under ice-cooling. A solution of 1.67 g (6.93 mmol) of methyl p-benzoylbenzoate in 15 ml of tetrahydrofuran was added thereto and the mixture was stirred for 30 minutes. Returning to room temperature, it was stirred for one hour. After brine was added, the reaction mixture was extracted twice with ethyl acetate, the extract was washed with brine, and dried (Na2SO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 15:1 (v/v)) to obtain 1.59 g (5.14 mmol) of methyl 4-(4-dimethylamino-1-phenyl-1-butenyl)benzoate as a pale brown oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [F:1][C@@H:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:4].C(OC1C=CC(C2C=CC(O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.F[C@@H](CCCCCC)C(Cl)=O.[F:58][C@@H:59]([CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:60][O:61][C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1>[F:58][C@@H:59]([CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[CH2:60][O:61][C:62]1[CH:70]=[CH:69][C:65]([C:66]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C:3](=[O:4])[C@@H:2]([F:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)=[O:67])=[CH:64][CH:63]=1
Reactant: CCCCCC[C@H](F)C(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCC[C@H](F)COc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCC[C@H](F)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC[C@H](F)COc1ccc(C(=O)Oc2ccc(-c3ccc(OC(=O)[C@@H](F)CCCCCC)cc3)cc2)cc1

Procedure:
0.02 mol of (S)-4-(2-fluorooctanoyloxy)-4'-hydroxybiphenyl (prepared by reaction of 4-benzoyloxy-4'-hydroxybiphenyl with (S)-2-fluorooctanoyl chloride in the presence of pyridine and subsequent removal of the benzyl group with hydrogenation), 0.02 mol of (S)-4-(2-fluorooctyloxy)benzoic acid and 0.002 mol of 4-dimethylaminopyridine are introduced into 30 ml of dichloromethane, a solution of 0.02 mol of dicyclohexylcarbodiimide is added dropwise at 10°with stirring, and the mixture is subsequently stirred at room temperature for a further 15 hours. Work-up gives (S,S)-[4-(2-fluorooctanoyloxy)-biphenyl-4'-yl] 4-(2-fluorooctyloxy)benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:4]=2[S:5][C:6]=1[CH:7]=O.[BH4-].[Na+].[CH3:16][NH2:17]>CO>[Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:4]=2[S:5][C:6]=1[CH2:7][NH:17][CH3:16]
Reactant: O=Cc1sc2c(F)cccc2c1Cl
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2c(F)cccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 3-chloro-7-fluoro-benzo[b]thiophene-2-carbaldehyde (610 mg, 2.78 mmol) in CH3NH2 (20 mL of a 2.0 M solution in MeOH, 40 mmol) was stirred at room temperature overnight. The mixture was concentrated. The residue was dissolved in EtOH (20 mL), and after cooling in an ice bath, NaBH4 (159 mg, 4.20 mmol) was added. The mixture was slowly warmed to room temperature and then stirred overnight. The mixture was concentrated. The residue was taken up in NaOH (20 mL) and the mixture extracted with Et2O (3×). The combined organics were washed with satd NaCl, dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, 95:5 CH2Cl2/MeOH) gave the title compound (460 g, 70%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=8.0 Hz, 1H), 7.38 (ddd, J=7.9, 7.9, 4.9 Hz, 1H), 7.06 (dd, J=8.8, 8.8 Hz, 1H), 4.09 (s, 2H), 2.53 (s, 3H), 1.55 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH:25](=[O:27])[CH3:26]>C1COCC1.C(OCC)(=O)C>[C:25]([NH:1][CH:2]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:27])[CH3:26]
Reactant: CC=O
Reactant: NC(COC(F)F)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC(COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of 2-amino-N-benzyl-3-(difluoromethoxy)propanamide (195 mg, 0.798 mmol) and triethylamine (322 mg, 3.19 mmol) in THF (5 mL), acetic hydride (98.5 mg, 0.958 mmol) was added. The reaction mixture was stirred at room temperature for an hour, diluted with ethyl acetate and washed with water. The organic layer was concentrated with silica gel and purified by column chromatography, eluting with 50-100% ethyl acetate in hexanes. The product was triturated with diethyl ether to give 2-(acetylamino)-N-benzyl-3-(difluoromethoxy)propanamide (135 mg, 59%) as a white solid, MP: 173.3° C. 1H NMR (300 MHz, CDCl3): (ppm) 7.25-7.39 (m, 5H), 6.68 (w, 1H), 6.42 (d, 1H), 6.24 (wt, 1H), 4.73 (m, 1H), 4.48 (d, 2H), 4.24 (dd, 1H), 4.01 (dd, 1H) and 2.05 (s, 3H).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[C:14]([CH3:16])[O:13][C:12](=[O:17])[C:11]=2[CH:18]=1)(=O)C.C1(N=C=NC2CCCCC2)CCCCC1>O.CO.C1COCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[N:15]=[C:14]([CH3:16])[O:13][C:12](=[O:17])[C:11]=2[CH:18]=1
Reactant: CC(=O)Oc1ccc2nc(C)oc(=O)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccc(O)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
Sodium hydroxide (4 g. 0.1 mol) was dissolved in water (4 ml) and methanol (50 ml). The 6-acetoxy-2-methyl (4H)3,1-benzoxazin-4-one (8.2 g, 0.04 mol), prepared above, in methanol (30 ml) was added, and the mixture refluxed for 3 hours. The solvent was removed by evaporation and the resulting sodium salt dissolved in water and acidified with hydrochloric acid. 5-Hydroxy N-acetyl anthranilic acid was collected as a beige solid and dried under vacuum. The dry solid (7.8 g, 0.04 mol) was then dissolved in dry THF (100 ml) and added to dicyclohexylcarbodiimide (8.24 g, 0.04 mol) in dry THF (50 ml). The mixture was stirred at room temperature for 18 hours and the insoluble urea removed by filtration. The filtrate was evaporated to dryness to give 6-hydroxy-2-methyl (4H)3,1-benzoxazin-4-one (2.7 g, 38%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[C:6](C(O)=O)[N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1.C(OCC)(=O)C>CN(C)C=O.[OH-].[NH4+].O.[Cu]=O>[Cl:2][C:3]1[CH:7]=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1cccnc1
Agent: O=[Cu]
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 120 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride (1.00 g, 3.65 mmol) was stirred in N,N-dimethylformamide (10 mL). Copper(II) oxide (58.0 mg, 0.730 mmol) was added and the reaction was heated at 120° C. for 16 hours, at which point the reaction was ˜20% complete. Additional copper(II) oxide (112 mg, 1.46 mmol) was added and the reaction was stirred for 5 hours, at which point the reaction was complete by thin layer chromatography (TLC) [Eluent: ethyl acetate]. The mixture was diluted with ammonium hydroxide (NH4OH) and water and extracted with ethyl acetate. The organic layer was washed with 15% lithium chloride and concentrated to provide an orange solid. The residue was purified by flash column chromatography using ethyl acetate as eluent and the pure fractions were concentrated to afford the desired product as a white solid (481 mg, 69.7%). The spectral characterization was in agreement with the product prepared previously.
Reaction SMILES: [H-].[Na+].[Si]([O:10][C:11]1[CH:20]=[C:19]([CH2:21]P(OCC)(OCC)=O)[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(C(C)(C)C)(C)C.[CH3:30][O:31][C:32]1[CH:39]=[C:38]([CH2:40][CH2:41][CH3:42])[CH:37]=[CH:36][C:33]=1[CH:34]=O.[NH4+].[Cl-]>CN(C=O)C>[OH:10][C:11]1[CH:20]=[C:19](/[CH:21]=[CH:34]/[C:33]2[CH:36]=[CH:37][C:38]([CH2:40][CH2:41][CH3:42])=[CH:39][C:32]=2[O:31][CH3:30])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCc1ccc(C=O)c(OC)c1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)c(O[Si](C)(C)C(C)(C)C)c1)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCc1ccc(/C=C/c2ccc(C(=O)OC)c(O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A solution of NaH (105.63 mg) in DMF (5.5 mL) was cooled to 0° C., and methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(diethoxyphosphoryl)methyl]benzoate (550 mg) was added thereto. The reaction mixture was warmed to 25° C., then stirred for 1 hour, and cooled to 0° C. again, and 2-methoxy-4-propylbenzaldehyde (235.34 mg) was added thereto. The reaction mixture was warmed to 25° C. and then stirred for 15 hours. To the reaction liquid was added a saturated aqueous NH4Cl solution (50 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 70:30) to obtain methyl 2-hydroxy-4-[(E)-2-(2-methoxy-4-propylphenyl)vinyl]benzoate (304.2 mg) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:16](N1C=CN=C1)(=[O:18])[CH3:17]>>[C:16]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)n1ccnc1
Reactant: c1ccc2c(Cn3ccnc3)c[nH]c2c1
Product: CC(=O)n1cc(Cn2ccnc2)c2ccccc21
Yield: 42.5 %

Procedure:
A mixture consisting of 3-(imidazol-1-ylmethyl)indole (0.97 g) and 1-acetylimidazole (1.10 g) was heated on a steam bath for a period of 3.5 hours to give an orange oil, which soon solidied on cooling. The resulting solid product was then chromatographed on silica gel. Elution with chloroform first gave some minor impurity, followed by the pure product. The product-containing fractions were then combined and subsequently evaporated to dryness while under reduced pressure to afford a solid residue, which was thereafter crystallized from ethyl acetate to yield pure 1-acetyl-3-(imidazol-1-ylmethyl)indole (yield, 0.50 g.), m.p. 122° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=[O:11])[CH3:10]>>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:9](=[O:11])[CH:10]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13]1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1c[nH]c2ccccc12
Product: O=C(C=Cc1ccccc1)c1c[nH]c2ccccc12

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and commercial 3-acetylindole, 1-(1H-indol-3-yl)-3-phenylprop-2-en-1-one was obtained as orange coloured solid.