Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].F[C:4]1[C:5](/[C:17](/[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:18]\[OH:19])=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[C:11]([OH:16])=[N:12][CH:13]=[N:14][CH:15]=1>C1COCC1.CN(C=O)C.C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[C:5]3=[N:6][CH:7]=[CH:8][C:9]([C:10]4[C:11]([OH:16])=[N:12][CH:13]=[N:14][CH:15]=4)=[C:4]3[O:19][N:18]=2)=[CH:21][CH:22]=1
Reactant: O/N=C(/c1ccc(F)cc1)c1nccc(-c2cncnc2O)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3)noc12
Temperature: 70 °C
Yield: 49 %

Procedure:
To a suspension of sodium hydride (0.030 g, 0.742 mmol) in THF (Ratio: 1.8, Volume: 2.272 ml) was added dropwise (Z)-(3-fluoro-4-(4-hydroxypyrimidin-5-yl)pyridin-2-yl)(4-fluorophenyl)methanone oxime (0.116 g, 0.353 mmol) in DMF (Ratio: 1.0, Volume: 1.262 ml) slowly. The reaction mixture was heated at 70° C. for 3.5 hr. Additional NaH (12 mg) was added. The reaction mixture was heated at 70° C. for 2.5 hr, and then allowed to cool to room temperature. The solvent was evaporated, and the mixture was further concentrated in vacuo to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-30% MeOH in CH2Cl2 over 25 min, tr=9 min) gave the title compound (53.4 mg, 0.173 mmol, 49.0% yield) as a yellow solid. ESI MS (M+H)+=309.1.
Reaction SMILES: C([N:4]([CH:23]1[CH2:25][CH2:24]1)[C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([F:22])=[CH:7][CH:6]=1)(=O)C.Cl>CO>[CH:23]1([NH:4][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:8]([F:22])=[CH:7][CH:6]=2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2F)CC1
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
A solution of 21.9 g (63 mmole) of 4-[6-(acetylcyclopropylamino)-3-fluoro-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 170 ml of 15% hydrochloric acid and 235 ml of methanol was refluxed for one hour and allowed to stir at room temperature for 18 hours. The methanol was removed in vacuo and the aqueous acid was made basic with 1.0N sodium hydroxide to pH 10.5. The mixture was extracted with chloroform, the chloroform layer washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 17.6 g of the title compound, mp 68°-70° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:17].C(N(CC)CC)C.ClC(OCC)=O.[NH2:42][OH:43]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:42][OH:43])=[O:24])=[O:17]
Reactant: NO
Reactant: O=C(O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
5-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)pentanoic acid (382 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (186 mg, 47%) as a brown solid. LC-MS (m/z) 398 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[C:60]([CH2:62][CH3:63])=[CH2:61].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:60]([CH2:62][CH3:63])=[CH2:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C=C(CC)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=C(CC)OC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33% methylene chloride in cyclohexane), sec-butenyl trichloroacetimidate (62 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (11 mg 4"-ether; 13 mg 3"-ether).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>CN(C)C=O.[Cl-].[Na+].O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:3]([C:1]#[N:2])[C:4]([O:6][CH3:7])=[O:5])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CC#N
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of methyl cyanoacetate (24.75 g; 0.25M) in dimethylformamide (70 ml) was added dropwise over 40 minutes to a stirred suspension of sodium hydride (8.25 g; 0.275M) in dimethylformamide (250 ml) at 0° under nitrogen atmosphere. The solution was stirred for 0.5 h, then a solution of 2-fluoronitrobenzene (17.65 g; 0.125M) in dimethylformamide (70 ml) added. After stirring for 16 h at room temperature, the red solution was poured onto excess brine, and extracted with ether (×6). The aqueous layer was then acidified with hydrochloric acid (5M) until the red colour was discharged. The resultant solution was extracted with ether (×4) and the combined organic extracts washed with brine, dried and evaporated to afford the title compound as a yellow oil (26.7 g; 97%) which slowly solidified.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][Si:6](C)([O:9][CH3:10])[O:7][CH3:8].C1(C)C=CC=CC=1.C([Si](C=C)(C)O[Si](C)(C)C)=C>C(O)(=O)C>[Cl:4][CH2:1][CH2:2][CH2:3][Si:6]([CH3:5])([O:9][CH3:10])[O:7][CH3:8]
Reactant: CO[Si](C)(C)OC
Reactant: C=CCCl
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CO[Si](C)(CCCCl)OC
Temperature: 50 °C
Yield: 40 %

Procedure:
306 mg Of allyl chloride, 530 mol of dimethyldimethoxysilane, and 77 mg of toluene were placed in a glass reaction tube and 0.01 ml of acetic acid was added to this mixture. Then, 0.005 mol of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed and heated for 2 hours in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of allyl chloride was 100% and γ-chloropropylmethyldimethoxysilane was produced at a yield of 40%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])(=[O:17])=[O:16])[NH2:14]>C(O)(=O)C>[OH:27][C:21]1[CH:20]=[CH:19][C:18]([S:15]([NH:13][N:14]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])(=[O:16])=[O:17])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 100 °C
Yield: 59 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 5-(hydrazinosulfonyl)-2-hydroxybenzoic acid. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 108 mg of the title compound (59%) as a yellow solid in 92.8% purity by HPLC (Rt: 4.85, gradient of 10 min, MaxPlot detection between 230 and 400 mn).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]([NH2:14])[CH2:6]2.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH:7]([N:14]1[CH2:10][CH2:11][CH2:3][CH2:4]1)[CH2:8]2
Reactant: COc1cc2c(cc1OC)CC(N)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CC(N1CCCC1)C2
Temperature: 100 °C

Procedure:
To a solution of 5,6-dimethoxy-2-aminoindan (Preparation 5, 4.5 mmol) in dimethylformamide/acetonitrile (1:6, 49 mL) was added sodium carbonate (1.43 g, 13.5 mmol) and was heated (100° C.) overnight. The mixture was diluted with ethyl acetate, filtered and the filtrate concentrated. The oily residue was chromatographed (400 g silica gel) eluting with methylene chloride/methanol (9:1) to yield a yellow oil. The oil was converted into the HCl salt and recrystallized from methanol/ethyl acetate: mp 267°-269° C.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH2:20][CH2:21][NH2:22]>ClC1C=CC=CC=1>[CH3:18][N:19]1[C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[C:10]([C:11](=[O:13])[N:22]2[CH2:21][CH2:20]1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: CNCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: Clc1ccccc1
Product: CN1CCN2C(=O)c3ccccc3C12c1ccccc1

Procedure:
22.6 Parts of o-benzoyl-benzoic acid are dissolved in 100 ml of chlorobenzene. 7.4 Parts of N-methylethylenediamine are added within 10 minutes. The temperature is then raised within 1 - 2 hours to such an extent that some chlorobenzene is continuously distilled off with the reaction water until the boiling point of the pure chlorobenzene (130°-132°) is attained. 80-90% of the theoretical amount of reaction water can be removed from the distillate. The remainder of the chlorobenzene is distilled off from the reaction mass in vacuo and the viscous oil which remains is crystallised by the addition of about 10 parts of ethyl acetate. The 1-methyl-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one so obtained of the formula ##STR10## is filtered off and recrystallised from a mixture of 30 parts of ethyl acetate and 30 parts of petroleum ether (B.P. 30°-60° ). M.P. 120°-122°.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1([C:7]2[N:12]=[C:11](C(Cl)(Cl)Cl)[N:10]=[C:9](C(Cl)(Cl)Cl)[N:8]=2)[CH2:6][CH2:5]1.[CH3:21][OH:22]>>[CH:4]1([C:7]2[N:12]=[C:11]([O:2][CH3:1])[N:10]=[C:9]([O:22][CH3:21])[N:8]=2)[CH2:6][CH2:5]1
Reactant: C[O-]
Reactant: ClC(Cl)(Cl)c1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Reactant: CO
Agent: [Na+]
Product: COc1nc(OC)nc(C2CC2)n1
Temperature: 25 °C

Procedure:
8.1 g of sodium methylate are added to a solution of 71.2 g of 2-cyclopropyl-4,6-bis-(trichloromethyl)-1,3,5-triazine in 200 ml of methanol, and stirring is maintained for 5 hours at room temperature. The solution is then evaporated to dryness, and the residue is stirred up with 200 ml of ether. The resulting suspension is filtered and the filtrate is concentrated by evaporation. The residue crystallises, and is recrystallised from ether/hexane. The yield is 35.7 g of the above triazine, m.p. 68°-70° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: OB(O)c1ccncc1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1ccncc1)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (120 mg, 0.29 mmol) and pyridine-4-boronic acid (72 mg, 0.59 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-60%EtOAc in hexane), the title product as a yellow solid. MP 229-234° C. MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O.[C:15](O)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:17])[CH3:16].[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)O
Agent: CCCCOC(=O)c1cccnc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1ccccn1
Reaction time: 63 h

Procedure:
An electrically heated tubular reactor with an i. d. of 12 mm was filled with 15 ml (≈15 g) of catalyst prepared according to EP-A-0 352 674, example 1. Over a period of 63 h, a mixture of butyl nicotinate (104 g), water (162 g) and acetic acid (606 g) was metered using a precision pump to the reactor operating at 405° C. From the reaction mixture, 30 g of acetyl pyridine, 3 g of pyridine and 26 g of butyl nicotinate were obtained. This corresponded to a yield of 43% 3-acetylpyridine at a butyl nicotinate conversion of 75% (selectivity 58%). The selectivity of pyridine formation was 5%.
Reaction SMILES: [F:1][C:2]1([F:41])[CH2:3][CH2:4][N:5]([C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:21][CH:20]=2)[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2/[C:8]/1=[CH:9]/[C:10]([O:12]C)=[O:11].O.[OH-].[Li+]>CO>[F:41][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:21][CH:20]=2)[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2/[C:8]/1=[CH:9]/[C:10]([OH:12])=[O:11]
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.8 %

Procedure:
Methyl (Z)-[4,4-difluoro-1-[4-(2phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate (857 mg) was dissolved in 10 ml of methanol, 2 ml of aqueous solution containing 195 mg of lithium hydroxide monohydrate was added dropwise to the above solution under ice-cooling, and the mixture was stirred at room temperature for 7 hours. After evaporating the solvent under a reduced pressure, 1N hydrochloric acid aqueous solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After evaporation of the solvent under a reduced pressure, the resulting residue was recrystallized from ethyl acetatehexane to obtain 633 mg of (Z)-[4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetic acid.
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]([CH3:25])([O:11][C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([OH:19])=O)=[O:13])[CH3:10].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:17](=[O:19])[C:16]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:15]=2[NH:14][C:12]([O:11][C:9]([CH3:8])([CH3:10])[CH3:25])=[O:13])=[CH:28][CH:29]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2c(C)cccc2NC(=O)OC(C)(C)C)cc1
Temperature: 18 °C
Reaction time: 16 h

Procedure:
Firstly N-methylmorpholine (6.15 mL. 5.64 g, 55.8 mmol) and then O-(benzotriazol-1-yl N,N,N′N′-tetramethyluronium hexalfuorophosphate (10.15 g, 26.8 mmol) are added to a stirred mixture of 2-{([(1,1-dimethylethoxy)carbonyl]amino}-6-methylbenzoic acid (5.60 g, 22.3 mmol) and p-toluidine 4.78 g, 44.6 mmol) in dry dimethylformamide (110 mL) under an argon atmosphere, and stirred at 18° C. for 16 hours. The solvent is evaporated off under reduced pressure to give a residue which is treated with aqueous sodium hydrogen carbonate solution (200 mL of 10%) and extracted with dichloromethane (3×100 mL). The combined extracts are washed with aqueous citric acid solution (100 mL of 10%), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 20% ethyl acetate in hexane, and recrystallised from tert-butyl methyl ether-hexane to give the title compound as a colourless crystalline solid, m.p. 250° C.
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[CH:9]([N:12]1[C:17](=[O:18])[CH2:16][O:15][CH:14]([C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[CH2:27][CH2:26][CH2:25]3)=[O:20])[CH2:13]1)([CH3:11])[CH3:10]>O.C(OCC)(=O)C>[OH:20][C:19]([O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH2:26][CH2:25]2)([CH:14]1[O:15][CH2:16][C:17](=[O:18])[N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13]1)[CH3:5]
Reactant: C1CCOC1
Reactant: CC(C)N1CC(C(=O)Oc2ccc3c(c2)CCC3)OCC1=O
Agent: C[Mg]Br
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N1CC(C(C)(O)Oc2ccc3c(c2)CCC3)OCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
After adding dropwise a solution of 5 g. of methyl magnesium bromide in 27 ml. of tetrahydrofuran to a mixture of 4.0 g. of 4-isopropyl-5-oxo-2-(1-oxo-5-indanyloxymethyl)morpholine and 100 ml. of tetrahydrofuran with stirring at room temperature, the mixture was stirred for 3 hours at room temperature. Then, after adding a small amount of water to the reaction mixture, the solvent was distilled off under reduced pressure. To the residue formed were added 50 ml. of ethyl acetate and 50 ml. of water to dissolve the residue and they were filtered. The ethyl acetate filtrate (100 ml.) was recovered, washed twice each with 50 ml. of saturated sodium chloride aqueous solution, and condensed under reduced pressure, the obtained residue was adsorbed on a silica gel column prepared from 100 ml. of silica gel in chloroform, and then eluted using ethyl acetate as the eluting solution. After removing the first 30 ml. of the ethyl acetate eluting solution emerging from the column, 300 ml. of the subsequent ethyl acetate eluting solution was collected and dried to provide 2.5 g. (yield 59.3%) of oily 2-(1-hydroxy-1-methyl-5-indanyloxymethyl)-4-isopropyl-5-oxomorpholine.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:8][C:9]([O:11]C)=O)[C:4]([Cl:7])=[CH:5][CH:6]=1.I.[NH2:14][C:15]1[NH:16][CH2:17][CH2:18][N:19]=1.[O-]CC.[Na+]>C(O)C>[Cl:7][C:4]1[N:3]([CH2:8][C:9]([N:14]=[C:15]2[NH:19][CH2:18][CH2:17][NH:16]2)=[O:11])[C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: NC1=NCCN1
Reactant: COC(=O)Cn1c(Cl)ccc1Cl
Agent: CC[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: O=C(Cn1c(Cl)ccc1Cl)N=C1NCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Methyl (2,5-dichloro-1H-pyrrol-1-yl)acetate (2.08 g.) was added to a solution of 2-aminoimidazoline hydroiodide (3.2 g.) and sodium ethoxide (from 0.35 g. of sodium) in ethanol (10 cm3). The solution was stirred at room temperature for 3 hr. and the precipitated title product collected by filtration (1.9 g.) m.p. 225°-227° C. The base was suspended in ethanol (25 cm3) and acidified with ethanolic hydrogen chloride to give the hydrochloride of the title compound (1.9 g.) m.p. 225° C.(d).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1SCC)[CH3:2].O[O:33][S:34]([O-:36])=O.[K+].O1CC[CH2:40][CH2:39]1>O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:34]([CH2:39][CH3:40])(=[O:36])=[O:33])[CH3:2]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1SCC
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(=O)(=O)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of methyl 7-(ethyloxy)-6-(ethylthio)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (10.32 g, 22.95 mmol) in tetrahydrofuran (150 mL) was added oxone (35.3 g, 57.4 mmol) in water (75 mL). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-15% ethyl acetate/methylene chloride) to give methyl 7-(ethyloxy)-6-(ethylsulfonyl)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.11 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ8.24 (s, 1H), 7.98-8.05 (m, 2H), 7.92 (d, J=7.78 Hz, 1H), 7.76-7.82 (m, 2H), 4.39 (q, J=6.94 Hz, 2H), 4.09 (s, 3H), 3.56 (q, J=7.28 Hz, 2H), 2.36 (s, 3H), 1.45 (t, J=6.90 Hz, 3H), 1.14 (t, J=7.40 Hz, 3H); MS (m/z) 482.1 (M+H+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]([CH3:10])[C:5](=[O:11])[C:4]=1[C:12](=[O:27])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:16]=1.[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][C:8]1[C:3]([OH:2])=[C:4]([C:12](=[O:27])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:16]=2)[C:5](=[O:11])[N:6]([CH3:10])[C:7]=1[CH3:9]
Reactant: BrBr
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(OC)cc(C)n(C)c2=O)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1cccc(C=CC(=O)c2c(O)c(Br)c(C)n(C)c2=O)c1
Reaction time: 1 h

Procedure:
To a solution of 0.50 g of 4-methoxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 15 ml of chloroform was added dropwise a solution of 70 μl of bromine in 7 ml of chloroform under ice-cooling. After stirred for 1 hour under ice-cooling, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.09 g of 5-bromo-4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (1d)] as a yellow crystal.