Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:23]=[C:22]2[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][C:22]4[C:21]5[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=5)[N:25]=[CH:24][CH:23]=4)=[CH:33][CH:34]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(Cl)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 22.5 °C
Reaction time: 10 h

Procedure:
The solution from the previous step containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30° C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20 to 25° C. for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25° C. and then at approximately 45° C. under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:14][N:13]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:43][CH2:44][C:45](Cl)=[O:46]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][N:10]([CH:11]1[CH:15]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH2:14][N:13]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:12]1)[C:45](=[O:46])[CH2:44][Cl:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCNC1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of {2-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester (389 mg, 0.78 mmol) at 0° C., was added DIPEA (0.150 mL, 0.85 mmol) and chloroacetyl chloride (62 uL, 0.78 mmol). The reaction mixture was stirred at RT for overnight. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Hexane:1:2) to give the desired product (260 mg, 58% yield) as a colorless oil. MS: (ESI), M/Z, 574 (M+1). Retention time: 2.78 min (FA-polar).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=4)=[CH:20][CH:19]=2)=[CH:3][CH:2]=1
Reactant: O=c1c2ccccc2c2ccccc2n1-c1ccc(Br)cc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1COCCO1
Product: O=c1c2ccccc2c2ccccc2n1-c1ccc(-c2cccc3c2oc2ccccc23)cc1

Procedure:
23 g (110.0 mmol) of 4-dibenzofuranboronic acid, 38 g (110 0 mmol) of 5-(4-bromophenyl)-5H-phenanthridin-6-one and 44.6 g (210.0 mmol) of tripotassium phosphate are suspended in 500 ml of toulene, 500 ml of dioxane and 500 ml of water. 913 mg (3.0 mmol) of tri-o-tolylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water each time and subsequently evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/isopropanol and finally sublimed in a high vacuum, purity is 99.9%. The yield is 38 g (92 mmol), corresponding to 84% of theory.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](N(OC)C)=[O:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[Li]>O1CCCC1>[CH2:1]([N:4]([CH2:12][C:13](=[O:14])[C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[CH:2]=[CH2:3]
Reactant: [Li]c1cccs1
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=CCN(CC(=O)c1cccs1)C(=O)OC(C)(C)C
Yield: 56 %

Procedure:
To a solution of tert-butyl N-allyl-N-[2-(methoxy(methyl)amino)-2-oxo-ethyl]carbamate (25 g, 96.8 mmol) in tetrahydrofuran (339 mL) at −78° C. is added drop wise 2-thienyllithium (145 ml, 1 M in tetrahydrofuran) over 20 min. The reaction is carefully quenched with aqueous ammonium chloride (20 mL), diluted with water (100 mL), and extracted with dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (5:1) to give the title compound (15.2 g, 56%). ES/MS (m/e): 182 (M+H-100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[CH3:20]>>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[CH:13][C:12]=1[CH3:20]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: Fc1cccc(CBr)c1
Product: Cc1cc(C(=O)Cc2cccc(F)c2)ccc1Br

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 169 using 3-fluorobenzyl bromide and 4-bromo-3-methylbenzoyl chloride (Cignarella, G.; Curzu, M. M.; Grella, G.; Loriga, M.; Anania, V.; Desole, M. S.; J. Farmaco. Ed. Sci., 1983, 38, 187-198.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>>[C:13]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-acetamidobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (5.6 mg) with purity >90%. LCMS (pos) m/z 384.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1cncc(Br)c1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) solution of (5-bromo-3-pyridinyl)acetic acid (1.00 g, 4.63 mmol) in diethyl ether (17 mL) and methanol (11 mL) was added a solution of (trimethylsilyl)diazomethane in diethyl ether (2.0 M, 4.6 ml, 9.3 mmol). The reaction was warmed to room temperature and then quenched by the dropwise addition of acetic acid. Once gas evolution ceased, the solution was concentrated under reduced pressure. The resulting material was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (20-80% ethyl acetate in hexanes) provided the title compound: LCMS m/z 231.66 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 7.01 (s, 1H), 6.88 (s, 1H), 6.45 (s, 1H), 2.21 (s, 2H), 2.17 (s, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(C)C=CC=CC=1>[F:22][C:23]([F:34])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: CNC(=O)COC(=O)N1CCN(c2ccc(I)cn2)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(OC(F)(F)F)cc3)cn2)CC1
Yield: 34.4 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.4.). Starting with 0.250 g (0.61 mmol) of 2-(methylamino)-2-oxoethyl 4-(5-iodo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 5.5., 0.51 g (2.44 moles) of 4-(trifluoromethoxy)-phenylboronic acid, 0.61 g (˜8 mol %) of palladium catalyst on a solid support, prepared in step 2.1. of Example 2, and 2.9 ml (7.32 mmol) of aqueous sodium carbonate solution (2.5M) suspended in 12 ml of toluene and 3 ml of ethanol, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.092 g of product is obtained in the form of a white solid.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.S(=O)(=O)(O)O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: O=S(=O)(O)O
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of sulfolane were added 1.41 g of 7-ACA, 1.96 g of ferric chloride, 0.29 ml of concentrated sulfuric acid and 1.22 ml of trimethyl borate. The mixture was heated at 30° C. for 3 hours to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.00 g. The yield of the desired product was 79%.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:28][CH:29]([F:43])[O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([C:40]([OH:42])=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1.Cl.Cl.[NH:46]1[CH2:50][CH2:49][C:48]2([C:58]3[CH:57]=[CH:56][N:55]=[CH:54][C:53]=3[C:52](=[O:59])[O:51]2)[CH2:47]1.CN1CCOCC1.[C:67]([OH:73])([C:69]([F:72])([F:71])[F:70])=[O:68]>CN(C=O)C>[OH:73][C:67]([C:69]([F:72])([F:71])[F:70])=[O:68].[F:43][CH:29]([F:28])[O:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2([C:40]([N:46]3[CH2:50][CH2:49][C:48]4([C:58]5[CH:57]=[CH:56][N:55]=[CH:54][C:53]=5[C:52](=[O:59])[O:51]4)[CH2:47]3)=[O:42])[CH2:38][CH2:39]2)=[CH:35][CH:36]=1
Reactant: O=C1OC2(CCNC2)c2ccncc21
Reactant: O=C(O)C1(c2ccc(OC(F)F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(OC(F)F)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
BOP (0.18 g, 0.42 mmol) was added to a mixture of 1-[4-(difluoromethoxy)phenyl]cyclopropanecarboxylic acid (0.10 g, 0.46 mmol) and 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (0.10 g, 0.38 mmol) in DMF (2.5 mL). After 5 min, 4-methylmorpholine (0.2 mL, 2.0 mmol) was added to the mixture. The resulting mixture was stirred at room temperature overnight, then was adjusted to be acidic (pH=2.0) with TFA, and then was purified by prep-LCMS to give 1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one TFA salt. The purified salt was neutralized by an addition of NaHCO3 aqueous solution (7.5%). The mixture was extracted with ethyl acetate and the organic phase was concentrated to give 1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one. The desired stereo-isomer was isolated by chiral column to afford (1R)-1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (49.5 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:34].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][C:16]([Cl:34])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[C:24]([F:32])[CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Reactant: ClCCl
Solvent: CO
Product: CCCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
Subsequent chlorination (70° C.; 3h30) of 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-propyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.310 g; 5.071 mmol), and purification by FC (DCM/MeOH=50/1) afforded 1-chloro-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-propyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (1.130 g; 45%). LC-MS: tR=1.10 min.; [M+H]+=489.94 g/mol.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[N:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CC(C)=O>[N:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:2][C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: ClCc1cccs1
Reactant: O=NN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=NN1CCN(Cc2cccs2)CC1
Yield: 91.5 %

Procedure:
2-Chloromethylthiophene (prepared as described by F. F. Blicke and J. H. Burkhatter in J. Amer. Chem. Soc., 64, 477, 1947) (5.0 g, 0.038 mole) was added to acetone (100 ml) containing N-nitrosopiperazine (5.4 g, 0.038 mole) (prepared as described in U.S. Pat. No. 2,907,767), anhydrous potassium carbonate (6.0 g, 0.04 mole) and a catalytic amount of potassium iodide (1 small crystal). The mixture was heated under reflux for 3 hours, cooled, treated with water (50 ml) evaporated to 1/3 volume and extracted with ethylacetate (3×150 ml). The combined extracts were dried (anhydrous K2CO3), filtered and evaporated in vacuo to yield N-nitroso-N'-2-thenylpiperazine (7.35 g, >99%) as a straw coloured oil.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:29]([O:31]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)=[O:4].O.[NH2:36][NH2:37]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]2[C:19]3=[N:36][NH:37][C:29](=[O:31])[C:17]4[CH:16]=[CH:15][CH:14]=[C:13]([C:18]=43)[NH:12][CH:11]2[C:8]2[CH:7]=[CH:6][C:5]([C:3]([N:2]([CH3:34])[CH3:1])=[O:4])=[CH:10][CH:9]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1ccc(C(=O)N(C)C)cc1)N2
Reactant: NN
Solvent: O
Product: CN(C)C(=O)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
A mixture of ethyl 2-(4-(dimethylcarbamoyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (490 mg, 1 mmol) and hydrazine monohydrate (15 mL) was stirred at 40° C. for 3 h. Then the mixture was cooled to room temperature and filtered to give the title compound (110 mg, yield 24%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.82 (s, 1H), 2.93 (s, 1H), 4.36-4.38 (d, J=9.2 Hz, 1H), 4.78-4.80 (d, J=9.2 Hz, 1H), 7.01-7.03 (m, 2H), 7.14-7.19 (m, 3H), 7.25-7.28 (m, 2H), 7.32-7.40 (m, 3H), 7.45 (s, 1H), 7.56-7.60 (t, J=8 Hz, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 429 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])[CH:11]=[CH:10][C:9]=1[OH:19].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C)C=O>[CH:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]([O:19][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)=[C:8]([Cl:7])[CH:13]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCC(C)Oc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2ccc(F)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.30 g of potassium carbonate, 0.40 g of 2-chloro-4-sec-butoxyphenol, 0.37 g of p-fluorobenzyl bromide and 15 ml of N,N-dimethylformamide is stirred at room temperature overnight. The reaction mixture is poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts are combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give 1-sec-butoxy-3-chloro-4-(4-fluorobenzyloxy)benzene.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:15][N:16]([CH3:20])[C:17](=[O:18])[O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 76325.2 %

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g, 0.01 mole) and 4-dimethylaminopyridine (200 mg) in pyridine (25 ml) was added dimethylcarbamoyl chloride (0.95 ml, 0.01 mmole). After stirring for 18 hours additional dimethylcarbamoyl chloride (1.5 ml) was added and stirring was continued for 18 hours. The reaction mixture was poured into ice water and excess hydrochloric acid to give 2.3 g of (2-sulfamoyl-6-benzothiazolyl) N,N-dimethylcarbamate which melts at 208°-209° C. after recrystallization from 2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[C:4]([F:14])[CH:3]=1.[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:14])(=[O:10])=[O:9])[C:12](=[O:13])[NH:15]2)=[CH:21][CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1F
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1F
Yield: 40 %

Procedure:
1.12 g (4.77 mmol) of 4-chloro-2-fluorobenzenesulfonylisocyanate and 819 mg (4.77 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 742 mg of the above-identified compound (yield 40.0%). Properties: colorless crystal, Melting point: 267°-268° C., PMR (δppm, DMSO-d6):7.16 (1H,s), 7.24 (1H,d), 7.56 (1H,t), 7.73 (1H,d), 7.87 (1H,d), 8.10 (1H,t), 12.2 (1H,br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH3:7])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Solvent: O
Product: COc1ccc(C)cc1

Procedure:
The cooled reaction gas forwarded through the pipe 4 is introduced into the step (III) of condensation and collection which comprises condensers 5, 6, wherein the p-methoxybenzaldehyde, the unaltered p-methoxytoluene, formed water, and small amounts of by-products contained in the reaction gas are condensed and collected. The condensers 5, 6 are formed of ordinary multi-tube condensers or packed column type condensers. The condenser 5 is cooled with water and the condenser 6 is cooled with a coolant such as brine.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:32])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH3:16])[C:3]([C:17](=[O:32])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[C:2]([O:1][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)cc1OC
Reaction time: 1 h

Procedure:
Then, 10 ml of dimethylformamide was dropped into a mixture of 2.0 g of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone and 0.2 g of sodium hydride, and the mixture was stirred for 60 minutes. Then, 0.5 ml of methyl α-bromoacetate was added to the mixture at 0° C., and the mixture was stirred for 45 minutes. After the reaction, the solvent was removed from the reaction liquid mixture by distillation, and the residue was dried under reduced pressure to obtain substantially quantitatively 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a colorless transparent oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([SiH2][O:24][C:25](C1C=CC=CC=1)(C1C=CC=CC=1)[C:26]([NH:30][C:31](=[O:48])[CH:32]([O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][C:40]([C:46]#[CH:47])=[CH:39]2)[S:33][CH3:34])([CH3:29])[C:27]#[CH:28])(C)(C)C.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[C:46]([C:40]1[CH:41]=[N:42][C:43]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:35][CH:32]([S:33][CH3:34])[C:31]([NH:30][C:26]([CH2:25][OH:24])([CH3:29])[C:27]#[CH:28])=[O:48])=[CH:45][CH:44]=2)#[CH:47]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)CO)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of tetrabutylammonium fluoride (1 M) in THF was added dropwise to a solution of N-[1-(tert-butyl-diphenyl-silanyloxymethyl)-1-methyl-prop-2-ynyl]-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (1.49 g) at 0° C. The reaction mixture was allowed to warm up to room temperature, further stirred for 1 h 20 and then, poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine and then dried over sodium sulphate. After filtration and concentration under reduced pressure 2.47 g of crude mixture were isolated as a yellow oil. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate) to give 0.646 g of 2-(3-Ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-1-methylprop-2-ynyl)-2-methylsulfanyl acetamide as a white solid (m.p.=150-150° C.).