Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[O:8]([CH2:26][CH2:27][C:28]1([CH2:34][CH2:35][OH:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:37][S:38]([O:36][CH2:35][CH2:34][C:28]1([CH2:27][CH2:26][O:8][Si:9]([C:22]([CH3:24])([CH3:25])[CH3:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)(=[O:40])=[O:39]
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(CCOS(C)(=O)=O)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 104.1 %

Procedure:
After adding triethylamine (2.20 mL, 15.8 mmol) to a solution of 2-[1-(2-tert-butyldiphenylsiloxyethyl)cyclohexyl]ethanol (3.24 g, 7.80 mmol) in methylene chloride (25 mL), methanesulfonyl chloride (0.91 mL, 11.7 mmol) was added dropwise while cooling on ice. The mixture was stirred at room temperature for 40 minutes, and then saturated aqueous sodium hydrogencarbonate (300 mL) was added, extraction was performed with chloroform and the organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain the title compound as a yellow oil (3.97 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(OC(=O)C2CCCc3ccc([N+](=O)[O-])cc32)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54.2 %

Procedure:
In 20 ml of pyridine were dissolved 1 g of 7-nitro-1,2,3,4-tetrahydro-1-naphthoic acid and 560 mg of p-methoxyphenol. To the solution which had been cooled was added 700 mg of phosphorus oxychloride and the mixture was allowed to stand for 2 days. The reaction mixture was poured into ice water, made slightly alkaline with a 5% sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and concentrated under reduced pressure to remove the ethyl acetate. The residue was recrystallized from an ethyl acetate-hexane mixture to obtain 0.8 g of p-methoxyphenyl 7-nitro-1,2,3,4-tetrahydro-1-naphthoate, m.p. 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:34]([NH2:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:22])(=[O:16])=[O:15])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)CN
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Product: CC(C)(C)CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM) and 0.023 cm3 of neopentylamine. 69 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide are thus obtained in the form of a pale yellow powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.90 (s, 9H), 2.98 (s, 3H), 3.11 (d, J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.37 (t, J=6.5 Hz, 1H)].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([OH:23])=O)=[CH:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])=[CH:17]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(=O)O)[nH]c23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C(=O)Nc4ccccc4)[nH]c23)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 55 %

Procedure:
A mixture of 7-{[(4-methylphenyl)sulfonyl]amino}-1H-indole-2-carboxylic acid (110 mg), aniline (38 μL), ethyldiisopropylamine (0.29 mL), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (180 mg) and N,N-dimethylformamide (4 mL) was stirred at 60° C. for 7 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (75 mg, yield 55%) as colorless crystals. melting point 247-248° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>C1(C)C=CC=CC=1.O1CCCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:2]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)=[CH:6][CH:5]=2)=[O:3])[CH:20]=1
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: Nc1cccnc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccnc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was prepared by treatment of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50, 2.50 g, 10.20 mmoles) in toluene/tetrahydrofuran (3:1) with pyridine-3-amine (51, 0.960 g, 10.20 mmoles). The reaction mixture was stirred at room temperature for 16 hours, then concentrated. Yield: 3.21 g (93%). LCMS (HP walk-on); 2.89 min., 340.6, M+H.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH2:15]([C:17]([O-:19])=[O:18])[CH3:16].C(O)(=O)C.[I:24]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:24][C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[C:11]3[NH:12][CH:13]=[CH:14][C:10]=3[C:9]=2[CH:8]=1.[CH2:15]([C:17]([O-:19])=[O:18])[CH3:16]
Reactant: II
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Agent: [Ag+2]
Agent: CCC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
1.49 g (4.7 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid is added to a suspension of 1.61 g (5.17 mmol) of diiodine and 1.31 g (5.17 mmol) of silver sulfate in anhydrous ethanol (100 mL). The reaction mixture is stirred at room temperature for 6 hours then the solvents are evaporated under vacuum. The residue is taken up in water and the product is extracted copiously with a mixture of ethyl acetate/methanol 95/5. The organic phases are dried over magnesium sulfate, filtered on celite and evaporated under vacuum to give 1.4 g (78%) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.Cl[CH2:13][CH2:14][N:15]([CH2:23][CH2:24]Cl)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[CH2:16]([N:15]1[CH2:23][CH2:24][N:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: Nc1cc(F)cc2c1OCC2
Solvent: CCCCO
Product: Fc1cc2c(c(N3CCN(Cc4ccccc4)CC3)c1)OCC2
Yield: 73.3 %

Procedure:
A solution of 5-fluoro-7-amino-2,3-dihydrobenzofuran (1.38 g, 9 mmol) and bis(2-chloroethyl)-benzylamine (3.14 g, 14 mmol) in butanol (20 ml) was stirred at 100° C. for 10 hours. The salt was filtered off, washed with ethyl ether (30 ml) and dried under vacuum: mp 232-233.5° C. The salt was converted to the free base to afford 2.06 g (73%) of the title compound.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].N[C:7]1([O:16]O)[CH2:12][CH:11]([CH3:13])[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8]1.S([O-])([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O>[CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:13][CH:11]1[CH2:10][C:9]([CH3:15])([CH3:14])[CH2:8][C:7](=[O:16])[CH2:12]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCC=O
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
Butyraldehyde (14.4 g.) was mixed with petrol (b.p. 40° - 60°) (50 c.c.) and to the stirred solution at below 0°C was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g.; 89% pure). The peroxide dissolved within a few minutes. To the solution were added magnesium sulphate and concentrated sulphuric acid (6 drops) and the mixture stored at 0°C overnight. The solution was filtered, the filtrate washed with water, dried and distilled to give unreacted butyraldehyde, dihydroisophorone and a product (11.1 g.), b.p. 85° - 110°C/1.0 mm. with a peroxide equivalent of 231, and a perchloric equivalent of 233. The elemental analysis gave C, 68.6%; H, 11.05%; N, 6.6%. The product was identified as: ##SPC55##
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])[CH3:4].Cl[C:13]1[C:14]([N+:27]([O-:29])=[O:28])=[C:15]2[C:20](=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.O>O1CCCC1>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:13]1[C:14]([N+:27]([O-:29])=[O:28])=[C:15]2[C:20](=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[CH3:4]
Reactant: CCc1ccccc1S
Reactant: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])c2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccccc1Sc1cc(NC(C)=O)c2ncccc2c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Sodium hydride (0.09 g of 60% in oil) is added to 2-ethylthiophenol (0.26 g) in tetrahydrofuran (10 mL) and stirred for 15 minutes. N-(6-chloro-5-nitro-quinolin-8-yl)-acetamide (Gilman H., et al., Journal of American Chemical Society, 1946;66:1577) (0.5 g) is added and the mixture stirred at room temperature for 12 hours. The mixture is added to water (150 mL) and extracted with ethyl acetate (3×100 mL). The extracts are washed with saturated brine (150 mL), dried over magnesium sulfate, filtered, and evaporated to leave an oil. The oil is purified by chromatography on silica gel eluting with 50% ethyl acetate/hexane to give the title compound as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Sc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccncc2)c(F)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
21 g (188.9 mmol) of 4-mercaptopyridine, 30.05 g (188.9 mmol) of 3,4-difluoro-nitrobenzene and 60.05 g (434.5 mmol) of potassium carbonate are dissolved in dimethylformamide, and the mixture is stirred at 40° C. for 3 hours. The reaction solution is then diluted with 500 mL of ethyl acetate and 300 mL of water. The aqueous phase is extracted five times with in each case 100 mL of ethyl acetate. The combined organic phases are washed with 200 mL of saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure using a rotary evaporator. The residue is purified by MPLC (mobile phase: ethyl acetate:cyclohexane 1:1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(Cl)cc1Cl)C(=O)OCC
Temperature: 70 °C
Yield: 101 %

Procedure:
To a stirred solution of diethyl malonate (0.92 g, 5.71 mmol) in toluene (10 mL) was added 2,4-dichlorobenzaldehyde (1 g, 5.71 mmol), piperidine (23 μL, 0.23 mmol), acetic acid (13 μL, 0.23 mmol) and molecular sieves (3 Å). The reaction was heated to 70° C. for 2 days and was concentrated under reduced pressure. The residue was filtered through a pad of silica flushing with EtOAc/hexane (1:1) solution. The filtrate was concentrated to give diethyl 2-(2,4-dichlorobenzylidene)malonate (1.83 g, 97%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([Cl:9])=[C:7](Cl)[S:6][N:5]=1)[CH3:2].[CH3:11][S:12][O-:13].[Na+].CN(C=[O:19])C>C(OCC)C>[CH2:1]([O:3][C:4]1[C:8]([Cl:9])=[C:7]([S:12]([CH3:11])(=[O:19])=[O:13])[S:6][N:5]=1)[CH3:2]
Reactant: CCOc1nsc(Cl)c1Cl
Reactant: CS[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: CCOCC
Product: CCOc1nsc(S(C)(=O)=O)c1Cl
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of 3-ethoxy-4,5-dichloroisothiazole (19.8 g, 0.10 mol) in DMF (50 ml) under a nitrogen atmosphere was added sodium methanesulfenate (20.4 g, 0.20 mol). The mixture was warmed to 100° C. and stirred for two days. The reaction mixture was then cooled, diluted with diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel column, eluting with chloroform, to give 7.1 g of the title compound, mp 85°-87° , crystallized from cyclohexane. A by-product, 3-ethoxy-4,5-bis(methylsulfonyl)isothiazole (3.9 g) was also obtained, mp 158°-160° (crystallized from cyclohexane).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[CH2:20](I)[CH3:21]>>[CH3:19][N:2]([CH3:1])[C:3]([C:4]1([N:5]2[CH:9]=[C:8]([CH3:10])[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:6]2)[CH2:21][CH2:20][CH2:17]1)=[O:18]
Reactant: CCI
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Product: Cc1cn(C2(C(=O)N(C)C)CCC2)nc1-c1ccccc1

Procedure:
Following the procedure of Example 95, but substituting α-(3-bromopropyl)-N,N,4-trimethyl-3-phenylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and without the addition of ethyl iodide there was obtained N,N-dimethyl-1-(4-methyl-3-phenylpyrazol-1-yl)cyclobutanecarboxamide having a melting point of 87°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:20])([CH3:19])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].N1C=CC=CC=1.C(Cl)(Cl)Cl>O>[C:21]([O:18][CH2:17][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][CH:11]=1)([OH:20])[CH3:19])(=[O:23])[CH3:22]
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A mixture of 3 g. of 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, 5 ml. of acetic anhydride and 8 ml. of pyridine is allowed to stand for 15 hours at 20°, poured into ice water and worked up with chloroform and water to give 1-acetoxy-3-(2',4'-difluoro-4-biphenylyl)butan-3-ol.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:8][C:9](=[O:31])[CH:10]([S:29][CH3:30])[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[N:18]=[CH:17][C:16]([C:23]#[C:24][Si](C)(C)C)=[CH:15]2)([CH2:5][O:6][CH3:7])[CH3:4].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:23]([C:16]1[CH:17]=[N:18][C:19]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:11][CH:10]([S:29][CH3:30])[C:9]([NH:8][C:3]([CH2:5][O:6][CH3:7])([CH3:4])[CH2:2][OH:1])=[O:31])=[CH:21][C:20]=2[CH3:22])#[CH:24]
Reactant: COCC(C)(CO)NC(=O)C(Oc1cc(C)c2ncc(C#C[Si](C)(C)C)cc2c1)SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-2-(8-methyl-3-trimethylsilanylethynyl-quinolin-6-yloxy)-acetamide (650 mg) in methanol (16 ml) was treated with potassium carbonate (97 mg) at room temperature. The reaction mixture was stirred for 1 h. The reaction mixture was diluted with ethyl acetate and washed with sat. aq. sodium hydrogen carbonate. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (cyclohexane/ethyl acetate/dichloromethane 2:2:1) to give 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (480 mg) as a white solid as mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1nc(-c2ccc(F)cc2)cs1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1nc(-c2ccc(F)cc2)cs1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 29 %

Procedure:
This compound was synthesized from 2-(4-(4-fluorophenyl)thiazol-2-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (50 mg, yield 29%). 1H NMR (400 MHz, CDCl3) δ 9.45 (d, J=1.3 Hz, 1H), 9.24 (d, J=1.5 Hz, 1H), 8.80 (t, J=2.1 Hz, 1H), 7.86-7.82 (m, 3H), 7.35 (s, 1H), 7.11-7.07 (m, 2H), 4.05-4.00 (q, J=5.7 Hz, 2H), 3.41-3.38 (m, 2H). MS (ESI) m/z: Calculated for C20H13F4N5O2S: 463.07. found: 464.0 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][OH:26]>CN1CCCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:23]4[CH2:29][CH2:28][CH2:27][C@H:24]4[CH2:25][OH:26])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: OC[C@@H]1CCCN1
Agent: CN1CCCC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC[C@H]3CO)c(F)cc2c1=O

Procedure:
A solution of 3.1 g (0.01 mmol) of ethyl 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylate and 3.03 g (0.03 mmol) of L-prolinol in 15 ml of N-methylpyrrolidine was stirred at 80° C. for 2.5 hours. The solvent was removed by distillation under reduced pressure and the oily residue was recrystallized from ethyl acetate/ether. The resulting ester was saponified analogously to Example 1A. There was obtained 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[(S)-2-hydroxymethyl-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid, m.p. 209°-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:26]([Cl:42])=[CH:25][N:24]=1>>[Cl:42][C:26]1[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.022 g, 31%). MP: 52-76° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.50 (s, 1H), 8.56 (d, 1H, J=8.6 Hz), 8.15 (s, 1H), 7.96 (s, 1H), 7.92 (d, 1H, J=8.1 Hz), 7.63-7.57 (m, 1H), 7.48 (s, 1H), 7.28-7.22 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.57-3.51 (m, 2H), 3.47-3.42 (m, 2H), 3.33 (s, 6H), 3.31-3.20 (m, 1H), 3.06-2.99 (m, 1H), 2.88-2.68 (m, 8H), 1.32 (d, 6H, J=6.8 Hz). MS: 604.51 (MH)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:23])(=[O:3])[CH3:2].[CH3:24][C:25]1[N:26]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:29]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:27]3[N:26]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:25]([CH3:24])=[N:29][CH:28]=3)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2C(Nc2ccc(Cl)cc2)CC1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C)n1COCC[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cnc(C)n3COCC[Si](C)(C)C)cc2C(Nc2ccc(Cl)cc2)CC1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 52.9 %

Procedure:
[Step 1] 44 mg (cis:trans=3:1) of 1-acetyl-6-bromo-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline (compound 74) and 56 mg of 2-methyl-5-(tributylstannyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole were dissolved in 1 mL of DMF, and 6 mg of tetrakis(triphenylphosphine)palladium was added to the solution. The mixture was stirred in a sealed tube for 12 hours at 120° C. After completion of the reaction, DMF was distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate, and then the solution was filtered through Celite to remove any insoluble materials. The ethyl acetate solution was washed with water, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:aqueous ammonia=1:0.01). Thus, 31 mg (cis:trans=3:1, yield 53%) of 1-acetyl-6-{2-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1 H-imidazol-5-yl}-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a brown oily substance.