Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9](I)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:13][N:14](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Brc1ccc(I)c2ncccc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1ccc(Br)c2cccnc12
Temperature: 95 °C

Procedure:
A mixture of 5-bromo-8-iodoquinoline (0.52 g, 1.55 mmol), Zn(CN)2 (218 mg, 1.86 mmol), and dppf (103 mg, 0.186 mmol) in DMF (2.5 mL) was purged with N2 (gas) for 5 minutes. Pd2(dba)3 (85 mg, 0.093 mmol) was added and the resulting mixture was heated at 95° C. for 5 h. After completion of the reaction, it was cooled to r.t., diluted with water, and the aqueous solution was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (5-25%) to get 5-bromoquinoline-8-carbonitrile as a brown solid (72 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.C(NC(C)C)(C)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.[Cu](I)I>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:3][C:4]=1[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1C
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(C#C[Si](C)(C)C)cc1C
Temperature: 45 °C

Procedure:
A solution of 4-bromo-1-methoxy-2-methylbenzene (6.702 g) in toluene was treated with tetrakis(triphenylphosphie)palladium (0) (1.15 g), followed by diisopropylamine (23 mL), trimethylsilyl acetylene (4.7 mL) and copper iodide (I) (0.127 g). The reaction was heated at 45° C. in nitrogen atmosphere overnight and evaporated to dryness. The resultant residue was applied on a large silica pad and eluted with hexane:ethyl acetate (2:1). The elute was evaporated to dryness to give the silane intermediate as a brown oil (7.167 g). The compound was characterized by LCMS analysis. LCMS Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% NH4OH in water; Solvent B 0.02% NH4OH in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11](I)=[CH:10][C:9]=1[N+:21]([O-:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:9]([N+:21]([O-:23])=[O:22])=[CH:10][C:11]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1F
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from [4-iodo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert.-butyl ester (Example B4) and 2-fluorophenylboronic acid according to the general procedure D. Obtained as a yellow solid (1.39 g).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=[N:19][CH:20]=3)[CH2:10][CH2:9]2)=CC=1>C(Cl)Cl.CO>[N:11]1([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:34]4[C:35]([Cl:45])=[C:36]([O:43][CH3:44])[CH:37]=[C:38]([O:41][CH3:42])[C:39]=4[Cl:40])=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)=[O:23])=[N:19][CH:20]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)nc3)CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)cn3)c3ncccc23)c1Cl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 105 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid {5-[4-(4-methoxy-benzyl)-piperazin-1-ylmethyl]-pyridin-2-yl}-amide (Example 166) and stirring the reaction mixture for 1 h at 120° C. Title compound: ESI-MS: 552.1 [M+H]+; TLC: Rf=0.12 (DCM/MeOH, 9:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=Cc2cc(OCc3ccc(Cl)cc3)ccc2S(=O)(=O)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
A mixture of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (300 mg), 4-chlorobenzyl chloride (210 mg), potassium carbonate (214 mg) and DMF (10 ml) was stirred at room temperature for 13 hours and at 50° C. for 3 hours. The reaction mixture was mixed with water and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[(4-chlorobenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (272 mg) as colorless crystals.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]1([C:40]2[C:41]([Cl:48])=[N:42][C:43]([CH2:46]Br)=[CH:44][CH:45]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C(#N)C.CO>[ClH:48].[C:34]1([C:40]2[C:41]([Cl:48])=[N:42][C:43]([CH2:46][N:22]3[C:23]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=4)=[CH:24][N:20]=[CH:21]3)=[CH:44][CH:45]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Clc1nc(CBr)ccc1-c1ccccc1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3ccccc3)c(Cl)n2)cc1
Temperature: 65 °C

Procedure:
To 1-trityl-4-(4-Cyanobenzyl)-imidazole (88.4 mg, 0.208 mmol) in acetonitrile (1 mL) was added 3-phenyl-2-chloro-6-bromomethylpyridine (53.5 mg, 0.189 mmol) and the mixture heated at 65° C. for 16 hours. The residue was dissolved in methanol (3 ml) and heated at reflux for 2 hours, cooled and evaporated to dryness. The residue was partitioned between sat. aq. Na2CO3 solution and CH2Cl2. The organic layer was dried, (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 2.5-3% MeOH in CH2Cl2) to afford the free base which was converted to the HCl salt by treatment with one equivalent of HCl in aqueous acetonitrile. Evaporation of solvent in vacuo afforded the title compound as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:7][CH:6]=1.[OH-].[Li+].Cl>CO.O>[C:29]1([CH3:32])[CH:28]=[CH:27][C:26]([S:23]([NH:22][C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=2[O:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:10][CH:9]=2)(=[O:24])=[O:25])=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)ccc2Oc2ccc(CC(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of {4-[2-(toluene-4-sulfonylamino)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester (97 mg, 0.202 mmol) in 1 mL of methanol was added 1 mL of a suspension of lithium hydroxide (42 mg, 1.01 mmol) in 1 mL of water. The resulting mixture was allowed to stir at room temperature until all starting material disappeared. Upon completion, 50 mL of 1N aqueous HCl was added and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with 1N HCl aqueous solution (20 mL), water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give 70 mg of {4-[2-(toluene-4-sulfonyl-amino)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid (1). 1H NMR (CD3OD): δ 7.84 (d, J=1.92 Hz, 1H), 7.58 (d, J=8.27, 1.6 Hz, 2H), 7.32 (dd, J=8.27, 1.6 Hz, 1H), 7.18-7.30 (m, 5H), 6.73 (d, J=8.53 Hz, 1H), 6.57 (d, J=8.53 Hz, 2H), 3.59 (s, 2H), 2.37 (s, 3H). LCMS (ESI−) 464 (M−1).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.C([Li])CCC.CCCCCC.CON(C)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:30])=[CH:5][CH:6]=1
Reactant: Brc1ccc(Br)s1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccc(F)cc1)c1ccc(Br)s1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85.9 %

Procedure:
A solution of 2,5-dibromothiophene (19.23 g, 75.5 mmol) in anhydrous THF (400 mL) was treated at -78° C. under nitrogen with a 2.5M solution of n-butyllithium in hexane (30.0 mL, 75.5 mmol). The resulting solution was stirred for 45 minutes at -78° C. and then transferred by cannula into a cold (-78° C.) solution of N-methoxy-N-methyl-4-fluorobenzamide (12.57 g, 68.6 mmol), prepared as in step 1, in anhydrous THF (300 mL) with siring. After 30 minutes at -78° C., the reaction was quenched by the addition of a saturated solution of NH4Cl (15 mL) and poured into ethanol (350 mL) containing 10% HCl (140 mL). The mixture was partitioned between brine and 1:1 ether and dichloromethane. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was crystallized from pentane to give 16.8 g (86%) of 2-bromo-5-(4-fluorophenylcarbonyl)thiophene.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12](C(C)=O)([CH3:14])=[O:13].O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:12]([C:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][C:1]([OH:11])([CH2:10]3)[CH2:2]1)[CH2:9]2)(=[O:13])[CH3:14].[C:1]12([OH:11])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(=O)C(C)=O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
A mixture of 0.3 mol of 1-adamantanol, 1.8 mol of biacetyl, 1.5 mmole of cobalt(II) acetate, and 300 ml of acetic acid was stirred at 60° C. in an oxygen atmosphere (1 atm) for 4 hours. The reaction mixture was concentrated to about 20% by weight, and was extracted with ethyl acetate, was dried, and was washed with hexane to yield 1-acetyl-3-adamantanol in a yield of 20% with a conversion rate from 1-adamantanol of 82%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:24])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1.C([Li])(CC)C.B(OC)(OC)[O:31]C.OO>C1COCC1.C1(C)C=CC=CC=1.O.C1CCCCC1.CCCCCC>[F:8][C:7]1[C:2]([F:1])=[C:3]([O:9][CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:24])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[CH:4]=[CH:5][C:6]=1[OH:31]
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3cccc(F)c3F)CC2)CC1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]C(C)CC
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: O
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(O)c(F)c3F)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15.7 g of 2,3-difluoro-1-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxybenzene was dissolved in 80 mL of THF, and 51 mL of sec-butyllithium (1.01 M hexane, a cyclohexane solution) was added dropwise thereto at an internal temperature of −45° C. or lower. Then, further stirring was continued for 30 min. To this solution, 5.9 g of trimethyl borate was added dropwise at an internal temperature of −40° C. or lower, and further stirring was continued for 30 min, and then the temperature was increased to 0° C. Then, 16 mL of water was added dropwise, and then 16 mL of 15% hydrogen peroxide solution was further added dropwise for 30 min. The stirring was continued for 3 hours. Water and toluene were added thereto, and the organic layer was fractioned while the aqueous layer was extracted with toluene. The organic layers were combined, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography and recrystallization, to thereby obtain 2,3-difluoro-4-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)methoxyphenol.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[NH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[CH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd+2].[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[NH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[C:11][C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1
Reactant: Clc1csc(Cl)n1
Reactant: C#CC(C)(C)N
Agent: [Cu]I
Agent: [Pd+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(C)(N)C#Cc1nc(Cl)cs1
Yield: 25.9 %

Procedure:
46.2 g (0.30 mol) of 2,4-dichloro-thiazole and 24.9 g (0.30 mol) of 3-amino-3, 3-dimethyl-1-propine are introduced into 300 ml of triethylamine. After 2.1 g (0.003 mol) of palladium(II)-bis(triphenylphosphine) dichloride, 2.28 g (0.012 mol) of copper(I) iodide and 3.2 g (0.012 mol) of triphenylphosphine have been added, the reaction mixture is refluxed for 19 hours. It is then filtered, the filtrate is concentrated under a water-pump vacuum, the residue is taken up in chloroform, and the mixture is extracted by shaking with dilute aqueous hydrochloric acid. The aqueous phase is rendered alkaline using sodium hydroxide solution and extracted several times by shaking with chloroform. After the organic phase has been dried over sodium sulphate, it is concentrated and the residue is chromatographed over silica gel (mobile phase: methylene chloride/methanol (96/4). 15.6 g (26 % of theory) of 3-amino-3, 3-dimethyl-1-(4-chloro-thiazol-2-yl)-1-propine with a melting point of 62-640° C. are obtained.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(Cl)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:1]2[O:13][C:5]([C:4]3[C:3]([CH:2]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:7])=[CH:18][CH:17]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2cc3ccccc3c(=O)o2)cc1
Temperature: 200 °C
Yield: 6 %

Procedure:
A well-stirred mixture of homophthalic acid (10 g; 56 mmol) and 2-(4-methoxyphenyl)acetyl chloride (10 g, 230 mmol) was heated at 200° C. for 3 hours under nitrogen then cooled to 50° C. and dissolved in toluene (100 ml), The solvent was removed in vacuo and the residue was dissolved in methanol (100 ml). Silica (30 g) was added and the solvent was removed in vacuo. The crude product, thereby adsorbed onto silica, was applied to the top of a column of silica and purified by chromatography using 10-50% mixtures of ethyl acetate and hexane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 3-(4-methoxybenzyl)isocoumarin (0.9 g, 26%) as an oil; δH 3.75 (3H, s), 3.80 (2H, s), 6.50 (1H, s), 6.95 (2H, d, J=8.9 Hz), 7.30 (2H, d, J=8.9 Hz), 7.40-7.90 (3H, m), 8.10 (1H, d); m/z (M+H)+. 267.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:15]1[NH:16][CH:17]=CN=1)=O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([N:16]([CH3:17])[CH3:15])=[O:6]
Reactant: CNc1ccc(C(=O)O)cc1Cl
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1ccc(C(=O)N(C)C)cc1Cl
Reaction time: 1 h

Procedure:
To 3-chloro-4-methylamino-benzoic acid (387 mg) in dry N,N-dimethylformamide (10 mL) was added carbonyl diimidazole (440 mg). After one hour, dimethylamine. HCl (221 mg) and triethylamine (0.38 mL) were added. The reaction mixture was stirred overnight, then diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification using flash chromatography yielded 3-chloro-N,N-dimethyl-4-methylamino-benzamide.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]=1[C:23](O)=[O:24].[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl>CN(C)C=O.[OH-].[Na+]>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][C:23]([C:3]1[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:13])([F:15])[F:14])=[O:24]
Reactant: O=C(O)c1c(Cc2ccccc2)nc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1c(Cc2ccccc2)nc2c(C(F)(F)F)cccc2c1O
Yield: 26.1 %

Procedure:
Using the procedure of Step F of Example 6, 8.6 g of the product of Step E and 2.47 g of 2-amino-thiazole were reacted in the presence of 5.59 g of dicyclohexylcarbodiimide in 125 ml of dimethylformamide to obtain a raw product which was dissolved in aqueous N sodium hydroxide. Addition of hydrochloric acid yielded 2.76 g of N-(2-thiazolyl)-4-hydroxy-2-phenylmethyl-8-trifluoromethyl-quinoline-3-carboxamide in the form of slightly ocre colored crystals melting at 256° C.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C1(O)CCC1.[CH2:13]([Sn:17]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]I)[CH2:14][CH2:15][CH3:16]>O.CCCCCCC.CN(C)C=O>[CH2:24]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][O:3][CH:7]1[CH2:6][CH2:5][CH2:4]1)[CH2:25][CH2:26][CH3:27]
Reactant: C1CCOC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)COC1CCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92 %

Procedure:
To a mixture of sodium hydride (66%, 250 mg, 7.0 mmol) and tetrahydrofuran (20 ml) were added cyclobutanol (0.55 ml, 7.0 mmol) and N,N-dimethylformamide (20 ml) at 0° C. (external temperature). Then, the reaction mixture was stirred at room temperature for 40 minutes. To the reaction mixture was added dropwise tributyl-iodomethyl-tin (2.0 g, 4.6 mmol) at 0° C. (external temperature). Then, the reaction mixture was stirred at room temperature overnight. To the reaction mixture were added heptane and water, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethylacetate=20:1) to obtain the title compound (1.6 g, 4.3 mmol, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1)O.Cl[Sn]Cl.[NH4+].[OH-]>CC(O)=O.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:13]1[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=1
Reactant: Cn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cn1ccnc1C(c1ccc(Cl)cc1)c1ccc(N)cc1Cl
Yield: 91 %

Procedure:
A mixture of (±)-α-(2-chloro-4-nitrophenyl)-α-(4-chlorophenyl)-1-methyl-1H-imidazole-2-methanol (0.0397 mol) and SnCl2 (0.2382 mol) in HOAc (150 ml) and HCl (150 ml) was stirred and refluxed for 2 hours, then cooled, poured out on ice, basified with NH4OH, filtered over celite and extracted with CH2Cl2 and CH3OH. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 12 g (91%) of (±)-3-chloro-4-[(4-chlorophenyl)(1-methyl-1H-imidazol-2-yl)methyl]benzenamine (interm. 24).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:18])([CH3:17])[CH:15]=[CH:16][C:6]3=[CH:5][C:4]=2[N:3]=1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH:8]=[C:7]3[O:13][C:14]([CH3:18])([CH3:17])[C@H:15]4[O:30][C@H:16]4[C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)C=C3
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H]1O[C@@H]31
Reaction time: 0.67 h
Yield: 94 %

Procedure:
To a solution of 7-chloro-2,2,9-trimethyl-2H-pyrano[2,3-g]quinoline (200 mg, 0.77 mmol) in ethyl acetate (3.0 mL), N-methyl imidazole (0.012 mL, 0.154 mmol) and ent-Ph,Ph salen manganese complex (8.0 mg, 0.0077 mmol) were added at room temperature and aqueous sodium hypochlorite solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise, and the resulting mixture was stirred for 40 minutes. Aqueous sodium hypochlorite solution (1.0 g, 1.513 mol/kg, 1.54 mmol) was added dropwise, and the resulting mixture was further stirred at room temperature for 30 minutes. Upon the completion of the reaction, aqueous sodium thiosulfate solution was added to the reaction solution, the resulting solution was filtered through celite and extracted. The organic phase was washed with aqueous sodium hydrogencarbonate solution and then with aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=10/1) to obtain (3S*,4S*)-7-chloro-3,4-epoxy-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinoline (yield: 94%).