Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]1=[O:17].C(N(CC)CC)C.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:38][C:26]([F:25])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([S:33]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=3)[C:3]2=[O:17])(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: O=C1[C@@H](O)CCN1c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1[C@@H](OS(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1c1ccc(C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
To a dichloromethane (10 mL) solution of (3S)-3-hydroxy-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one (691 mg, 2.82 mmol), triethylamine (589 μL, 4.23 mmol), and 4-(dimethylamino)pyridine (69 mg, 0.56 mmol) at 0° C. was added a dichloromethane (10 mL) solution of 4-(trifluoromethyl)benzenesulfonyl chloride (827 mg, 3.38 mmol) dropwise. After stirring for 3 hours, the mixture was partitioned between diethyl ether (100 mL) and water (100 mL). The organic layer was washed with brine (2×100 mL), dried (magnesium sulfate) and concentrated to give the title compound, which was subjected to the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=7.9 Hz, 2H), 7.85 (d, J=7.4 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 5.25 (t, J=8.0 Hz, 1H), 3.98-3.93 (m, 1H), 3.85-3.81 (m, 1H), 2.81-2.75 (m, 1H), 2.49-2.43 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)(=[O:3])[CH3:2].[BrH:14].BrBr>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[N:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)=[O:3]
Reactant: CC(=O)c1cc2c(cn1)CCCC2
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cc2c(cn1)CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-acetyl-5,6,7,8-tetrahydroisoquinoline (287.7 mg, 1.64 mmol) and hydrobromic acid (25% solution in acetic acid, 3.1 ml) was added a solution of bromine (93.3 μl, 1.81 mmol) in acetic acid (0.4 ml) at 0° C. The mixture was stirred at room temperature for an additional 3 h. and concentrated. The residue was made basic with saturated aqueous hydrogen bicarbonate and extracted with diethyl ether (150 ml). The organic layer dried (MgSO4) and concentrated to afford 524.9 mg of the crude title compound as an brown oil.
Reaction SMILES: [C:1]([C@@H:4]1[CH:9]2[CH2:10][CH2:11][CH:6]([CH2:7][CH2:8]2)[NH:5]1)(=[O:3])[NH2:2].[CH2:12]([O:14][C:15]([C@@H:17]([NH:21][C@H:22]([C:24](O)=[O:25])[CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C@@H:17]([NH:21][C@@H:22]([CH3:23])[C:24]([N:5]1[C@H:4]([C:1](=[O:3])[NH2:2])[CH:9]2[CH2:10][CH2:11][CH:6]1[CH2:7][CH2:8]2)=[O:25])[CH2:18][CH2:19][CH3:20])=[O:16])[CH3:13]
Reactant: NC(=O)[C@H]1NC2CCC1CC2
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Product: CCC[C@H](N[C@@H](C)C(=O)N1C2CCC(CC2)[C@H]1C(N)=O)C(=O)OCC
Yield: 58 %

Procedure:
Using the (DCC/HOBT) peptide coupling method described by W. KONIG and R. GEIGER (Ber, 103, 788, 1970) the expected product is prepared from 0.02 mol of (3S)-3-carbamoyl-2-azabicyclo[2.2.2]octane, described in Patent FR 2,585,709, and 0.02 mol of (S)-N-[(S)-1-(ethoxycarbonyl)butyl]alanine, described by VINCENT et al (Tetrahedron Letters 23, (1982), 1677-1680), the product being purified by chromatography on silica gel (elution solvent: dichloromethane/ethanol, 90:10) and then lyophilized.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([NH:16][CH3:17])=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]([C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CNc1ccc(F)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)nc1)c1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
6-Chloronicotinoyl chloride (353 mg, 2.0 mmol) was dissolved in anhydrous DMF (2 mL) and slowly added to a stirring solution of 4-fluoro-N-methylaniline (242 μL, 2.0 mmol) and DBU (300 μL, 2.0 mmol) in anhydrous DMF (2 mL). After 90 minutes, the DMF was removed in vacu and the reaction was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate, filtered, and dried in vacu. The crude solid was purified by silica plug (1:1 ethyl acetate/hexanes) to yield 6-Chloro-N-(4-fluoro-phenyl)-N-methyl-nicotinamide as an off-white, glassy solid (411 mg, 77%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)([Cl:25])=O.[NH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[N:32][N:33]2[CH2:38][C:39]1[C:40](=[O:46])[N:41]([CH3:45])[CH:42]=[CH:43][CH:44]=1>CC(N(C)C)=O>[ClH:25].[ClH:25].[CH3:45][N:41]1[CH:42]=[CH:43][CH:44]=[C:39]([CH2:38][N:33]2[C:34]3[C:30](=[C:29]([NH:28][C:20]([C:17]4[N:14]5[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:12][C:13]5=[N:19][CH:18]=4)=[O:22])[CH:37]=[CH:36][CH:35]=3)[CH:31]=[N:32]2)[C:40]1=[O:46]
Reactant: CN1CCN(CCOc2ccn3c(C(=O)O)cnc3c2)CC1
Reactant: Cn1cccc(Cn2ncc3c(N)cccc32)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4cccn(C)c4=O)cnc3c2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
7-(2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.072 g, 0.21 mmol) was added to DMA (1 mL) and cooled to 0° C. Phosphorus oxychloride (0.038 mL, 0.41 mmol) was added and the reaction mixture was stirred for 30 minutes. 3-((4-Amino-1H-indazol-1-yl)methyl)-1-methylpyridin-2 (1H)-one (0.035 g, 0.14 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction was concentrated and then suspended in 2 M LiOH (2 mL). The resulting mixture was stirred for 30 minutes and then diluted with CHCl3 and saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with CHCl3. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by preparative thin layer chromatography (1:6 2.3 M NH3 in MeOH:CH2Cl2), added to MeOH (2 mL) and reacted with HCl (2 M in Et2O, 2 mL). The mixture was stirred for 60 minutes and then concentrated. The resulting solids were suspended in Et2O and filtered to provide N-(1-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (0.035 g, 41% yield) as a solid. MS (ES+APCI) m/z=541 (M+H-2HCl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([CH3:10])[CH:3]=1.Cl[CH:12]([O:14][CH3:15])Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:12]=[O:14].[CH3:10][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([S:8][CH3:9])[C:5]=1[CH:15]=[O:14]
Reactant: COC(Cl)Cl
Reactant: CSc1cc(C)cc(C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CSc1cc(C)c(C=O)c(C)c1
Product: CSc1cc(C)cc(C)c1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 129.8 %

Procedure:
A solution of 1,3-dimethyl-5-methylsulfanyl-benzene (8.95 g; 0.059 mol) in 120 ml of dry dichloromethane is cooled to −15° C. under nitrogen. Titanium tetrachloride (12.9 ml; 0.117 mol) is added dropwise, and the resulting dark solution is cooled to −78° C. Dichloromethyl methylether (7.4 ml; 0.082 mol) is then added dropwise during 30 min. and the temperature is allowed to rise to 0° C. After stirring for 20 min at 0° C., the reaction mixture is poured onto 80 g of ice and 10 ml of concentrated hydrochloric acid. The organic phase is separated, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. A yellow solid (10.5 g; 99%) consisting of a regioisomeric mixture of 2,4-dimethyl-6-methylsulfanyl-benzaldehyde and 2,6-dimethyl-4-methylsulfanyl-benzaldehyde is obtained, from which the pure 2,4-dimethyl-6-methylsulfanyl-benzaldehyde (6.9 g; 65%), m.p. 64-66° C., is isolated by recrystallization from hexane. 1H-NMR (CDCl3). δ [ppm]: 10.58 (s, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 2.60 (s, 3H), 2.46 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C1C=CC=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>C(Cl)Cl>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:22]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: [O-][n+]1cccc2ccccc21
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: c1ccc2nc(-c3c[nH]c4ccccc34)ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 6 %

Procedure:
To a solution of quinoline-N-oxide (0.5 mmol) in 2 mL DCM at 0° C. in a 3 mL plastic tube fitted with a frit was added 58 uL of benzoyl chloride (0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then indole (0.5 mmol) was added. The reaction was warmed to 20° C. and stirred for 4 h. The solid precipitate was filtered and washed with DCM (3×2 mL) to give solid 2-(3-indolyl)quinoline (6-100% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[O:21][C:20]=23)[CH:23]=1
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Reactant: CN(C)CCCN
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)NCCCN(C)C)c4)c3o2)cc(OC)c1OC
Yield: 33 %

Procedure:
Starting from 3-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]benzoic acid (0.062 mmol) and N,N-dimethyltrimethylendiamin (0.064 mmol) the product is prepared analogously to “A43” and obtained as yellow solid in a yield of 33%. HPLC (method A): Rt 2.45 min (purity 99.3%); LCMS (ESI+) (method E): Rt 1.56 min, M+H+ 490.3 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.82 (s, 1H), 8.77-8.68 (m, 1H), 8.60 (d, J=5.1, 1H), 8.27 (d, J=7.8, 1H), 8.01 (d, J=7.8, 1H), 7.78 (s, 1H), 7.77-7.69 (m, 2H), 7.37 (s, 2H), 3.93 (s, 6H), 3.74 (s, 3H), 3.49-3.18 (m, 2H), 2.45-2.10 (m, 8H), 1.78-1.63 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a white solid (229 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:11][C:6]1[CH:5]=[C:4]([C:2]2[O:3][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:1]=2)[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cc(Cl)cc(Cl)c2)oc1=O
Yield: 70 %

Procedure:
The title compound was prepared by Method A using 3,5-dichloroacetophenone (2 g, 10.58 mmol), trimethylsilyl triflate (2.35 g, 10.58 mmol), triethylamine (2.14 g, 21.16 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.64 g, 5.29 mmol). Isolated yield: 70% m.p. 168°-169° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.42 (m, 1H), 6.92 (d, 1H), 7.01 (s, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.83 (m, 1H), 7.88 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]([O:38]CC)=[CH2:37])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C(=O)N([Br:50])C(=O)C1>C1COCC1.O>[N+:1]([C:4]1[CH:42]=[CH:41][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=[O:37])[CH2:38][Br:50])=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C=C(OCC)c1cc(C#N)nc2cc(Cn3cc([C@](CC)(OC(=O)c4ccc([N+](=O)[O-])cc4)C(F)(F)F)nn3)ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-(1-{[2-cyano-4-(1-ethoxyvinyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (593 mg, 1.05 mmol) in THF (4 ml) and water (0.25 ml) was added NBS (205 mg, 1.16 mmol). The mixture was stirred at room temperature for 30 min. The solution was then evaporated to dryness and purified by flash chromatography (eluting solvent: 3% acetone in dichloromethane) to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.55 (s, 1H), 8.50 (s, 1H), 8.40 (d, 2H), 8.37 (d, 1H), 8.30 (d, 2H), 8.07 (s, 1H), 7.85 (d, 1H), 6.05 (s, 2H), 5.05 (s, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 1.15 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:33])[CH:39]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.34 mmol, see step (b) Example 9) and 3-chlorophenylboronic acid (10 mg, 0.68 mmol). Yield 180 mg (95%).
Reaction SMILES: [OH:1][C:2](C)([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])/[CH:3]=[CH:4]/[CH:5]1[CH2:7][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11]C)=[O:9].O1CCC[CH2:26][CH:25]1OC1CCCCO1.[OH:37][CH:38]([CH:54]([CH3:59])[CH2:55][CH2:56][CH2:57][CH3:58])/[CH:39]=[CH:40]/[CH:41]1[CH2:43][C:42]1([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45]>>[O:15]1[CH2:13][CH2:6][CH2:8][CH2:17][CH:16]1[O:37][CH:38]([CH:54]([CH3:59])[CH2:55][CH2:56][CH2:57][CH3:58])/[CH:39]=[CH:40]/[CH:41]1[CH2:43][C:42]1([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:49]([O:51][CH2:52][CH3:53])=[O:50].[CH2:25]([CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:38][CH3:39])[CH:2]([OH:1])/[CH:3]=[CH:4]/[CH:5]1[CH2:7][C:6]1([C:8]([O:10][CH3:11])=[O:9])[C:13]([O:15][CH3:16])=[O:14])[CH3:26]
Reactant: CCCCC(C)C(O)/C=C/C1CC1(C(=O)OCC)C(=O)OCC
Reactant: CCCCCC(C)(O)/C=C/C1CC1(C(=O)OCC)C(=O)OCC
Reactant: C1CCC(OC2CCCCO2)OC1
Product: CCCCC(C)C(/C=C/C1CC1(C(=O)OCC)C(=O)OCC)OC1CCCCO1
Product: CCCCCCC(CC)C(O)/C=C/C1CC1(C(=O)OC)C(=O)OC

Procedure:
In the same manner but using an equivalent amount of one of the compounds of formula 4 (R7 = H), for example, the compounds listed in Examples 17 to 40, instead of diethyl trans-2-(3-hydroxy-3-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate, then the corresponding tetrahydropyranyl ether compound of formula 4 (R7 = tetrahydropyranyl) is obtained, for example, the corresponding tetrahydropyranyl ether compounds of Examples 17 to 40, respectively. More specifically exemplified, in the same manner diethyl trans-2-(3-hydroxy-4-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate, described in Example 17 gives diethyl trans-2-{3-[(tetrahydropyran-2-yl)oxy]-4-methyl-1-octenyl}-cyclopropane-1,1-dicarboxylate, γmaxfilm 1035, 1140, 1220 cm-1, and dimethyl trans-2-(4-ethyl-3-hydroxyl-1-decenyl)cyclopropane-1,1-dicarboxylate, described in Example 24, gives dimethyl trans-2-{4-ethyl-3-[(tetrahydropyran-2-yl)oxy]-1-decenyl}-cyclopropane-1,1-dicarboxylate.
Reaction SMILES: [Br:1]Br.[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Br:1])[CH:13]=2)[NH:8][C:7]1=[O:16])=[O:4]
Reactant: BrBr
Reactant: O=CNC1Cc2ccccc2NC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=CNC1Cc2cc(Br)ccc2NC1=O
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Bromine (16.0 g, 0.1 mol) was added to a stirred solution of 3-(formylamino)-3,4-dihydro-2(1H)quinolinone (19.0 g, 0.1 tool) and anhydrous sodium acetate (12.7 g, 0.2 tool) in acetic acid (500 mL). After 1 hour, water (1.5 L) was added and the precipitate was filtered off and air dried to give 17.8 g of 3-(formylamino)-6-bromo-3,4-dihydro-2(1H)quinolinone, mp 275°-282° C. This was dissolved in trifluoracetic acid (300 mL) and sodium nitrate (9.0 g) was added to the stirred solution. After I hour, water was added and the precipitate was filtered off and air dried to give 18.2 g of 3-(formylamino)-6-bromo-3,4-dihydro-8-nitro-2(1H) quinolinone, mp 232°-235° C.
Reaction SMILES: [CH3:1][I:2].[CH:3]1([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH2:14][N:15]([CH3:17])[CH3:16])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CCOCC>[I-:2].[CH:3]1([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH2:14][N+:15]([CH3:1])([CH3:17])[CH3:16])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)Cc1cccn1C1CCCCC1
Reactant: CI
Solvent: CCOCC
Product: C[N+](C)(C)Cc1cccn1C1CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
A solution of methyl iodide (3.55 g) in dry ether (20 ml) was added dropwise to a stirred solution of 1-cyclohexyl-2-dimethylaminomethylpyrrole (4.12 g) in dry ether (50 ml) at 5°. The resulting mixture was stirred at room temperature for 5 hours and then allowed to stand overnight. The solid was filtered off, washed with ether and dried to give [1-cyclohexyl-pyrrol-2-yl]methyl trimethylammonium iodide (6.0 g), m.p.>250° (darkening ca. 190°).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].I[CH2:14][CH3:15].O>CCO>[CH2:14]([S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)[CH3:15]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of NaOH (0.13 g, 3.2 mmol) in EtOH (10 mL) was added 4-nitrothiophenol (0.50 g, 3.2 mmol) and iodoethane (0.26 mL, 3.2 mmol). After stirring 2 h the reaction mixture was added to water (30 mL) and extracted with Et2O (3×25 mL). The combined extracts were washed with satd NH4Cl (3×25 mL) and brine, dried (MgSO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex 0:100 to 30:70) to yield 1-ethylthio-4-nitrobenzene (0.35 g, 59%) as a yellow crystalline solid. 1H-NMR (CDCl3) δ 8.13 (2H, d, J=8.8), 7.32 (2H, d, J=8.8), 3.06 (2H, q, J=7.3), 1.41 (3H, t, J=7.3). The title compound was prepared from 1-ethylthio-4-nitrobenzene in a manner similar to that described in Example 3A: MS (ESI): 419 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:4].C(O)(C)(C)C.CC(C)([O-])C.[K+].Br[CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)C>[CH2:31]([O:30][C:28]([C:27]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:3]([OH:4])([CH:2]([CH3:1])[CH3:14])[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[O:9]1)=[O:29])[CH3:32]
Reactant: CC(C)C(=O)c1ccccc1C(=O)O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(C(=O)OCC)OC(=O)c2ccccc2C1(O)C(C)C
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
A stirred mixture of 2-(2-methylpropanoyl)benzoic acid (44.27 g) and tert-butanol (300 ml) was treated portionwise with potassium tert-butoxide (28.14 g) over 5 minutes at room temperature and the reaction mixture stirred for a further 10 minutes and then treated dropwise over 10 minutes with a solution of diethyl bromomalonate (55.1 g) in ethanol (200 ml). The stirred mixture was refluxed for 18 hours and then evaporated to dryness. The residue was treated with diethyl ether (400 ml) and washed with water (400 ml). The aqueous phase was re-extracted with diethyl ether (200 ml) and the combined ethereal extracts washed with water (200 ml), saturated aqueous sodium hydrogen carbonate solution (200 ml) and water (200 ml), dried over magnesium sulphate and evaporated to give crude 3,3-bis(ethoxycarbonyl)-4-hydroxy-4-isopropyl-3,4-dihydroisocoumarin (76 g) as an amber oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[C:18]([OH:26])([CH3:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.[Cl-].[Na+].O>[CH2:27]([O:26][C:18]([C:5]1[CH:6]=[CH:7][C:8]([O:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:9][C:4]=1[Cl:3])([CH3:25])[CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cn1cncn1)(OCc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reaction time: 18 h
Yield: 68.9 %

Procedure:
Sodium hydride (0.04 g) was added to a solution of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol (0.5 g) in THF (15 mL). After 30 min benzylbromide (0.27 g) was added and the mixture was stirred for 18 h at reflux. Brine was added and the mixture was extracted with dichloro methane (3×). The combined organic phases were dried, filtered through a silica plug and evaporated. The crude product was purified by column chromatography to yield 0.43 g of the desired compound.