Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](O)=[O:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl>C(N(CC)CC)C>[CH3:34][O:33][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:30]=1[O:31][CH3:32])[C:25]([N:4]([CH2:3][C:2]([CH3:1])=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:26]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(=Cc1ccccc1)CNCCN1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(CCN2CCCCC2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 12 %

Procedure:
Experimental condition analogous to Example 13 were used with (2-Methyl-3-phenyl-allyl)-(2-piperidin-1-yl-ethyl)-amine, 0.5 g (1.9 mmol), 3,4,5-trimethoxy benzoic acid 0.49 g (2.3 mmol), 0.2 ml of triethylamine, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 1.2 g (3.8 mmol). The reaction yielded 102 mg of an off-white solid as an HCl salt. Yield: 12%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Reactant: Oc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)cc(Oc2ccc(F)cc2)cc1C
Temperature: 100 °C
Yield: 69.2 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (4.50 g, 24.6 mmol), K3PO4 (10.5 g, 49.3 mmol), 4-fluorophenol (3.31 g, 29.5 mmol) in toluene (49.3 mL), was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (314 mg, 0.74 mmol), Pd(OAc)2 (233 mg, 1.04 mmol). The reaction was heated at 100° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (100 mL), and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4-(4-Fluorophenoxy)-2,6-dimethylphenyl)ethanone (4.40 g) as yellow oil in 68% yield: 1H NMR (500 MHz, CDCl3) δ 7.03 (m, 2 H), 6.98 (m, 2 H), 6.60 (s, 2 H), 2.47 (s, 3 H), 2.22 (s, 6 H).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][N:19]4[Si](C(C)C)(C(C)C)C(C)C)=[CH:11][C:10]=2[C:34]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:35])=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl.CSC>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][NH:19]3)=[CH:11][C:10]=1[C:34]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)=[O:35]
Reactant: COc1ccc(COc2ccc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)cc2C(=O)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CSC
Product: O=C(c1cccnc1)c1cc(-c2cccc3[nH]ccc23)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
To a solution of [2-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone (42 mg, 0.07 mmol) in dichloromethane (0.5 mL) and dimethylsulfide (0.5 mL) at 0° C. was added TFA (1 mL) dropwise. After stirring at 0° C. for 30 mins, the starting material was gone. Saturated aqueous NaHCO3 was added to adjust the pH of the mixture to around 6, and the reaction mixture was extracted with EtOAc several times. The combined EtOAc layers were washed with brine, dried and concentrated. Purification by silica gel column chromatography, followed by further preparative SFC chromatography afforded 3.1 mg (14%) of [2-hydroxy-5-(1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 11.87 (s, 1H), 9.13-8.89 (m, 1H), 8.88-8.69 (m, 1H), 8.37-8.23 (m, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.91 (dd, J=8.6, 2.1 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.49-7.40 (m, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.27-7.19 (m, 4H), 7.05 (d, J=7.4 Hz, 1H), 6.57 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([CH3:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(N(CC)C(C)C)(C)C.P([O-])(OCC)(OCC)=O.Cl>ClC(Cl)C.C(OCC)(=O)C.O>[Br:15][CH2:13][C:11]1[C:10]([F:14])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1cc(F)c(C)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CCOP(=O)([O-])OCC
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(CBr)cc1F
Temperature: 70 °C
Yield: 72.5 %

Procedure:
To a solution of ethyl 2,5-difluoro-4-methylbenzoate (Preparation 12, 450 mg, 2.25 mmol) in dichloroethane (10 mL) was added N-bromosuccinimide (520 mg, 2.92 mmol) followed by benzoyl peroxide (54 mg, 0.025 mmol). The reaction was heated at 70° C. for 5 hours then benzoyl peroxide (54 mg, 0.025 mmol) followed by N-bromosuccinimide were added. The reaction was heated at 70° C. for 3 days, then an aqueous solution of sodium thiosulfate (10 mL) and water (30 mL) were added. The organic phase was extracted with dichloromethane (3×20 mL) and the combined organic phases were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford a light yellow oil. The oil was dissolved in ethyl acetate (7 mL) and N,N-diisopropylethylamine (0.39 mL, 2.25 mmol) was added. The solution was cooled to 0° C. in an ice bath and diethyl phosphate (2.25 mmol, 0.22 mL) was added dropwise. The reaction was stirred at 0° C. for 2 hours before the addition of an aqueous solution of hydrochloric acid (2M, 3 mL). The organic phase was extracted with ethyl acetate (3×10 mL), and the combined organic phases were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude compound was purified by silica gel column chromatography eluting with heptane:ethyl acetate (gradient from 98:2 to 80:20) to afford the title compound as a colourless oil (455 mg, 75%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[NH:27][C:26]3[C:28]4[C:22]([C:23](=[O:29])[NH:24][N:25]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[N:11]1([CH2:15][C:16]2[NH:27][C:26]3[C:28]4[C:22]([C:23](=[O:29])[NH:24][N:25]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC2=Nc3cccc4c(=O)[nH]nc(c34)N2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)N=C(CN1CCCNCC1)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesized from compound 24. To a solution of 24 (1.5 g, 3.7 mmol) in 30 mL of CH2Cl2 was added 6 mL of TFA while stirring at room temperature. After 30 minutes, the solvents were evaporated and the residue was washed with acetonitrile to afford 1.0 g (90%) of analytically pure white solid. MP: 147-149° C.; MS (ES−): 297; 1H NMR (400 MHz, D2O): 1.96 (m, 2H), 2.82 (t, 2H), 3.01 (t, 2H), 3.28 (t, 4H), 3.53 (s, 2H), 7.22 (d, 1H), 7.47 (d, 1H), 7.61 (t, 1H). Anal. Calcd. for C15H18N6O. 1.1 CF3CO2H. 1.0 H2O.: C, 46.76; H, 4.81; N, 19.02; Found: C, 46.64; H, 4.98; N, 19.02.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33].CCN(C(C)C)C(C)C>>[CH2:32]([S:34]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]2[C:5]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:18]4=[N:19][CH:20]=3)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:10]1)(=[O:36])=[O:35])[CH3:33]
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCNC2)n1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCCC(Nc2nc(C)ccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
(1-Ethanesulfonyl-piperidin-3-yl)-{6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from {6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-piperidin-3-yl-amine, and ethanesulfonyl chloride, using 3 equivalents of DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]([N:15]=[N:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]=[N:30][CH:31]([C:35]([NH:37][C:38]4[CH:43]=[CH:42][C:41](C)=[CH:40][C:39]=4[CH3:45])=[O:36])[C:32]([CH3:34])=[O:33])=[C:25]([Cl:46])[CH:24]=3)=[CH:19][C:18]=2[Cl:47])[C:12]([CH3:14])=[O:13])=[O:10])=[C:4]([CH3:48])[CH:3]=1.ClC1C=C(C2C=CC(N)=C(Cl)C=2)C=CC=1N>>[CH3:45][C:39]1[C:38]([NH:37][C:35]([CH:31]([N:30]=[N:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]3[CH:21]=[CH:22][C:17]([N:16]=[N:15][CH:11]([C:9]([NH:8][C:5]4[C:4]([CH3:48])=[CH:3][CH:2]=[CH:7][CH:6]=4)=[O:10])[C:12]([CH3:14])=[O:13])=[C:18]([Cl:47])[CH:19]=3)=[CH:24][C:25]=2[Cl:46])[C:32]([CH3:34])=[O:33])=[O:36])=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(=O)C(N=Nc1ccc(-c2ccc(N=NC(C(C)=O)C(=O)Nc3ccc(C)cc3C)c(Cl)c2)cc1Cl)C(=O)Nc1ccc(C)cc1C
Agent: Nc1ccc(-c2ccc(N)c(Cl)c2)cc1Cl
Product: CC(=O)C(N=Nc1ccc(-c2ccc(N=NC(C(C)=O)C(=O)Nc3ccccc3C)c(Cl)c2)cc1Cl)C(=O)Nc1ccccc1C

Procedure:
The pigment suspension was prepared similarly to C.I. Pigment Yellow 13 by coupling 77 g of tetrazotized 3,3'-dichlorobenzidine (42 g of sodium nitrite) with 112 g of acetoacet-2-methylanilide.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[OH:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([O:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)=[O:13])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C(CO)Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1nc(Cl)nc(Cl)n1)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a 200 mL recovery flask was added cyanuric chloride (504 mg, 2.73 mmol, 1.0 eq.) and CH2Cl2 (50 mL). The solution was cooled to 0° C. In a separate flask, a solution of 2-hydroxy-N-(3-trifluoromethyl-phenyl)-acetamide (599 mg, 2.73 mmol, 1.0 eq.) and i-Pr2NEt (524 μL, 2.00 mmol, 1.1 eq.) in 10 mL was prepared and then slowly added to the reaction flask. The reaction was stirred for 2 h while warming to room temperature. The reaction was quenched with H2O (50 mL). The organic phase washed with brine (1×50 mL). The combined aqueous phases were extracted with CH2Cl2 (2×25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid. The crude material was purified via flash chromatography (1:4 EtOAc/Hexanes) to give 2-(4,6-dichloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (600 mg, 60%). LC/MSD (HP Series 1100 MSD) Expected MW: 365.99, Observed M+H: 367.0, Retention time: 1.59. 1H-NMR, DMSO-d6, Varian 400 MHz δ 11.19 (s, 1H), 10.63 (s, 1H), 8.08 (s, 1H), 7.75 (d, 1H), 7.59 (t, 1H), 7.44 (d, 1H), 4.99 (s, 2H) ppm.
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH3:7].[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:7]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCOCn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccn1COCC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1.6 M n-BuLi (12.0 mL, 19.2 mmol) is slowly added to a solution of 1-ethoxymethyl-1H-imidazole (2.20 g, 17.4 mmol; prepared essentially as described by Tang, et al. (1978) J. Am. Chem. Soc. 100:3918) in THF (30 mL) at −78° C. under N2. The reaction mixture is stirred at −78° C. for 20 minutes, whereupon tributyltin chloride (5.7 mL, 20.9 mmol) is slowly added. The reaction mixture is stirred at −78° C. for 10 minutes, and then warmed to room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture is concentrated in vacuo. The residue is triturated with hexanes and filtered, and the filtrate is concentrated in vacuo. The residue is again triturated with hexanes and filtered, and the filtrate concentrated in vacuo. The 1H NMR of the resulting oil indicates a 2:1 mixture of 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole: 1-ethoxymethyl-1H-imidazole. This material is used in the next reaction without further purification. Selected 1H NMR resonances (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.14 (s, 1H), 5.24 (s, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc(O)cc2o1
Reactant: CCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCOc1ccc2nc(C)oc2c1

Procedure:
37.3 g (0.1 mol) of 2-methyl-6-hexadecyloxybenzoxazole obtained by the reaction of 2-methyl-6-hydroxybenzoxazole with hexadecyl bromide was added to a mixture composed of 30 ml of hydrochloric acid and 300 ml of ethanol and the mixture was stirred at a temperature range between 40° C. and 50° C. for 1 hour. After cooling, the crystals deposited were collected by filtration and washed with ethanol to obtain 35.8 g of 2-acetylamino-5-hexadecyloxyphenol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:21]1[N:22]=[CH:23][N:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:25]=1)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:13]C(OC(C)(C)C)=O)=[CH:11][CH:12]=1)[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:21]1[N:22]=[CH:23][N:24]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:25]=1)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)c1cn(C2CCCCC2)cn1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Yield: 99.4 %

Procedure:
39.0 g (88.1 mmol) 3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-(1-cyclohexyl-1H-imidazol-4-yl)-propionic acid ethyl ester as prepared in process step b) were suspended in 200 ml Ethanol (EtOH) at RT. The mixture was saturated with HCl and was then refluxed for 2 h. The mixture was concentrated and the residue was treated with saturated aqueous K2CO3 (pH 9.0). The aqueous layer was extracted with AcOEt (3×200 ml). The combined organic layers were washed with brine (100 ml), dried with MgSO4 and concentrated to yield the title compound (30 g, 87.6 mmol, 99%) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[O:5]CC[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([OH:5])[CH:12]=[CH:13][C:14]=1[C:15]([F:17])([F:18])[F:16]
Reactant: C[Si](C)(C)CCOc1ccc(C(F)(F)F)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1COCCO1
Product: Oc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 125.2 %

Procedure:
To a solution of (2-(3-chloro-4-(trifluoromethyl)phenoxy)ethyl)trimethylsilane (Preparation 15, 3.1 g, 10 mmol) in 1,4-dioxane (5 mL) was added tetrabutylammonium fluoride (10 mL, 1M in THF) and the resulting mixture was stirred at room temperature for 18 hours under nitrogen. The mixture was poured onto water and neutralised with aq. ammonium chloride and extracted with ethyl acetate (3×30 mL). The organic layer was separated and washed with 1M sodium hydroxide (3×30 mL). The aqueous layers were separated, combined, acidified with aqueous 2M HCl and re-extracted with ethyl acetate (3×30 mL), dried (MgSO4), filtered and concentrated in vacuo to afford 2.46 g of a pale yellow oil. The crude oil was purified by silica gel column chromatography eluting with a gradient of 0-50% ethyl acetate in heptane to afford 619 mg (31%) of the title compound as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=2)[N:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH3:31])[C:2]1[C:11]([C:12]2[N:16]=[N:15][NH:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:24])([F:26])[F:25])[CH:8]=2)[N:3]=1)[CH3:28]
Reactant: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Reactant: CCNCC
Product: CCN(CC)c1nc2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1-c1nn[nH]n1

Procedure:
The title compound was prepared in analogy to example 102 step C from 2-chloro-4-phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-quinoline (prepared as described in example 102 step B) and diethylamine. Light yellow solid. MS (ESI): 413.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCc1cn(C(=O)OC(C)(C)C)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCc1cn(C(=O)OC(C)(C)C)c2ccc(O)cc12
Yield: 49.9 %

Procedure:
A solution of 5-benzyloxy-3-(2-dimethylamino-ethyl)-1H-indole-1-carboxylic acid tert-butyl ester (303 mg, 0.77 mmol) and 4N hydrochloric acid (192 ml, 0.77 mmol) in ethanol (10 ml) was hydrogenated over 10% palladium on carbon (100 mg) at 40 psi for 4 hours. The catalyst was removed by filtration. The filtrate was evaporated and the residue was partitioned between aqueous sodium hydrogen carbonate and dichloromethane. The aqueous was further extracted with dichloromethane (×2). The combined extracts were dried (K2CO3), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol/aqueous ammonia (60:8:1) to give the title compound (117 mg, 50%) as a colourless solid. δH (360 MHz, CDCl3) 1.64 (9H, s), 2.45 (6H, s), 2.73-2.80 (2H, m), 2.88-2.93 (2H, m), 6.82-6.85 (1H, m), 6.96 (1H, br s), 7.33 (1H, br s), 7.92 (1H, m). m/z (CI+) 305 [MH]+. Found: C, 64.07; H, 8.07; N, 8.71. C17H24N2O3. 0.8 H2O requires C, 64.01; H, 8.15; N, 8.78%.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>O>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:16].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)[c-]1cccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
A thoroughly dried, 2-L three-necked, round-bottomed flask was equipped with a mechanical stirrer, a funnel for the addition of air-sensitive solid, and a two-necked adapter holding a thermometer and a gas-inlet tube. The flask is charged with 74.4 g (0.4 mol) of ferrocene, 53.4 mL (0.4 mol) of 2-chlorobenzoyl chloride and 600 mL of CH2Cl2, and the addition funnel contains 56 g (0.42 mol) of AlCl3. The mixture was stirred in an ice bath and AlCl3 was added in small potions at such a rate that the reaction mixture remained below 5° C. This addition took about 20 min. and the mixture was stirred for 30 min. in the ice bath and was stirred for 2 h at rt. The reaction mixture was cooled in an ice bath and 400 ml of water was added. The mixture was loaded to a separatory funnel, the organic layer was separated, and aqueous layer was extracted with 400 mL of CH2Cl2. The combined CH2Cl2 solution are washed with 100 mL of water, 100 mL of 10% NaOH, 100 mL of brine and dried with Na2SO4. After filtration, the solution was evaporated to dryness at reduced pressure to give 129.2 g (>99%) of (2-chlorobenzoyl) ferrocene as a dark red solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:20]O.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(OC)cc1OC
Yield: 90 %

Procedure:
5-Bromo-2,4-dimethoxybenzoic acid (10.0 g) and con sulfuric acid (2.4 g) were added to methanol (80 mL). After reaction at 70° C. for 5 hr, completion of the reaction was confirmed by HPLC. The reaction mixture was cooled and adjusted to pH 7 with 2 mol/L aqueous sodium hydroxide solution, and ethyl acetate (50 mL) was added. The organic solvent was evaporated from the mixture under reduced pressure. To the concentrated residue was added ethyl acetate (50 mL), and the mixture was concentrated again under reduced pressure. To the concentrated residue was added ethyl acetate (70 mL), and the mixture was stirred and partitioned. The obtained organic layer was washed successively with water (50 mL), 5% sodium hydrogencarbonate (50 mL) and water (50 mL). After washing, ethyl acetate was evaporated under reduced pressure to give methyl 5-bromo-2,4-dimethoxybenzoate (9.4 g) (90%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:29])=[C:5]([C:20]([O:27]C)=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH:17]([CH3:19])[CH3:18])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:24][O:23][C:22]1[C:3](=[O:2])[C:4]([CH3:29])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH:17]([CH3:18])[CH3:19])=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:20](=[O:27])[C:21]=1[O:25][CH3:26]
Reactant: COc1c(C)c(Cc2ccc(OC(C)C)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)O)c2)=C(C)C1=O
Yield: 83.1 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-isopropoxybenzoic acid (0.472 g, 1.17 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (1.60 g, 2.92 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.364 g, 0.972 mmol, 83%).