Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=[CH:3][CH:2]=1.[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](Cl)=[O:11].C1(C)C=CC=CC=1.[NH2:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])(C)C)=[O:29]>O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][CH2:31][CH2:34][CH2:2][CH3:3])=[O:29])=[O:11]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
0.090 mL of pyridine and 0.12 mL of 2,6-dichlorobenzoyl chloride were added to 3.0 mL of toluene solution containing 0.15 g of tert-butyl 2-amino-4-phenylbenzoate at room temperature sequentially, and the resulting mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and 0.023 mL of pyridine and 0.040 mL of 2,6-dichlorobenzoyl chloride were added sequentially and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and water was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain herb-butyl 2-(2,6-dichlorobenzamido)-4-phenylbenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][O:16][CH2:17][CH:9]1[CH2:10][N:11]([C:19]1[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)[C:12](=[O:18])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH3:45])[C:28]([C:30]1[N:39]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:33]2[N:34]=[C:35](Cl)[N:36]=[CH:37][C:32]=2[CH:31]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][O:16][CH2:17][CH:9]1[CH2:10][N:11]([C:19]1[CH:20]=[N:21][C:22]([NH:25][C:35]3[N:36]=[CH:37][C:32]4[CH:31]=[C:30]([C:28](=[O:29])[N:27]([CH3:26])[CH3:45])[N:39]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:33]=4[N:34]=3)=[CH:23][CH:24]=1)[C:12](=[O:18])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2COCC1CN(c1ccc(N)nc1)C(=O)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5COCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 75.2 %

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (350 mg, 1.047 mmol) was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (337 mg, 1.151 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butyl ester (476 mg, 0.787 mmol) in 75% yield.
Reaction SMILES: C[C:2]1([NH:18][C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH2:3]1.[H][H].[CH2:24](O)C>[C].[Pd]>[C:19]([NH:18][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([OH:9])[C:10]2[CH:11]=[CH:12][C:13]([CH3:24])=[CH:14][CH:15]=2)=[CH:16][CH:17]=1)(=[O:21])[CH3:20]
Reactant: [H][H]
Reactant: CC(=O)NC1(C)C=CC(OCC(=O)c2ccccc2)=CC1
Reactant: CCO
Agent: [Pd]
Product: CC(=O)Nc1ccc(OCC(O)c2ccc(C)cc2)cc1

Procedure:
10% Palladium-carbon (0.1 g) was added to a solution of 4-methyl-α-(4-acetamidophenoxy)acetophenone (XIII: R=CH3) (2.83 g, 0.01 mole) in ethanol (50 ml), and catalytic reduction was carried out at 25° C. for 2 hours during which 290 ml of hydrogen was absorbed. After removing the catalyst by filtration, after-treatment was carried out in the same manner as in Example 35 to obtain 2.55 g of β-(4-acetamidophenoxy)-α-(4-methylphenyl)ethyl alcohol (XIV: R=CH3) as white crystals (yield, 89.5%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[CH3:24][NH:25][CH3:26].CO>>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:25]([CH3:26])[CH3:24])[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Reactant: CNC
Solvent: CO
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccc(OC)cc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.12 g, 0.36 mmol), 2.0M dimethylamine in methanol (1.44 mL, 2.91 mmol) in sealed tube was stirred at 70-80° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate, brine, dried over anhydrous MgSO4, filtered and concentrated to give 90 mg of the titled compound (75% yield). 1H NMR (DMSO): δ 7.28 (d, 1H), 7.20-7.18 (dd, 2H), 7.06-7.00 (d, 1H), 7.00-6.98 (dd, 2H), 6.2 (d, 1H), 3.7(s, 3H), 3.4 (s, 3H), 3.22 (s, 3H), 3.18 (s, 6H). LC\MS: 339, (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[C:14]=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)cc(OC)c1OC

Procedure:
A mixture of 3,4,5-trimethoxyaniline (365 mg; 2.0 mmol) in toluene (20 ml) and phosgene (6 ml 20% in toluene; 12 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4,5-trimethoxyphenylisocyanate. The crude product was added 3-[4-(4-chloro-phenyl)-1-piperazinyl]propanol (800 mg; 3.1 mmol) in toluene (25 ml) and refluxed for 16 h. The solvent was evaporated and the residue taken up in ethanol, which was treated with hydrogen chloride in ether. Recrystallization from ethanol/ether afforded 620 mg of the title compound M.p. 173.5°-174.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br.[OH-].[Na+]>S(=O)(=O)(O)O.O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][CH:3]=1
Reactant: Cc1cccc(N)n1
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(N)ccc1Br
Temperature: 0 °C
Yield: 55.2 %

Procedure:
32.4 g(0.3 mole) of 6-aminopicoline was dissolved in a mixture of 28 g of conc. sulfuric acid and 120 ml of water and the resulting solution was cooled in ice water. 52.8 g(0.33 mole) of bromine was added dropwise to the solution over 30 minutes at 0° C. The reaction solution was stirred for 20 minutes at room temperature and neutralized with cold aqueous NaOH solution. The resultant was filtered and purified by column chromatography using methylene chloride and ethyl acetate as an eluent to obtain 31 g of the title compound(yield 55%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 29.2 %

Procedure:
DIPEA (149.8 mg, 0.2 mL, 1.15 mmol) was added to a stirred solution of 2-chloro-5-fluoro-benzoic acid (44.9 mg, 0.25 mmol) in DMF (3 mL). HOBT (38.2 mg, 0.28 mmol) and EDCI (123 mg, 0.34 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 35 mg (28.3% yield) of biphenyl-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.32%. 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 8.02-7.92 (d, 2H), 7.84-7.7 (q, 4H), 7.68-7.58 (m, 1H), 7.54-7.28 (m, 5H), 4.3-4.1 (dd, 2H), 3.8-3.44 (m, 6H), 3.26-3.12 (m, 2H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].Br[C:27]1[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=1>O.C1(C)C=CC=CC=1.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>[Br:33][C:30]1[CH:29]=[N:28][C:27]([C:11]2[CH:10]=[N:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:13][CH:12]=2)=[N:32][CH:31]=1
Reactant: CCCCCCOc1ccc(B(O)O)cn1
Reactant: Brc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Yield: 39.6 %

Procedure:
233 mmol of 2-hexyloxypyridine-5-boronic acid, 300 ml of ethanol, a solution of 466 mmol of sodium carbonate in 150 ml of water and 2.3 mmol of tetrakis(triphenylphosphine)palladium(0) are added to a solution of 233 mmol of 2,5-dibromopyrimidine in 600 ml of toluene. The mixture is heated at the boil until the reaction is complete. The organic phase is separated off, the aqueous phase is extracted with dichloromethane, and the combined organic extracts are dried using sodium sulfate. After the solvent has been removed in vacuo, the crude product is separated off by column chromatography on silica gel 60 using dichloromethane as eluent and is recrystallized from n-heptane, giving 31 g (40%) of a colorless solid. m.p. 103-106° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCNCC1
Product: COc1ccc(CN2CCC(=O)CC2)cc1

Procedure:
1-(4-Methoxybenzyl)-4-piperidone is prepared from 4-piperidone and 4-methoxybenzyl chloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:36])=[C:4]([CH:29]=[CH:30][C:31]=1[C:32](=[O:35])[CH2:33][CH3:34])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#N)=[CH:9][CH:8]=1.[OH-:37].[K+].[OH2:39]>C(O)C>[OH:1][C:2]1[C:3]([CH3:36])=[C:4]([CH:29]=[CH:30][C:31]=1[C:32](=[O:35])[CH2:33][CH3:34])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]([OH:39])=[O:37])=[CH:9][CH:8]=1
Reactant: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C)c1O
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CCO
Product: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Yield: 40 %

Procedure:
The title compound is prepared essentially as described in Preparation 113 employing 3-[[4-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (5.00 g, 10.3 mmol) and potassium hydroxide (11.6 g, 206 mmol) in ethanol (100 mL) and water (25 mL) at reflux for 3 days. Concentrate the reaction mixture and acidify with 1N hydrochloric acid, then extract with dichloromethane (3×). Combine organic layers, dry (sodium sulfatesodium sulfate) and evaporate to afford the title compound as a white solid (2.11 g, 4.18 mmol, 40%): MS (m/z): 503 (M−H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:4]=1[NH2:5].Cl.[N:12]([O-])=O.[Na+].[Cl:16][Sn]Cl>O>[ClH:16].[Br:2][C:3]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:4]=1[NH:5][NH2:12]
Reactant: Nc1cc(F)ccc1Br
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(F)ccc1Br
Reaction time: 0.08 h

Procedure:
To a mechanically stirred suspension of 2-bromo-5-fluoroaniline hydrochloride (94.7 g, 0.418 mol; obtained above) in a mixture of conc-HCl (250 mL) and water (250 mL) was added drop-wise a solution of sodium nitrite, NaNO2 (29 g, 0.420 mol) in water (60 mL) in a dry-ice/acetone bath, maintaining the bath temperature at −5–0° C. over a period of 10–15 min. Additional NaNO2 (1 g) was added and stirred at the same temperature for 5 min to obtain a clear solution. To this clear solution was added a solution of stannous chloride, SnCl2 (276.8 g, 1.46 mol) in conc-HCl (600 mL) drop-wise at 0–5° C. over a period of 30–40 min. A precipitate starts forming immediately after the addition. This thick mixture was stirred for another 1.5 h, and the precipitate was collected by suction-filtration, washed with a minimum amount of water (˜200 mL), then with diethyl ether, and dried in vacuo to obtain the title compound as an off-white powder: HPLC rt=0.73 min; LC/MS m/z 205 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 6.78 (1H, dt, J=8.5, 3 Hz, 5-CH), 7.04 (1H, dd, J=11, 3 Hz, 3-CH), 7.60 (1H, dd, J=8.5, 6 Hz, 6-CH), 8.15 (1H, s, NH), 10.49 (3H, brs, NH3+); 13C NMR (DMSO-d6, 125.8 Hz) δ ppm 102.6 (d, J=28 Hz, 3-CH), 103.4 (d, J=2.6 Hz, 1-C), 109.0 (d, J=23 Hz, 5-CH), 133.8 (d, J=9.6 Hz, 6-CH), 144.0 (d, J=10.7 Hz, 2-C), 161.7 (d, J=243 Hz, 4-CF).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:9]=1[CH2:26][CH2:27][OH:28]>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:9]=1[CH2:26][CH:27]=[O:28]
Reactant: Cc1c(CCO)n(S(=O)(=O)c2ccccc2)c2ccccc12
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(CC=O)n(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A mixture of chromium trioxide (1.2 g) and pyridine (1.9 g) in dichloromethane was stirred at ambient temperature for 15 minutes, and then 2-[3-methyl-1-(phenylsulfonyl)indol-2-yl]ethanol (630 mg) in dichloromethane [2 ml) was added. The resultant mixture was stirred at room temperature for 15 minutes. The separated organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel (eluted with 5% ethyl acetate in toluene) to give 3-methyl-1-(phenylsulfonyl)-2-indole acetaldehyde (423 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:2]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Yield: 67.5 %

Procedure:
A mixture of 1-bromododecane (43.5 g, 0.22 mol), 4-hydroxybenzaldehyde (25 g, 0.20 mol), potassium carbonate (69 g, 0.5 mol) and butanone (500 cm3) was heated under reflux for 24 hours. The cooled solution was filtered and the filtrate evaporated down under reduced pressure. The crude product was then distilled at 142° C.@0.6 mmHg, to give a liquid, which crystallised on cooling to yield 39.2 g (67.6%) of a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O-:18])=[O:17])[CH:11]=1.[CH2:19]1COCC1>>[F:1][C:2]([F:7])([F:6])[CH:3]([O:5][CH2:19][C:15]1[N:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)[CH3:4]
Reactant: O=C([O-])c1cccnc1
Reactant: C1CCOC1
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC(OCc1ccc(C(=O)O)cn1)C(F)(F)F
Reaction time: 0.25 h
Yield: 46 %

Procedure:
1,1,1-Trifluoropropan-2-ol (0.406 mL, 4.483 mmol) was added drop wise to a suspension of sodium hydride (60% in mineral oil) (0.239 g, 5.977 mmol) in dry THF (20 mL) at 0 C. The mixture was stirred at 0 C for 15 minutes. A solution of methyl 6-(methanesulfonyloxy)methyl]pyridine-3-carboxylate (Intermediate 189, 0.733 g, 2.989 mmol) in THF (10 mL) was added drop wise. The reaction mixture was stirred at 0 C for 30 minutes and room temperature for 3 days. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (30 mL). The phases were separated, and the organic phase was extracted with a saturated aqueous solution of sodium bicarbonate (3×15 mL). The aqueous extracts were combined, washed with EtOAc (1×10 mL). The organic phase was discarded and the aqueous phase was acidified to pH 4 using 2N HCl and extracted with EtOAc (3×30 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to provide a brown crude residue. The crude material was purified by flash chromatography (DCM:MeOH 98:2) to afford the title compound as a beige solid (0.345 g, 46%). Method B HPLC-MS: MH+ requires m/z=250 Found: m/z=250, Rt=1.61 min (89%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].[CH:18](=O)[CH2:19][CH3:20]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[CH:18][CH2:19][CH3:20])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Reactant: CCC=O
Solvent: CO
Product: CCC=NNC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100 mL volume three-necked flask, 10.0 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazine ((12-1)-(11)-39), 38 ml of methanol and 6.16 ml of propanal were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with hexane and dried under reduced pressure to give 9.44 g or 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-propylidenehydrazine ((40-a)-(14)-3).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[F:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][CH:41]=[C:40]2[CH2:46][CH2:47][CH2:48][C:49](O)=[O:50]>CO>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:40]2[C:39]3[C:43](=[CH:44][CH:45]=[C:37]([F:36])[CH:38]=3)[NH:42][CH:41]=2)[CH2:8][CH2:7]1
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)CCCc2c[nH]c3ccc(F)cc23)CC1
Reaction time: 24 h

Procedure:
A mixture of the diastereoisomers of (4-aminomethyl-1-phenylcyclohexyl)dimethylamine (465 mg, 2 mmol.) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (830 mg, 3 mmol.) was added to a solution of 4-(5-fluoro-1H-indol-3-yl)butanoic acid (443 mg, 2 mmol.) in abs. methanol (10 ml), and stirring was carried out for 24 h at RT. For working up, the mixture was concentrated, water (5 ml) was added to the solid residue, and the pH was adjusted to 11 with 2M NaOH. Extraction was carried out with EE (5×10 ml), and the combined extracts were washed with 1M NaOH (2×3 ml), dried, filtered and concentrated. The residue was a diastereoisomeric mixture of the bases of the target product, which was separated by flash chromatography on silica gel (50 g) and purified (eluant: 700 ml of ethanol/EE 1:1). 260 mg (0.59 mmol.) of the non-polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)butanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide were obtained in the form of a light-yellow viscous oil; the oil was dissolved in 2-butanone (7 ml), and chlorotrimethylsilane (113 μl, 0.89 mmol.) was added thereto. There immediately formed a white precipitate, which was deposited in a tacky manner on the wall of the flask. The solvent was reduced to about 3 ml in vacuo and, after addition of ether (3 ml), vigorous stirring was carried out at RT for 1 h. The solid that formed was filtered off with suction, washed with ether (3×1.5 ml) and dried in vacuo. The hydrochloride of the non-polar diastereoisomer of 4-(5-fluoro-1H-indol-3-yl)butanoic acid (4-dimethylamino-4-phenylcyclohexylmethyl)amide was thus obtained in the form of a hygroscopic solid in a yield of 272 mg.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31]C(NC(=O)CC2C=CC(F)=CC=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])C(OCCN3CCN(C)CC3)=CN2N=CN=1.[OH:45][C:46]1[N:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48]([OH:50])=O.CN(C(O[N:63]1N=NC2C=[CH:67][CH:68]=[N:69][C:64]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH:63]1[C:64]2=[N:69][CH:68]=[CH:67][C:11]([O:10][C:9]3[CH:8]=[CH:7][C:6]([NH:31][C:48]([C:47]4[C:46](=[O:45])[NH:54][CH:53]=[CH:52][CH:51]=4)=[O:50])=[CH:5][C:4]=3[F:3])=[C:16]2[CH:17]=[CH:30]1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Reactant: O=C(O)c1cccnc1O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1)c1ccc[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
To a stirred solution of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (24 mg, 0.1 mmol, Compound B of Example 132), 2-hydroxynicotinic acid (27 mg, 0.2 mmol), and HATU (76 mg, 0.2 mmol) in DMF (1 mL) was added DIPEA (0.1 mL) and DMAP (5 mg). The resulting mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was was purified by preparative HPLC to give the desired product (8 mg, 22%) as a white solid. LC/MS(ESI+) m/z 365 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:32]=[CH:31][C:24]([C:25](N(OC)C)=[O:26])=[C:23]([CH3:33])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:1]([C:3]([C:21]1[CH:32]=[CH:31][C:24]([CH:25]=[O:26])=[C:23]([CH3:33])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)N(C)OC)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide (0.76 g, 1.75 mmol) and THF (20 mL) is added 1M LAH in THF (1.75 mL, 1.75 mmol) with cooling, and the solution stirred for 1 hour. The solution is diluted with Et2O (100 mL) and washed with 1M HCl (50 mL). The aqueous phase is extracted with Et2O (50 mL). The combined organic layers are washed with 1M HCl (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.48 g, 1.21 mmol, 73%).