Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1([CH3:47])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5C=[CH:30][CH:29]=[CH:28][C:27]=5CCC=C)[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:38]([O:40][CH3:41])=[O:39])[CH2:7][CH2:6]1)C=C.[CH3:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].CCOC(C)=O>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:43]([O:42][C@@H:37]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:47])([O:4][CH2:48][CH:49]=[CH:50][CH2:51][CH2:52][C:53]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:38]([O:40][CH3:41])=[O:39])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCCCCC
Reactant: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(N4CCC(C)(OCC=C)CC4)n3n2)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OC/C=C\CCc1ccccc1-c1cccc-3c1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CCCc1ccccc1-c1cccc-3c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (116 mg, 0.182 mmol) was dissolved in DCE (150 mL). The solution was heated to 75° C. in an oil bath under an N2 atmosphere. Once the reaction flask had reached 75° C. the Hoveyda-Grubbs Catalyst 2nd generation (11.45 mg, 0.018 mmol) was added. The yellow reaction mixture turned green. Stirring at 85° C. was continued for 2 h at which time the reaction appeared complete by TLC (4:1 hexane/EtOAc) and HPLC (˜4:1 mixture of E/Z isomers). The cooled reaction mixture was concentrated in vacuo and purified by Biotage chromatography (0-50% EtOAc/hexanes) to give 84 mg of the desired product as a colorless oil. LCMS (M+H).=609.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:31]([O:30][C:26]1[C:25]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][C:27]=1[CH:14]=[O:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(C=O)c1ccccc1
Reactant: c1ccc(COc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Kolonits, P. et al., Acta Chim. Hung. 113:367 (1983). POCl3 (155 mL, 1.66 mol) was slowly added to N-methylformanilide (175 mL, 1.4 mol) at room temperature under Ar which resulted in formation of a yellow solid. After 2 h, the solid was treated with a solution of 1,2,3-tribenzyloxybenzene 8 (20 g, 51 mmol) in anhydrous DMF (40 mL) and heated to 60° C. After 3 h, the resulting crimson solution was cooled to room temperature and then poured into ice water (3 L) with vigorous stirring for 12 h. The resulting brown precipitate was filtered, washed with hexanes (3×100 mL) and finally recrystallized from MeOH to afford 10 (19.8 g, 93%) as a white powder. mp 73-74° C. 1H NMR (CDCl3): δ10.11 (s, 1 H), 7.57 (d, J=9 Hz, 1 H), 7.44-7.28 (m, 15 H), 6.83 (d, J=9 Hz, 1 H), 5.21(s, 2 H), 5.16 (s, 2 H), 5.08 (s, 2 H); 13C NMR (CDCl3): δ188.8, 158.5, 155.9, 141.1, 136.9, 136.2, 135.8, 128.6, 128.5 (2), 128.3 (2) 128.2, 127.5, 124.0, 109.1, 76.8, 75.5, 70.9. Anal. Calcd for C28H24O4: C, 79.22; H, 5.70. Found: C, 79.17; H, 5.80. HRMS (FAB) calcd for C28H24O4 (M+H+): 424.1675. Found: 424.1669.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)=[O:16]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][CH3:13])=[CH:18][CH:19]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: CC(O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(=O)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26.5 g of 1-(4-chlorophenyl)-ethanol are added dropwise to 7.9 g of sodium hydride (55% in oil) in 250 ml of dimethylacetamide and the mixture is stirred at room temperature for 30 minutes. 25.7 g of 4-fluoropropiophenone are then added dropwise; the mixture is heated to 100° C. and stirred for 90 minutes. After cooling, the reaction mixture is concentrated in vacua; the residue is taken up in ethyl acetate, washed twice with water and once with saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated off in vacuo and the residue is purified by recrystallisation from hexane to yield the title compound having a melting point 70-71° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:13][C:14]([O:16]CC)=[O:15].[Li+].[OH-].CO.Cl>C1COCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[NH:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNc1n[nH]c2ccc(C(F)(F)F)cc12
Reaction time: 2 h

Procedure:
Preparation I6, Step 3: A sample of ethyl 2-(5-(trifluoromethyl)-1H-indazol-3-ylamino)acetate (75 mg) was dissolved in THF (6 mL). The resulting solution was charged successively with an aqueous solution of LiOH (12.5 mg in 2 mL water) and methanol (2 mL). The reaction mixture was stirred for 2 h before being acidified with 1N HCl and extracted with EtOAc. The organic extracts were combined, washed with water and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford 2-(5-(trifluoromethyl)-1H-indazol-3-ylamino)acetic acid. MS found: (M+H)+=260.22.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[OH:20]O.O>C(O)(=O)C>[NH2:1][C:2]1[N+:10]([O-:20])=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: OO
Reactant: Nc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1c2ncn(Cc3c(Cl)cccc3Cl)c2nc[n+]1[O-]
Reaction time: 120 h
Yield: 40 %

Procedure:
The crude 6-amino-9-(2,6-dichlorobenzyl)purine obtained from the initial reaction was dissolved in one liter of acetic acid. A 30% aqueous solution of hydrogen peroxide was then added in the amount of 350 milliliters. The solution was allowed to stand for 5 days at room temperature, after which about 400 milliliters of water was added and the solution was cooled. The resulting precipitate was recovered by filtration, reslurried in 500 milliliters of a 30% aqueous solution of acetic acid, and then in one liter of water. The solids recovered from the aqueous slurry were vacuum dried to yield 75 grams of a crude 6-amino-9-(2,6-dichlorobenzyl)purine-N1 -oxide having a melting point of 296°-301° C, representing a 40 percent yield. An analytical sample of the same having a melting point of 298°-302° C. was prepared by recrystallization from acetic acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1.[O:34]1CCC[CH2:35]1>CCCCCC.[Cl-].[Na+].O.C(O)(=O)C.CN(C)C=O>[F:21][C:22]1[C:29]([CH:35]=[O:34])=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:31])([F:32])[F:33])[CH:23]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: N#Cc1cc(C=O)c(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution (75 mL) of diisopropylamine (3.89 mL) in tetrahydrofuran was added dropwise 1.6 mol/L solution (17.30 mL) of n-butyllithium in hexane at 0° C., and the mixture was stirred for 30 min. To the prepared lithium diisopropylamide was added dropwise a solution (25 mL) of 4-fluoro-2-(trifluoromethyl)benzonitrile (3.00 g) in tetrahydrofuran at −78° C., and the mixture was stirred at the same temperature for 20 min. N,N-Dimethylformamide (2.14 mL) was added thereto. The reaction mixture was stirred for 15 min, and acetic acid (4 mL) was added thereto. After the temperature of the reaction mixture was raised to room temperature, saturated brine was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=15:1→1:1) to give a mixture (2.30 g) of the title compound and 4-fluoro-3-formyl-2-(trifluoromethyl)benzonitrile (3:1) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][OH:17])[CH2:10][CH:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:27][C:28](Cl)=[O:29].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:27][C:28]3=[O:29])[CH2:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(Br)cnc1C1=CCC(NCCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Br)cnc1C1=CCC(N2CCOCC2=O)CC1

Procedure:
To a solution of 2-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-yl]aminoethanol (860 mg) and triethylamine (0.424 ml) in dichloromethane (10 ml) was added chloroacetic acid chloride (0.242 ml) under ice-cooling with stirring. The mixture was stirred at the same temperature for 1 hour, then water was added thereto, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was dissolved in isopropyl alcohol (10 ml), and hydroxide potassium (129 mg) was added thereto at room temperature with stirring. The mixture was stirred at the same temperature for 8 hours, and then to the reaction solution was added water, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (855 mg) as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH3:37])[C:22]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[O:23])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:37][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:39])[CH3:38])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[C:22](=[O:23])[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C(=O)N1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixture of tert-butyl 4-{2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoyl}piperazine-1-carboxylate (3.14 g, 5.65 mmol) in methylene chloride (20 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (7.06 mL, 28.2 mmol). The reaction mixture was stirred at RT for 1 h, then evaporated to dryness under reduced pressure. The residue was diluted with EtOAc and washed with 1 N NaOH, brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to give the desired product (2.57 g, 99.8%). LCMS calculated for C22H34N7O2Si (M+H)+: m/z=456.3; Found: 456.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.CS(O[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=1)(=O)=O>O1CCCC1.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=2)[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: COc1cccc(CCOS(C)(=O)=O)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: COc1cccc(CCC(C(=O)O)c2cccc(OC)c2)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of m-methoxyphenylacetic acid (1.33 g.) in tetrahydrofuran (10 ml.) was added to a stirred solution of lithium diisopropylamide, generated from diisopropylamine (2.1 ml.) and n-butyllithium (9.23 ml. of a 1.6 molar solution in hexane) in tetrahydrofuran (15 ml.), which was cooled to -70° C.; and the mixture was allowed to warm up to laboratory temperature, stirred at that temperature for 30 minutes and cooled to -70° C. A solution of 2-m-methoxyphenylethyl methanesulphonate (1.9 g.) in tetrahydrofuran (5 ml.) was added, the mixture was allowed to warm up to laboratory temperature and was stirred at that temperature for 18 hours, and water (50 ml.) was added. The mixture was washed with diethyl ether, acidified with aqueous 6N-hydrochloric acid and extracted three times with ethyl acetate (50 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and there was thus obtained as residue 2,4-bis-(m-methoxyphenyl)butyric acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[Mg].II.[Br:14][C:15]1[CH:16]=[C:17]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[N:23]S(C(C)(C)C)=O)[CH:18]=[CH:19][C:20]=1[F:21]>C(OCC)C.O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([C:22]2([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=3)[C:30]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]([NH2:37])=[N:23]2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: COc1ccc(Br)cc1C
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1ccccc1C#N
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2(c3ccc(F)c(Br)c3)N=C(N)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of 4-bromo-1-methoxy-2-methylbenzene (1.21 g, 6.0 mmol) in diethyl ether (10 mL) was added dropwise to magnesium (0.22 g, 9.0 mmol) and iodine. The resulting mixture was heated to reflux for 2 h and was then allowed to cool to room temperature. The prepared reagent was added to a solution of N-((3-bromo-4-fluorophenyl)(2-cyanophenyl)methylene)-2-methylpropane-2-sulfinamide (Scheme #11 F, 0.82 g, 2.0 mmol) in tetrahydrofuran (20 mL) at 0°. The mixture was stirred at 0° C. for 1 h and then quenched by addition of saturated aqueous ammonium chloride. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in methanol (20 mL) and was treated with hydrochloric acid (2M in diethyl ether, 2 mL) overnight. The solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate and chloroform, the organic phase was dried over magnesium sulfate and evaporated. Purification by flash chromatography using chloroform:methanol (9:1) afforded 0.53 g (63% yield) of the title compound. 1H NMR (DMSO-d6) δ 7.90-7.74 (m, 1 H), 7.74-7.67 (m, 1 H), 7.59-7.42 (m, 3 H), 7.35-7.21 (m, 2 H), 7.12-7.00 (m, 2 H), 6.97-6.71 (m, 3 H), 3.74 (s, 3 H), 2.06 (s, 3 H); MS (ESI) m/z 425, 427 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1>O.NN.CO>[CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH2:21])=[CH:4][N:3]=1
Reactant: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.5 %

Procedure:
A mixture of (2-methyl-5-nitro-pyridin-3-yl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine (450 mg, 11.84 mmol), catalytic ferric chloride (50 mg) in hydrazine hydrate (20 mL) and methanol (20 mL) was refluxed for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure and the crude residue was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was stirred with hexane (20 mL) for 5 min, the hexane layer was decanted and the residue was dried to give 280 mg of product as a pale yellow solid (Yield: 68%). Mp: 135° C.; 1H NMR (200 MHz, CDCl3): δ 2.51 (s, 3H), 3.65 (bs, 2H), 6.99 (s, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.44 (m, 1H), 7.78 (d, J=10.0 Hz, 1H), 8.05 (d, J=2 Hz, 1H), 8.36-8.31 (m, 1H), 8.51 (d, J=4.0 Hz, 1H), 8.75-8.72 (m, 1H), 9.27 (d, J=2.0 Hz, 1H); Mass [M+H]+: 279.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[C:14]#[N:15])(=O)C.O.CO>C1COCC1>[NH2:15][CH2:14][C:7]1[C:8]([Cl:13])=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1cc(Cl)cc(Cl)c1C#N
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NCc1c(Cl)cc(Cl)cc1CO
Temperature: 75 °C

Procedure:
To a solution of 3,5-dichloro-2-cyanobenzyl acetate (11.7 mmol) in 50 mL THF was added a solution of BH3 (50 mmol, 1M in THF). The reaction mixture was heated to 75° C. for 7 h and then cooled to 0° C. Water was added followed by MeOH and the mixture was concentrated. The residue was taken up in water and EtOAc, acidified with 1N HCl solution and extracted with DCM. The aqueous phase was then basified with 1M NaOH solution and extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification with CC using DCM/Et3N (99/1) to DCM/MeOH/Et3N (90/10/1) gives the desired compound as pinkish solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 1-(4-bromophenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 457.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[C:11]2[CH:10]=[C:9]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:8]3=[CH:7][C:6]=2[CH2:5][C:4]=1[CH3:20].[Li:22]CCCC>CCCCCC>[CH3:1][N:2]([CH3:21])[C:3]1[C:11]2[CH:10]=[C:9]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[C:8]3=[CH:7][C:6]=2[CH:5]([Li:22])[C:4]=1[CH3:20]
Reactant: CC1=C(N(C)C)c2cc3c(cc2C1)C(C)(C)CCC3(C)C
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]C1C(C)=C(N(C)C)c2cc3c(cc21)C(C)(C)CCC3(C)C
Reaction time: 8 h
Yield: 93 %

Procedure:
3-(dimethylamino)-5,6,7,8-tetrahydro-2,5,5,8,8-pentamethyl-1H-benz(f)indene (2.11 g, 7.46 mmol) was stirred in hexane (75 mL) as n-BuLi (4.10 mL of 2.0 M solution in hexane, 8.20 mmol) was added slowly. This mixture was allowed to stir overnight during which time a pale yellow precipitate formed. After the reaction period the desired product was collected via filtration, washed with hexane, and dried under vacuum resulting in the isolation of a pale yellow solid which was used without further purification or analysis (2.00 g, 93 percent yield).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[K+].S(O[CH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:31][CH2:30]1)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:5][C:4]([CH3:7])([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][O:11][CH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:31][CH2:30]1)=[O:2])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To BOC-L-prolinol (10 mmol) in xylene (10 mL) was added KOH (20 mmol), 4-tosyloxymethyl-N-carbobenzyloxy piperidine (11 mmol) and the reaction was heated to reflux for 3 hours. The reaction mixture was stirred at room temperature for 16 hours, quenched with NH4Cl, extracted with ethyl acetate and purified by column chromatography to provide the title ether.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[F:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[C:21](Cl)=[O:22].C(N(CC)CC)C>O1CCCC1>[F:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[C:21]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1])=[O:22]
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: CC(C)CCc1ccccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1CCC(C)C
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
326.5 mg (2.0 mmol) of [2-(3-methylbutyl)phenyl]amine (III-1) are added to a solution comprising 388.5 mg (2.2 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride and 0.45 ml (3.2 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction solution is stirred at 60° C. for 90 min, filtered through silica gel and concentrated. Column chromatography (cyclohexane/ethyl acetate gradient) gives 592 mg (98% of theory) of 5-fluoro-1,3-dimethyl-N-[2-(3-methylbutyl)phenyl]-1H-pyrazole-4-carboxamide of logP (pH 2.3)=3.12.
Reaction SMILES: [CH3:1][N:2]1[CH2:33][CH2:32][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:33][CH2:32][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCCN(C(=O)OC(C)(C)C)C2)CCN(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCCNC2)CCN(C)C1
Yield: 35.3 %

Procedure:
tert-butyl 3-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethylcarbamoyl)piperidine-1-carboxylate (40 mg, 0.08 mmol) was stirred with trifluoroacetic acid (0.1 mL) in dichloromethane (2 ml) to obtain 10 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)piperidine-3-carboxamide as di-TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=O.[Cl:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:20][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[N:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: Cc1cccc(Cl)n1
Product: O=C(Cc1cccc(Cl)n1)c1cccc(Br)c1
Yield: 86.9 %

Procedure:
In a similar manner as described in Example 1 from ethyl 3-bromobenzoate (50.6 g, 220 mmol) and 6-chloro-2-picoline (24 mL, 220 mmol), 1-(3-bromophenyl)-2-(6-chloro-2-pyridinyl)ethanone (59.4 g, 87%) was obtained as a yellow solid. 1H NMR (CDCl3): δ 7.96 (broad s, 1H), 7.71 (d, 1H), 7.35–7.25 (m, 3H), 6.98 (t, 1H), 6.81 (d, 1H), 6.58 (d, 1H), 5.84 (s, 1H); MS m/z 310 (M+1).