Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[N:12]=2)=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH3:21]
Reactant: OB(O)c1ccncc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(-c3ccncc3)cc2)nc1CCN1CCCCC1C
Yield: 8.2 %

Procedure:
Add 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl }-2-methylpiperidine (0.724 g, 1.99 mmol), Pd(Ph3)4 (0.101 g, 0.088 mmol), 4-pyridylboronic acid (0.367 g, 2.99 mmol), 2N Na2CO3 (5 mL), and 1,4-dioxane (1.5 mL) to a microwave vessel. Subject the reaction mixture to microwave irradiation at 30 W, 90° C. for 30-45 minutes. Concentrate and purify on silica gel eluting with 10% 2N NH3 in methanol/dichloromethane to give 4-(4-{5-methyl-4-[2-(2-methyl-piperidin-1 -yl)-ethyl]-oxazol-2-yl}-phenyl)-pyridine (0.059 g, 10%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].Cl.[CH2:17](O)[CH3:18]>>[CH3:15][N:2]([CH3:1])[CH:3]([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[CH2:4][C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CCO
Reactant: CN(C)C(CC(=O)O)c1ccc(F)cc1
Agent: Cl
Product: CCOC(=O)CC(c1ccc(F)cc1)N(C)C
Temperature: 25 °C

Procedure:
A cold solution of 4.0 g of 3-dimethylamino-3-(4-fluorophenyl)propionic acid in 75 ml of ethanol was saturated with hydrogen chloride gas. The mixture was heated at reflux for approximately 16 hours and cooled to room temperature. The mixture was concentrated under vacuum and the residue was dissolved in water. The resulting mixture was washed with diethyl ether and the aqueous phase was made basic with 5N sodium hydroxide. The aqueous phase was extracted twice with diethyl ether and the ether extracts were combined, and washed with water, and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum to provide 2.83 g of ethyl 3-dimethylamino-3-(4-fluorophenyl)propionate as an oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2C(=O)C)=[CH:4][CH:3]=1.[ClH:16]>CO>[ClH:16].[I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc(I)cc21
Agent: Cl
Solvent: CO
Product: CC1(C)CNc2cc(I)ccc21
Temperature: 25 °C

Procedure:
1-(6-Iodo-3,3-dimethylindolin-1-yl)ethanone (6.95 g, 22.08 mmol) was combined with MeOH and concentrated HCl (25 mL, 300 mmol). The solution was heated at a gentle reflux for 1 h before it was cooled to rt. After cooling the solution to 0° C. a white solid was filtered off to give 6-iodo-3,3-dimethylindoline hydrochloride. The HCl salt was neutralized to give 6-iodo-3,3-dimethylindoline hydrochloride. Mass Spectrum (ESI) m/e=274.0 (M+1).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([C:10]([F:9])([F:20])[F:21])[CH:12]=2)=[O:15])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 3-(trifluoromethyl)benzoyl chloride (2.086 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. overnight. The reaction mixture was treated in the same manner as described in Example 120 to obtain 719 mg of the title compound (yield: 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=O)[CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CC(OO)=O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:10])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)ccn1
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
4-Chloro-2-pyridinecarboxamide (93.9 g, 0.6 moles) and TEA (125 mL, 0.9 moles) in EtOAc (500 mL) was cooled to 0.2° C. via an external chiller unit. TFAA (92 mL, 0.66 moles) was added via addition funnel over 40 min. The internal temperature rose to 10° C. during the addition. The temperature at the completion of the addition was 0.0° C. After addition, the chiller was turned off. After an additional 30 min, HPLC analysis showed 4.3% (LCAP) of the starting material. An additional 8.3 mL (0.06 moles) of TFAA was added. After stirring the reaction mixture for an additional 20 min, HPLC analysis indicated complete conversion. 10% Aqueous K2CO3 (w/v, 500 mL) was added. The internal temperature rose from 13.7 to 22.0° C. The mixture was transferred to a separatory funnel after stirring for 20 min. The layers were separated and the aqueous layer extracted with EtOAc (150 mL). The combined organic layers were washed with 10% aqueous citric acid (w/v, 300 mL), dried (Na2SO4), filtered, and concentrated. The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 72.85 g (87%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 8.6 (m, 1 H), 7.7 (m, 1 H), 7.5 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 151.8, 145.3, 134.9, 128.7, 127.4, 116.1; HPLC>99% (LCAP).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[CH:37][CH:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][CH:38]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (27.7 g) in tetrahydrofuran (200 mL) was added 3M hydrochloric acid (200 mL), and the mixture was stirred at 60° C. for 15 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate, and neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was crystallized using ethyl acetate, and the resulting solid was collected by filtration, and dissolved in tetrahydrofuran (100 mL). This solution was added dropwise to a solution of lithium borohydride (2M tetrahydrofuran solution, 37 mL) in tetrahydrofuran (150 mL) at −5° C. over 30 min. After stirring for 1.5 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (21.1 g, 83%).
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1([C:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([O:39]C)=[O:38])=[CH:34][CH:35]=3)[NH:30][CH:29]=2)CCCCC1>C(Cl)(Cl)Cl.C1COCC1>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[C:33]([C:37]([OH:39])=[O:38])[CH:32]=2)[CH:28]=[CH:29]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
Freshly recrystallized pyridinium tribromide (recrystallization from hot AcOH (5 mL per 1 g), rinsed with cold AcOH and dried under high vacuum over KOH) was added in portions (over 10 min.) to a stirring solution of methyl 3-cyclohexyl-1H-indole-6-carboxylate (60 g, 233 mmol) (prepared using procedures describe in WO2004/065367) in CHCl3/THF (1:1, 1.25 L) at 2° C. The reaction solution was stirred at 0-5° C. for 2.5 h, and washed with sat. aq. NaHSO3 (1 L), 1N HCl (1 L) and brine (1 L). The organic layer was dried (MgSO4) and concentrated. The resulting red oil was diluted with Et2O and concentrated. The resulting pink solid was dissolved into Et2O (200 mL) treated with hexanes (300 mL) and partially concentrated. The solids were collected by filtration and rinsed with hexanes. The mother liquor was concentrated to dryness and the procedure repeated. The solids were combined to yield 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester (64 g, 190 mmol, 82%) as a fluffy pink solid, which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 1.50-1.27 (m, 3H), 1.98-1.72 (m, 7H), 2.82 (tt, J=3.7, 11.7 Hz, 1H), 3.92 (s, 3H), 7.69 (d, J=8.8 Hz, 1H), 7.74 (dd, J=1.4, 8.8 Hz, 1H), 8.03 (d, J=1.4 Hz, 1H), 8.47 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ 26.1, 27.0 (2), 32.2 (2), 37.0, 52.1, 110.7, 112.8, 118.7, 120.3, 120.8, 123.1, 130.2, 135.6, 168.2. LCMS: m/e 334 (M−H)−, ret time 3.34 min., 4 minute gradient. Stop time: 5 minutes; Gradient time: 4 minutes; Starting conc: 0% B; Ending conc: 100% B; Eluent A: 5% CH3CN/95% H2O with 10 mM NH4OAc; Eluent B: 95% CH3CN/5% H2O with 10 mM NH4OAc; Column: Phenomenex 10μ 4.6×50 mm C18.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.C([C:30]([CH3:32])=[O:31])C(C)C.N([C:42](C)(CC)[C:43]([O-:45])=O)=NC(C)(CC)C([O-])=O>CCCCCCC>[C:1]([O:6][CH:7]([O:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.[CH3:7][O:6][CH2:1][CH2:2][O:45][CH2:43][CH2:42][O:31][CH2:30][CH3:32]
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Reactant: CC(=O)CC(C)C
Agent: C=C(C)C(=O)OC(C)OC1CCCCC1
Agent: C=Cc1ccc(OC)cc1
Solvent: CCCCCCC
Product: CCOCCOCCOC
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 63.7 g (0.30 mol) of 1-cyclohexyloxyethyl methacrylate, 40.3 g (0.30 mol) of p-methoxystyrene and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in diethylene glycol ethyl methyl ether, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A1-6 (1-cyclohexyloxyethyl methacrylate/p-methoxystyrene) as a diethylene glycol ethyl methyl ether solution.
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O.CN(C)C1C=CC=CC=1>ClC(Cl)=C(Cl)Cl>[C:1]1([C@H:7]([CH3:11])[C:8]([Cl:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@H](C(=O)O)c1ccccc1
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: C[C@H](C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
Into a 10 L four-necked flask, 600 g (4.00 mol) of (S)-(+)-2-phenylpropionic acid, 2.4 L of tetrachloroethylene, 951 g (8.00 mol) of thionyl chloride and a small amount of dimethylaniline were added, followed by stirring at room temperature overnight, and excess of thionyl chloride and tetrachloroethylene were distilled off under reduced pressure to obtain 691 g of (S)-2-phenylpropionic chloride.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:35])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([C@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22]3)=[O:20])=[CH:14][C:13]=2[Cl:34])=[CH:6][CH:5]=1)=[O:3].[Cl:36][C:37]1[CH:38]=[C:39]([OH:46])[CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44]>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:36][C:37]1[CH:38]=[C:39]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[O:46][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:35])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([C@H:21]3[CH2:22][CH2:23][C@H:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26]3)=[O:20])=[CH:14][C:13]=2[Cl:34])=[CH:8][CH:9]=1)=[O:3]
Reactant: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C(=O)Cl)cc3)c(Cl)c2)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C(=O)Oc4ccc([N+](=O)[O-])c(Cl)c4)cc3)c(Cl)c2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-(chlorocarbonyl)phenyl ester obtained was dissolved in 70 ml of benzene and then added dropwise to a solution of 1.04 g of 3-chloro-4-nitrophenol in 50 ml of pyridine. The reaction mixture was stirred overnight at a bath temperature of 65° C., then poured into ice-cold dilute hydrochloric acid and extracted with diethyl ether. The extract was washed four times with 50 ml of 3N hydrochloric acid each time and once with 50 ml of 2N sodium carbonate solution, washed neutral with water, dried and concentrated. The crude 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-[(3-chloro-4-nitrophenoxy)carbonyl]phenyl ester (3.2 g) obtained was chromatographed on silica gel with hexane/dioxan (volume ratio 3:1). The fractions which were pure according to thin-layer chromatography (1.8 g) were recrystallized twice from ethyl acetate; m.p. (C-N) 138° C., cl.p. (N-I) 237.5° C.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1Br
Reactant: COc1ccc(B(O)O)cc1OC
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: COCCOC
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1-c1ccc(OC)c(OC)c1
Yield: 93.8 %

Procedure:
263 g (0.885 mol) of ethyl 2-bromo-4-(trifluoromethyl)benzoate, 750 ml of 1,2-dimethoxyethane, 4 g of tetrakis(triphenylphosphine)palladium, 177 g (0.974 mol) of 3,4-dimethoxyphenylboronic acid and 1000 ml of a 2M aqueous sodium carbonate solution are introduced successively, under an inert atmosphere, into a four-liter round-bottomed flask. The reaction mixture is brought to reflux for fourteen hours and then evaporated to a third under reduced pressure. The reaction mixture is poured onto two liters of water; the precipitate which forms is filtered on sintered glass, rinsed with water and then dried under a stream of air. There is thus obtained 294 g (yield: 94%) of ethyl 2-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)benzoate in the form of a beige solid melting at 89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22](Br)[C:23]#[CH:24].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC.C([O-])C.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:24][C:23]#[CH:22])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: C#CCBr
Agent: CC[O-]
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: [Na+]
Product: C#CCN1N=C(c2ccc(OC)c(OC)c2)[C@@H]2CCCC[C@@H]2C1=O

Procedure:
Prepared from compound 1 and propargylbromide as described for compound 8, using sodium ethanolate instead of sodium hydride. Purified by chromatography (dichloromethane). Crystallized from methanol. M.p. 118-121° C.
Reaction SMILES: B.[C:2]([CH:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]2=[C:16]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]3[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:22]=3[N:7]2[CH2:6]1)(O)=[O:3]>C1COCC1>[CH:27]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:22]=3[N:7]3[CH2:6][CH:5]([CH2:2][OH:3])[CH2:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8]=23)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Cc1ccccc1-3
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Reaction time: 18 h

Procedure:
A solution of borane in THF (0.18 mL of 1 N, 0.18 mmol) was added to a solution of methyl (±)-6-carboxy-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (50 mg, 0.12 mmol) in THF (5 mL) at 0° C. The cooling bath was removed and stirring continued at ambient temperatures for 18 hr. The solution was diluted with ethyl acetate and washed with dilute HCl (1×), brine (3×), and then dried (Na2SO4). The crude product was purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white film (25 mg, 52%). ESI-MS m/z 404 (MH+); 1H NMR (300 MHz, MeOD) δ 1.14–2.19 (m, 11 H) 2.34–2.80 (m, 2 H) 2.82–3.26 (m, 2 H) 3.25–3.38 (m, 1 H) 3.44–3.82 (m, 1 H) 3.92 (s, 3 H) 4.48–4.61 (m, 1 H) 7.35–7.46 (m, 4 H) 7.68 (m, 1 H) 7.85 (m, 1 H) 8.17 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][N:44]1[C:52]2[CH:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][NH:62][CH3:63])=[C:55]([C:64]([F:67])([F:66])[F:65])[CH:54]=3)[N:49]=[C:48]([C:68]#[N:69])[C:47]=2[N:46]=[CH:45]1>ClCCl>[C:68]([C:48]1[C:47]2[N:46]=[CH:45][N:44]([CH3:43])[C:52]=2[CH:51]=[C:50]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][N:62]([CH3:63])[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[O:9])=[C:55]([C:64]([F:67])([F:65])[F:66])[CH:54]=2)[N:49]=1)#[N:69]
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 50.1 %

Procedure:
To a solution of (S)-1-methylpyrrolidine-2-carboxylic acid (16 mg), DIPEA (60 ul) and HBTU (51.7 mg) in dichloromethane (2 ml) was added 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (51.1 mg). The reaction was left stirring at room temperature for 60 hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)—N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N,1-dimethylpyrrolidine-2-carboxamide (30.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([I:18])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10]CC[CH2:7]1.IC1C=NNC(=O)C=1.COC(=O)C(Br)CC(C)C>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([I:18])[CH:13]=[N:12]1)[CH2:5][CH:6]([CH3:10])[CH3:7]
Reactant: COC(=O)C(CC1CCCC1)n1ncc(I)cc1=O
Agent: COC(=O)C(Br)CC(C)C
Agent: O=c1cc(I)cn[nH]1
Product: COC(=O)C(CC(C)C)n1ncc(I)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 73, starting from 5-iodo-2H-pyridazin-3-one (Intermediate 18, Step 1) and 2-bromo-4-methyl-pentanoic acid methyl ester (Intermediate 11) afforded 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid methyl ester which was reacted in an analogous manner to the reaction outlined in Intermediate 85 to afford 2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid as a white solid (1.93 g, 91% for the final step); ES+-HRMS m/e calcd for C10H13N2O3I [M+H+] 337.0044, found 337.0043. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.4 Hz, 6H), 1.24-1.42 (m, 1H), 1.82 (ddd, J=14.0, 9.6, 4.3 Hz, 1H), 1.97-2.16 (m, 1H), 5.35 (dd, J=10.9, 4.3 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 13.12 (br. s., 1H).
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([NH2:18])[CH:10]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH3:8])=[CH:10]2)[CH:25]=1
Reactant: Cc1cn(N)c2ccccc12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(Nc2cc(Cl)ncn2)c2ccccc12
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To 125 ml of 1-methyl-2-pyrrolidinone was added 3-methyl-1H-indol-1-amine (10.0 g), and this mixture was heated to 120° C. Then 4,6-dichloropyrimidine (10.43 g), was added to the hot solution and this mixture was stirred for four hours. The reaction was cooled, poured into water, basified with Na2CO3 (aq) extracted with ethyl acetate and the organic layer washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: C([O:3][C:4](=[O:29])/[CH:5]=[C:6](\[CH3:28])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:27])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]([F:24])([F:23])[F:22])=[C:15]([CH3:25])[C:14]=1[CH3:26])C.O1CCOCC1.[OH-].[K+].S(=O)(=O)(O)O>CCCCCC>[CH3:28]/[C:6](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:27])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]([F:22])([F:24])[F:23])=[C:15]([CH3:25])[C:14]=1[CH3:26])=[CH:5]\[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C)=C\C=C\C(C)=C\C(=O)O

Procedure:
A mixture of 15.3 g (0.0375 mol) of ethyl-(2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoate, 76.5 ml of dioxane and 30 ml of 2N methanolic KOH was heated to reflux for 4 hours. The mixture was then poured into 300 ml of ice-H2O and acidified to pH 2 with 2N sulfuric acid. The yellow precipitate was extracted with 3×200 ml of chloroform, washed with sodium chloride solution and dried (MgSO4). Evaporation of the solvent gave a yellow solid, which was treated with 150 ml of hexane and filtered to give 12 g of crude (2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoic acid. Recrystallization from 200 ml of ethyl acetate gave 9.25 g of (2E,4E,6E,8E,)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoic acid; mp 190°-193° C.