Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C@H](C)C1C=CC=CC=1)C1C=CC=CC=1.C([Li])C[CH2:19][CH3:20].[C:22]1([C:27]([O:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][CH:23]=1.ICC>>[NH2:8][C@@H:23]1[CH2:24][CH2:25][CH2:26][C@:22]1([CH2:19][CH3:20])[C:27]([O:29][CH3:30])=[O:28]
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Reactant: COC(=O)C1=CCCC1
Solvent: CCI
Product: CC[C@]1(C(=O)OC)CCC[C@H]1N

Procedure:
According to the procedure of Example 53, Step 1, using (R)-N-benzyl-N-α-methylbenzylamine (4.2 mL, 4.24 g, 20 mmol), n-butyllithium (2.4 M, 7.4 mL), methyl 1-cyclopentene-1-carboxylate (1.3 mL, 1.29 g, 10.2 mmol), and iodoethane (1.6 mL, 3.12 g, 20 mmol), methyl (1S,2R)-2-amino-1-ethylcyclopentanecarboxylate was obtained as a mixture of two components (1.103 g) after purification on silica gel, eluting with 2% ethyl acetate/hexanes.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:41](=[O:43])[CH3:42].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:41](=[O:43])[CH3:42])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)[Si](OCc1cn(COCC[Si](C)(C)C)cn1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in (1) (30.0 g) was dissolved in tetrahydrofuran (hereinafter sometimes referred to as THF) (500 mL) and cooled to −78° C. with stirring under an argon atmosphere. n-Butyllithium (a 2.66 M hexane solution, 36.2 mL) was slowly added dropwise to this solution by using a syringe, and stirring was conducted at the same temperature for 30 minutes. N-Methoxy-N-methylacetamide (13.1 mL) was then added by using a syringe, and stirring was continued for 90 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution to stop the reaction, and extraction was conducted by using ethyl acetate. The combined extract liquid was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%→30%) using a silica gel column (trade name: Hi-Flash column 5L, manufactured by Yamazen Corporation) to give the title compound (24.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@@H:18](O)[CH2:17]1)=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@H:18]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:17]1)=[O:15]
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: COC(=O)[C@H]1C[C@@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 75 °C

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (280 mg, 1.00 mmol), cis-3-hydroxycyclobutanecarboxylic acid methyl ester (trans/cis=1:5) (180 mg, 1.38 mmol), and PS-PPh3 (loading 2.02 mmol/g; 951 mg, 2.02 mmol) in dry THF (10 mL), cooled by ice/water, was added DIAD (295 μL, 303 mg, 1.50 mmol), then the cooling bath was removed, and the mixture was vortexed (220 rpm) for 2 d. The resin was filtered off and washed thoroughly with THF (≈80 mL), the filtrate and washings were combined, concentrated, and chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→5% EtOAc in CH2Cl2 (15-30)], fractions containing product were combined and chromatographed again under the same conditions. This material was suspended in iPrOH (≈1.5 mL), heated to 75° C. for 10 min and cooled to −20° C. for 2 h. The solid was filtered off, washed with cold (−20° C.) iPrOH, and dried in vacuo, giving the title compound as white solid, trans/cis=5:1. 1H NMR (CDCl3, 400 MHz) δ 2.83-2.97 (m, 4H), 3.23-3.32 (m, 1H), 3.79 (s, 3H), 5.50 (quint, J=8.7 Hz, 1H), 7.51 (s, 1H), 8.61 (s, 1H). MS (ES+): m/z 391.9/393.9 (100/35) [MH+]. HPLC: tR=3.5 min (OpenLynx, polar—5 min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:23]=[C:10]3[CH:11]=[CH:12][C:13]([NH:15]C(=O)OC(C)(C)C)=[CH:14][N:9]3[N:8]=2)[CH:2]=1.Cl.C(OCC)C>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:23]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
A mixture of tert-butyl 2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamate (1.34 g, 4.3 mmol), dichloromethane (10 ml) and hydrochloric acid (5 molar in diethyl ether (36.0 g, 30 ml, 987 mmol) was stirred for 18 hours at 25° C. The solvents were evaporated under reduced pressure and the residue treated with sodium hydroxide solution (2 molar in water). The mixture was extracted with ethyl acetate, the organic layers were washed with water and brine, dried over magnesium sulfate, filtrated and evaporated to dryness, affording 2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (482 mg, 53%) as light brown solid. Mp.: 230° C. MS: m/z=212.1 (M+H+).
Reaction SMILES: O[CH2:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]([NH2:15])=[O:14])=[C:6]2[N:5]=[N:4]1.BrC[C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21].C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[O:9]=[C:8]1[N:3]([CH2:2][C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:4]=[N:5][C:6]2=[C:12]([C:13]([NH2:15])=[O:14])[N:11]=[CH:10][N:7]12
Reactant: NC(=O)c1ncn2c(=O)n(CO)nnc12
Reactant: C[Si](C)(C)C#CCBr
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)C#CCn1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 0.5 h

Procedure:
To a cooled solution of 3-(Hydroxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-][1,2,3,5]tetrazine-8-carboxamide (MM-001) (1 equiv) in acetonitrile (0.17 M concentration substrate in solvent) was added 3-bromo-1-(trimethylsilyl)-1-propyne (4 equivs) and DBU (1.4 equivs). The mixture was stirred at this temperature for 30 minutes whereupon it was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×1 reaction volume). The combined organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give an oily residue which was then precipitated from Et2O and washed with further Et2O to give the title compound. 1H NMR (400 MHz, d6-DMSO) □ ppm: 8.87 (1H, s), 7.86 (1H, s), 7.72 (1H, s), 5.18 (2H, s), 0.16 (9H, s). LCMS: rt=3.24 min.; m/z: 313.4 (M+Na)+, 291.2 (MH)+, 151.4 (100).
Reaction SMILES: [F:1][CH:2]([F:13])[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.N#N.C([N-]C(C)C)(C)C.[Li+].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([I:33])[CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:6]2([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH:3]([CH:2]([F:13])[F:1])[CH2:8][CH2:7]2)=[C:27]([I:33])[CH:26]=1
Reactant: COC(=O)C1CCC(C(F)F)CC1
Reactant: BrCc1ccc(Br)cc1I
Agent: CC(C)[N-]C(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(Br)cc2I)CCC(C(F)F)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Methyl 4-(difluoromethyl)cyclohexanecarboxylate (Intermediate 89, 2.46 g, 12.8 mmol) was dissolved in THF (25 mL). The atmosphere was exchanged to N2 (g), and the solution was cooled to −78° C. Lithium diisopropylamide (1.8M in THF/heptane/ethylbenzene) (8.51 mL, 15.3 mmol) was added, while the temperature was kept at −78° C. The solution was stirred for 60 min at −78° C. A solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A.; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239., 4.8 g, 12.8 mmol) in THF (5.0 mL) was added via syringe. The reaction was removed from the cooling bath, and allowed to reach r.t., while stirred for 2.5 h. Water (30 mL) was added, followed by DCM (30 mL). The organic layer was collected and dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography, (0-100% EtOAc in heptanes, 220 g SiO2) to give the title compound (3.29 g, 53% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.11-1.20 (m, 2H), 1.39 (td, 2H), 1.67-1.80 (m, 3H), 2.30 (d, 2H), 3.01 (s, 2H), 3.70 (s, 3H), 5.49 (d, 1H), 6.89 (d, 1H), 7.38 (dd, 1H), 7.99 (d, 1H), MS (CI) m/z 487 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=[O:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CO.C(Cl)Cl>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:24][OH:25])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1ccccc1CO
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Sodium borohydride (89 mg, 1.8 mmol) was added to a solution of 2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)benzaldehyde (Step 1; 233 mg, 0.61 mmol) in MeOH (7 mL) and CH2Cl2 (3 mL). After 2 h, the mixture was partitioned between CH2Cl2 (10 mL) and water (10 mL), the phases were separated and the aqueous portion extracted with further CH2Cl2 (10 mL). The combined organics were then dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (eluant 40% EtOAc/isohexane) gave the title compound as a white solid (208 mg). δH (500, d6 DMSO): 8.08 (1H, d, J 7.7), 7.89–7.83 (5H, m), 7.77 (1H, d, J 7.6), 7.72 (1H, t, J 7.4), 7.55 (1H, t, J 7.5), 7.42–7.34 (2H, m), 7.33–7.27 (1H, m), 7.15 (1H, td, J 2.1, 8.4), 5.39 (1H, t, J 5.7), 4.69 (2H, d, J 5.7). m/z (ES+) 369 [(M−OH)+].
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=O)[CH3:7])(=[O:4])=[O:3].[Cl-].[NH4+:10].[C-:11]#[N:12].[K+]>O.[NH4+].[OH-]>[NH2:10][C:6]([CH3:7])([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]#[N:12]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: [C-]#N
Reactant: [NH4+]
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(N)(C#N)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a solution of 1-(methylsulfonyl)propan-2-one (CAN 5000-46-4, 15 g, 110 mmol) in water (60 ml) and ammonia aqueous 25% (10 ml) was added ammonium chloride (7.07 g, 132 mmol). The reaction mixture was stirred at room temperature for 1 hour followed by addition of potassium cyanide (9.32 g, 143 mmol). The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was then poured into a mixture of ice/water and the aqueous phase was extracted three times with ethylacetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (8.12 gr, 45%) as a light yellow solid. MS (ESI, m/z): 163.2 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:22])[CH2:15][C@H:16]1[CH2:20][C:19](=[O:21])[CH:18]=[CH:17]1.O1CCC[CH2:26]1.C[Li]>CCOCC>[CH3:24][Si:2]([CH3:23])([CH3:1])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:22])[CH2:15][C@H:16]1[CH2:20][C@@:19]([CH3:26])([OH:21])[CH:18]=[CH:17]1
Reactant: C[C@H](C[C@@H]1C=CC(=O)C1)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Product: C[C@H](C[C@@H]1C=C[C@](C)(O)C1)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -78 °C
Yield: 84 %

Procedure:
A 1.76 g amount of the compound (1-10), (4S)-4-{(2R)-2-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-2-cyclopenten-1-one was placed into a 300 ml eggplant-shaped flask. A 150 ml amount of tetrahydrofuran was added and the solution stirred and cooled to −78° C., and then, 6.5 ml of an ether solution of methyllithium (1.16 mol/liter) was added, followed by stirring for 15 minutes. A 50 ml amount of saturated saline was added, the excess methyllithium was broken down, then 100 ml of ether was added for separation. The organic layer was washed with saturated saline, then was dried over anhydrous magnesium sulfate. The desiccant was filtered out, the solvent was distilled off under reduced pressure, and the crude product was purified by a silica gel column (Merck gel: 300 g, hexane/ethyl acetate=15/1 to 9/1) to obtain the desired product (1-11), (1R,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-1-ol in an amount of 1.55 g (yield 84%) and the desired product (1-12), (1S,4S)-4-{(2R)-2-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-propyl}-1-methyl-2-cyclopenten-1-ol, in an amount of 0.27 g (yield 14%).
Reaction SMILES: [Cl:1][Pt-2:2](Cl)(Cl)Cl.[K+].[K+].[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH2:15]>O>[CH2:13]1[CH2:14][CH:9]([NH2:8])[CH:10]([NH2:15])[CH2:11][CH2:12]1.[Cl-:1].[Cl-:1].[Pt+2:2]
Reactant: Cl[Pt-2](Cl)(Cl)Cl
Agent: NC1CCCCC1N
Agent: [K+]
Solvent: O
Product: [Cl-]
Product: [Pt+2]

Procedure:
Dichloro (1,2-diaminocyclohexane)platinum (II) was synthesized as described by Gale et al, Research Communications in Chemical Pathology and Pharmacology, Volume 7, No. 3, Pages 529-538, March 1974. Thus, Potassium tetrachloroplatinite, K2Pt Cl4 (20 mM) in 75 ml water was mixed with 1,2-diaminocyclohexane (20 mM) for three hours at room temperature. The insoluble product was removed by filtration, washed with water and then with methanol, and oven-dried. The yield was approximately 90% of theory. The product was then purified by dissolution in dimethylformamide, filtration, and addition of three volumes of methanol or 0.1 N HCl. This product was filtered, washed, and dried as above. The yield in purification was 47%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
In methanol (284 ml) is suspended 2',3',4'-trichloroacetophenone (94.7 g), and thereto is added sodium borohydride (7.6 g) at 15° C.-25° C. The mixture is stirred at 25° C. for two hours, and evaporated to remove the methanol. To the residue is added 2N hydrochloric acid (110 ml), and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated to remove the solvent to give crude 1-(2,3,4-trichlorophenyl)ethanol (95 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=[NH:11])=[CH:4][CH:3]=1.O=[C:20]([CH3:24])[C:21](=[S:23])[NH2:22]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]42[NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:11]4)[CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=N
Reactant: CC(=O)C(N)=S
Solvent: CO
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(=S)N1
Temperature: 60 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
6′-Bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example 19 Step 2, 1.41 g, 4.57 mmol) and 2-oxopropanethioamide (Intermediate 2, 1.42 g, 13.7 mmol) were dissolved in dry MeOH (30 mL) and the resulting solution was heated at 60° C. under an atmosphere of nitrogen. After 15 h the reaction was allowed to cool to r.t. A precipitate had formed which was filtered off and dried in vacuo, yielding the title compound (1.16 g, 64% yield) as a mixture of isomers. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.18 (m, 4H), 1.47 (m, 2H), 1.87 (m, 2H), 2.27 (m, 3H), 3.03 (m, 3H), 3.20 (s, 3H), 6.98 (d, 1H), 7.34 (d, 1H), 7.51 (dd, 1H); MS (APCI+) m/z 394 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:8]=2)[O:3]1.O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:8]=2)[O:3]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 40 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
550 mg of (RS)-methyl 4-[2-(2,2,4,4-tetramethyl-chroman-6-yl)-heptyloxy]-benzoate, dissolved in 40 ml THF/10 ml H2O/10 ml methanol, was treated with 600 mg of lithium hydroxide hydrate. The mixture was stirred at 40° C. for 6 hours. The mixture was diluted with 10 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 40 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 20 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by trituration in acetonitrile, providing 510 mg of a pale yellow solid, m.p. 94-96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:53]=[CH:54][CH:55]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)=[C:23]([O:40][CH3:41])[CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:52])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:53]=[CH:54][CH:55]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]5)=[C:23]([O:40][CH3:41])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:52])=[N:7]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 63.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy phenyl)piperazine-1-carboxylate (140 mg, 0.18 mmol) was hydrolyzed by lithium hydroxide (23 mg, 0.554 mmol), THF/Methanol/water (5/5/2 ml) to afford 70 mg of the titled compound. MS: m/z=610.9 (M+1).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5](S(OCCC#C)(=O)=O)=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)C=C[CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:16]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23]1)[CH2:17][C:18]#[CH:19]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C#CCCN1CCN(c2ccccc2)CC1

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (1.72 g), N-phenyl piperazine (1.17 mL) and diisoproylethylamine (1.45 mL) in 1,2-dichloroethane (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (3% Et3N in EtOAc) afforded 1-(but-3-ynyl)-4-phenylpiperazine (0.76 g)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:16]2[CH2:15][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC1Cc2ccccc2C1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 2-indanone.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][C:14]3[CH:20]=[C:19]([CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=3[O:16][C:8]=12>CC(C)=O>[O:2]=[C:13]1[C:9]2[C:8](=[N:7][CH:12]=[CH:11][CH:10]=2)[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH:21]([OH:25])[CH:22]([CH3:23])[CH3:24])=[CH:20][C:14]1=2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)C(O)c1ccc2c(c1)Cc1cccnc1O2
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)C(O)c1ccc2oc3ncccc3c(=O)c2c1
Reaction time: 1 h

Procedure:
15 g of potassium permanganate is added in small portions to a solution of 11 g of 1(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-2-methyl-1-propanol in 200 ml of acetone, while the temperature is kept at 10°C. Then the mixture is allowed to stand at 20°C for 1 hour. The reaction mixture is filtered, and the crystalline residue is washed with chloroform. The filtrate and washings are concentrated, and the residue is purified by column chromatography on silica gel with chloroform as eluent, and further by recrystallization from ethanol to give 1-(5-oxo-5H-[1]-benzopyrano[2,3-b]-pyridin-7-yl)-2-methyl-1-propanol melting at 160°C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCC>ClCCCl>[ClH:2].[CH2:7]([O:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[CH2:23][CH2:22][N:21]=2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cccc(CCNC(=O)c2ccc(OCc3ccccc3)cc2)c1
Solvent: ClCCCl
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCN=C2c1ccc(OCc2ccccc2)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
Phosphorus pentachloride (58.557 g, 281.2 mmol) was added in portions to a solution of 4-benzyloxy-N-[2-(3-methoxyphenyl)ethyl]benzamide (59.775 g, 165.4 mmol) in 1,2-dichloroethane (500 ml) at 0° C. under N2. The resulting reaction was stirred at 0° C. for 30 min, then refluxed for 18 hr. After cooling to rt, hexane (1200 ml) was added and the resulting suspension was cooled to 0° C. The solvent was decanted off from the oil that separated and the remaining oil was dried in vacuo to give 54.56 g (87% yield) of orange residue.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([OH:19])=O)=[N:6][C:7]=1[S:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[N:6][C:7]=1[S:8]([N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)(=[O:9])=[O:10]
Reactant: Cc1ccc(C(=O)O)nc1S(=O)(=O)N1CCCCC1
Reactant: C1CCNCC1
Product: Cc1ccc(C(=O)N2CCCCC2)nc1S(=O)(=O)N1CCCCC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-methyl-6-(piperidine-1-sulfonyl)-pyridine-2-carboxylic acid and piperidine (CAN 110-89-4) as starting materials, MS (EI): 352.2 [M+H]+.