Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][C:26]2([C:39]([O:41]CC)=[O:40])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.C1COCC1.CO.[Li+].[OH-]>O>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:24]=2)([C:39]([OH:41])=[O:40])[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CCOC(=O)C1(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)(C(=O)O)CC1
Yield: 86.8 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 4-((1-trityl-1H-imidazol-4-yl)methyl)piperidine-1,4-dicarboxylate from step A (330 mg, 0.57 mmol) in 1:1:2 THF:MeOH:H2O (10 mL) was added LiOH (136 mg, 5.7 mmol). The mixture was refluxed until LCMS showed complete conversion to product, then concentrated under vacuum, dissolved in water (3 mL), neutralized to pH 5-6 with aq. NaHSO4, and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum to give the title compound (273 mg, 86%). MS (ES+) [M+H]+=552.2.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[F:22][C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][Br:34])=[CH:29][CH:28]=1)([F:25])[F:24]>CC#N>[Br-:34].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][C:23]([F:22])([F:24])[F:25])=[CH:28][CH:29]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](Cc3ccc(OC(F)(F)F)cc3)(CC1)C2
Product: [Br-]
Yield: 72.2 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (29.9 mg, 0.107 mmol) and 4-(bromomethyl)phenyl trifluoromethyl ether (51 mg, 0.20 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (41.3 mg, 72%). EI-MS m/z 454 (M+) Rt (1.95 rain).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH2:8])[CH2:4][CH3:5])[CH3:2].[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([Cl:21])=[O:20])[C:13]=2[O:12][CH2:11][CH2:10]1>CC(C)=O>[ClH:21].[CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:19]([C:18]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:14]=2[CH:15]=[CH:16][CH:17]=1)=[O:20])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: O=C(Cl)c1cccc2c1OCCO2
Solvent: CC(C)=O
Product: CCN(CC)CCNC(=O)c1cccc2c1OCCO2
Product: Cl
Temperature: 0 °C
Yield: 64.2 %

Procedure:
21 g of diethylaminoethylamine and 85 ml of acetone were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 0° C. and then 36 g of 1,4-benzodioxane-5-carbonyl chloride were added. The crystals formed at ambient temperature were dried off, washed with acetone, dried and purified by recrystallization from isopropyl alcohol. 36.5 g of N-(diethylaminoethyl)-1,4-benzodioxane-5-carboxamide hydrochloride were obtained (M.P.: 120° C.; yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=3)[C:4]=2[CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1.CN1CCOCC1.O>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:12]=[C:13]([N:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:19]4)[CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Fc1cccc(-n2ncc3cnc(Cl)cc32)n1
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)C1
Temperature: 100 °C
Yield: 83.5 %

Procedure:
A mixture of 6-chloro-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (2.998 mmol; 745.3 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (4.496 mmol; 900.5 mg), and N-Methylmorpholine (8.993 mmol; 919 mg; 0.999 mL) in 1-methyl-2-pyrrolidinone (10 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was poured into water. The precipitate was collect by filtration, then purified on silica eluted with 0 to 40% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]-3-piperidyl]carbamate (1.0738 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.Cl>C1COCC1>[C:23]([O:22][C:20](=[O:19])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8])([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1cnccc1Cl
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of 3-amino-4-chloropyridine (6.56 g, 51 mmol) in THF (46 mL) is added 2 M NaHMDS in THF (50 mL, 100 mmol). After stirring at rt for 15 min BOC2O (10.1 g, 46.4 mmol) in THF (26 mL) is added in one portion and the mixture is stirred for 3 h at rt. 0.1% aqueous HCl (590 mL) is added. The mixture is extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel chromatography eluting with 0-50% EtOAc in heptane to afford (4-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (6.78 g, 76%). MS: 229 (M+H); 1H NMR (300 MHz, CDCl3): δ 9.38 (ms 1H), 8.23 (d, 1H), 7.30 (dd, 1H), 6.85 (broad s, 1H), 1.57 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[NH2:14][C:15]([CH:19]([F:21])[F:20])=[CH:16][C:17]#[N:18]>C(O)(=O)C.C1COCC1.CO>[F:20][CH:19]([F:21])[C:15]1[NH:14][C:15]([CH:19]([F:21])[F:20])=[C:16]([C:17]#[N:18])[CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][N:4]=[C:3]3[CH2:1][CH3:2])[C:16]=1[C:17]#[N:18]
Reactant: N#CC=C(N)C(F)F
Reactant: CCc1n[nH]c2ccc(C=O)cc12
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12

Procedure:
A mixture of 80 mg (0.46 mmol) 3-ethyl-1H-indazole-5-carbaldehyde (Example 10A), 119 mg (1.21 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] and a trace amount of powdered 4 Å molecular sieve in acetic acid (0.44 ml) was heated to reflux temperature for 4 h. After cooling, the reaction mixture was diluted with THF/methanol and filtered. The filtrate was purified twice by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 99 mg (57% of th.) of the title compound.
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[Ca+2:5].[NH2:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8]CC(O)=O>O>[Ca:5].[NH2:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][C:1]([OH:3])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: [Ca+2]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O
Product: [Ca]
Yield: 225.4 %

Procedure:
20 g of calcium carbonate (calcium content: 38%) was dispersed in 500 ml of water and dissolved therein by stirring, and 60 g of glutamic acid was added thereto to perform a reaction, then the solution was continually stirred until the calcium carbonate and glutamic acid were entirely dissolved. Bubbles were generated in the initial stage of reaction but they disappeared after a certain time. The resulting reaction solution was centrifuged to remove insoluble materials, and the clear supernatant was separated. The supernatant was freeze-dried to obtain about 78 g of calcium-aspartic acid chelate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([OH:14])=O.[C:15](=O)([O-])[O-].[K+].[K+].S([O:26][CH3:27])(OC)(=O)=O.O>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([O:26][CH3:27])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: O=C1COc2c1ccc(O)c2C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OC)ccc2c1OCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A solution of 6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (0.30 g, 1.6 mmol) in DMF (10 mL) was added with potassium carbonate (0.63 g, 4.6 mmol) and dimethyl sulfate (0.48 g, 3.8 mmol), and the mixture was stirred at room temperature for 1 hour, and at 40° C. for 3 hours. The reaction mixture was added with water, the mixture was extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain methyl 6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate (0.25 g, 71%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](O)=[CH:9][CH:10]=1)=[O:4].C1(=O)O[CH2:15][CH2:14][O:13]1.[BrH:18]>>[Br:18][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: O=C1OCCO1
Reactant: Br
Reactant: COC(=O)c1ccc(O)cc1
Product: O=C(O)c1ccccc1OCCBr

Procedure:
The composition below was prepared, filtered through a polypropylene filter having a pore size of 0.2 μm, and the filtrate was used as coating liquids LC-2 for forming the optically anisotropic layer. LC-2-1 was synthesized according to a method described in Japanese Laid-Open Patent Publication “Tokkaihei” No. 2001-166147. LC-2-2 was synthesized by dissolving a commercial hydroxyethyl methacrylate, acrylic acid, and M5610 (product of Daikin Industries, Ltd.) in a ratio by weight of 15/5/80 into methyl ethyl ketone (concentration 40%), and the mixture was allowed to polymerize using V-601 (product of Wako Pure Chemical Industries, Ltd.) as a polymerization initiator. LC-2-3 was synthesized by first introducing octyloxybenzoic acid (product of Kanto Chemical Co., Inc.) into an excessive hydroquinone (product of Wako Pure Chemical Industries, Ltd.) based on the mixed acid anhydride process so as to obtain monoacyl phenol compound. Next, methyl p-hydroxybenzoate was converted to a hydroxyl ethyl compound using ethylene carbonate, the resultant ester is hydrolyzed, and brominated with hydrobromic acid to obtain 2-bromoethyloxybenzoic acid. Two these compounds were then esterified by the mixed acid anhydride process to obtain a diester compound, and the product was then converted to a quaternary compound using dimethylaminopyridine, to thereby obtain LC-2-3 as an onium salt.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11](O)([CH3:13])[CH3:12])=[C:8]([CH2:15][CH2:16][OH:17])[C:6]=2[N:7]=1.C1(C)C=CC=CC=1.FC(F)(F)C(O)=O>O>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]3[C:11]([CH3:12])([CH3:13])[O:17][CH2:16][CH2:15][C:8]=3[C:6]=2[N:7]=1
Reactant: CC(C)(O)c1sc2c(N3CCOCC3)nc(Cl)nc2c1CCO
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OCCc2c1sc1c(N3CCOCC3)nc(Cl)nc21
Temperature: 120 °C
Yield: 35.1 %

Procedure:
Impure 2-(2-chloro-7-(2-hydroxyethyl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol (30 mg) was dissolved in toluene (5 mL, 50 mmol). Trifluoroacetic acid (0.5 mL, 6 mmol) was added and the reaction mixture was heated at 120° C. for two h. Complete reaction was confirmed by LCMS. Diluted with water and extracted with ethyl acetate, dried over magnesium sulfate, concentrated in vacuo and was purified by silica gel chromatography (0 to 100% ethyl acetate/heptanes) on the CombiFlash® Rf system using an amine column and concentrated in vacuo to give 3-Chloro-8,8-dimethyl-1-morpholin-4-yl-5,8-dihydro-6H-7-oxa-9-thia-2,4-diaza-fluorene (10 mg, 10% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[N:13]=[C:12]([CH2:14][C:15]#N)[O:11][N:10]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[OH2:20].[CH:21]([OH:24])([CH3:23])[CH3:22]>>[CH:21]([O:24][C:15](=[O:20])[CH2:14][C:12]1[O:11][N:10]=[C:9]([C:7](=[O:8])[C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:13]=1)([CH3:23])[CH3:22]
Reactant: CC(C)O
Reactant: O
Reactant: COc1ccc(C(=O)c2noc(CC#N)n2)cc1
Agent: Cl
Product: COc1ccc(C(=O)c2noc(CC(=O)OC(C)C)n2)cc1

Procedure:
A mixture of [3-(4-methoxybenzoyl)-1,2,4-oxadiazol-5-yl]acetonitrile (39 g) in dry isopropanol (1 liter) was saturated with HCl gas. The resulting solution was refluxed for 5 hours, cooled, and poured into cold water (2 liters) with stirring. The aqueous mixture was extracted with Et2O (3×800 ml). The organics were washed with water (4×1 liter) until neutral and saturated NaCl, dried over Na2SO4, and concentrated in vacuo to give 59 g of an oil. The ester crystallized on standing and the supernatant oil was decanted away. The crystals (40 g) were purified by high pressure liquid chromatography (1.5% ethyl acetate/CH2Cl2) to yield 36 g (73%) of an oil which crystallized, m.p. 63°-64°.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:30]=[CH:29][S:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:30]=[CH:29][S:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccsc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccsc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (373 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (297 mg) as yellow crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:10]1[N:11]=[C:12]([C:15]([NH:17][C:18]2[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][C:19]=2[C:27](=[O:29])[CH3:28])=O)[S:13][CH:14]=1)([CH3:9])[CH3:8].O.Cl>C(O)(C)(C)C.CCOCC>[OH:29][C:27]1[C:19]2[C:18](=[C:23]([CH3:24])[C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:17]=[C:15]([C:12]2[S:13][CH:14]=[C:10]([CH:7]([CH3:9])[CH3:8])[N:11]=2)[CH:28]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 100 °C
Yield: 89.2 %

Procedure:
Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3′-methylacetophenone (35, 30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixtures was heated at 100° C. overnight. Then, the reaction mixture was cooled at room temperature and diluted with ether (100 mL). The precipitate was filtered off and washed with Et2O to give a powder (fraction A). The mother liquor was concentrated in vacuo, triturated in ether, filtered off, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 mL). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with HCl 1N. The precipitate was filtered off, washed with water and dried. Then, the solid was triturated in diisopropyl ether, filtered off and dried to give 26 g (88%) of the title product 36 as a brownish solid: m/z=315 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].CO>C(#N)C.C(Cl)Cl>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])[CH:18]=[CH2:17]
Reactant: NC(=O)c1cccc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: C=CCOc1cccc(C(N)=O)c1

Procedure:
A 15 To 3-hydroxybenzamide (274 mg; 2.0 mM) under a nitrogen atmosphere was added potassium carbonate (276 mg; 21.0 mM). This was dissolved in acetonitrile (20 ml) containing allyl bromide (169 ul; 2.0 mM). The mixture was refluxed for 5 hours, and the reaction followed by T.L.C.: 10% MeOH: 90% CH2Cl2. The excess solvent was then removed under vacuum, the organics extracted into dichloromethane, dried, and the solvent removed, to yield a white solid. This was recrystallised from hot water to produce a white “needle” solid (63%) as the final product.
Reaction SMILES: [O:1]=[S:2]1(=[O:52])[CH2:7][CH:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:45])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH2:39][CH:38]4[CH:36]([CH:37]4[C:40]([O:42]CC)=[O:41])[CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1.[OH-].[Na+].Cl.O>O1CCOCC1>[O:52]=[S:2]1(=[O:1])[CH2:7][C@H:6]2[CH2:8][C@@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:45])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:32])([CH3:33])[C:21]([C:34]2[CH2:39][CH:38]4[CH:36]([CH:37]4[C:40]([OH:42])=[O:41])[CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4CC3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4C[C@@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C

Procedure:
To a solution of ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S)2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate (28 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was added sodium hydroxide (1N) (0.149 mL, 0.149 mmol). The mixture was warmed to 70° C. After heating the mixture for 16 h, it was cooled to rt and was acidified by adding 1 mL of 1N HCl. Then water was added until solids formed. The solids were collected by filtration, dissolved in 1,4-dioxane and methanol and purified by prep HPLC (method 12) to afford 3-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-3a-((2-((1R,4R)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylic acid as two different isomers (isomer 1, 16.5% and isomer 2, 11.5%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:16]=2[O:15][CH2:14]1>C(O)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([NH:35][N:36]=[C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=5)[NH:7][C:6]4=[O:11])=[O:34])=[CH:29][CH:28]=3)=[O:25])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)CCc2ccc3c(c2)OCO3)cc1
Solvent: CC(=O)O
Product: O=C(CCc1ccc2c(c1)OCO2)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3dione in acetic acid was added 3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 151 mg of the title compound (89%) as a yellow solid in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=3)[C:12]([Cl:29])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:43][CH2:44][O:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C(Cl)(Cl)Cl>[Cl:29][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:43][CH2:44][O:45][C:46]([F:49])([F:48])[F:47])[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (42 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 32 mg of 5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 528.4 (MH+), retention time=0.53 min.; 1H NMR (400 MHz, DMSO-d6) d ppm 1.09-1.34 (m, 4 H) 1.35-1.54 (m, 2 H) 1.55-1.69 (m, 2 H) 1.73-1.89 (m, 1 H) 1.94-2.17 (m, 4H) 3.04-3.15 (m, 1 H) 3.14-3.20 (m, 2 H) 3.20-3.30 (m, 2 H) 3.30-3.47 (m, 2 H) 3.55-3.72 (m, 1 H) 3.84 (dd, J=11.15, 2.54 Hz, 2 H) 4.35 (t, J=4.70 Hz, 2 H) 6.65 (s, 1 H) 6.67-6.83 (m, 2 H) 7.05 (br. s., 0 H) 7.46-7.68 (m, 0 H) 8.06 (s, 0 H) 8.82 (d, J=3.52 Hz, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:21]1=[O:37]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:11][N:10]=2)=[CH:4][C:3]=1[N:20]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][C:30]([OH:32])=[O:31])[C:21]1=[O:37]
Reactant: Cn1c(=O)n(CC(=O)OC(C)(C)C)c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Temperature: 25 °C

Procedure:
A solution of tert-butyl 3-{2-bromo-5-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy}phenyl}tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (7.00 g, 0.012 mol) in trifluoroacetic acid (40 mL) is refluxed for 2.5 hours, cooled to room temperature and concentrated in vacuo to give the title product which is identified by 1HNMR spectral analysis.