Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:12]([O:25][CH3:26])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[CH3:33].[CH3:34][NH2:35]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:12]([O:25][CH3:26])[CH2:13][NH:35][CH3:34])[CH:6]=[C:5]2[CH3:33]
Reactant: COC(COS(=O)(=O)c1ccc(C)cc1)C(c1ccccc1)n1cc(C)c2cc(Cl)ccc21
Reactant: CN
Solvent: CO
Product: CNC[C@@H](OC)[C@H](c1ccccc1)n1cc(C)c2cc(Cl)ccc21
Reaction time: 1 h

Procedure:
A mixture of (2S,3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (Intermediate in EXAMPLE 119, step 6, 0.52 g, 1.1 mmol), trifluoro-methanesulfonic acid methyl ester (0.6 mL, 5.5 mmol), and 2,6-di-tert-butyl-4-methyl-pyridine (1.1 g, 5.5 mmol) was heated at reflux in dichloromethane (20 mL) for 2 hours. The reaction was partitioned between ethyl acetate (25 mL) and a 1N aqueous solution of hydrochloric acid (25 mL). The organics were separated and washed with a saturated aqueous solution of sodium bicarbonate (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 20% ethyl acetate in hexane) to give (2S,3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester. To a solution of toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester (0.13 g, 0.27 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (1.4 mL, 2.7 mmol) and the reaction heated in a sealed tube for 12 hours. Upon completion, the reaction was partitioned between a saturated aqueous solution sodium bicarbonate (25 mL) and dichloromethane (25 mL). The organics were separated and removed in vacuo. The residue was taken up in diethyl ether (25 mL) and washed with a 1 N aqueous solution of hydrochloric acid (25 mL). The aqueous layer was basified to pH 8 with a saturated aqueous solution of sodium bicarbonate (50 mL). The product was extracted with diethyl ether (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The free base was dissolved in a minimum amount of ethanol and treated with a 4N solution of hydrochloric acid in dioxane and stirred for 1 hour s. The ethanol was removed in vacuo to give [(2R,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]methylamine as a yellow oil. MS (ESI) m/z 343
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[BH4-].[Na+]>COCCOCCOCCOC>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOCCOC
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 150 mmoles) is dissolved in the first distillate from the above mixture, allowed to stir at room temperature for about 2 hours, and cooled to about −70° C. Sodium borohydride (6 g) as a solution in 75 mL triglyme is added slowly at between −65° C. to −75° C. After the addition, the reaction mixture is warmed to 15° C. to 25° C., quenched by the addition of acetic acid and concentrated by vacuum distillation. The residue is diluted with methanol and concentrated by vacuum distillation. The residue is dissolved in a mixture of water and ethyl acetate, the layers separated, and the organic layer is concentrated by vacuum distillation. The residue is dissolved with methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in crude [R(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:15][O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([CH2:3][OH:2])[CH2:13]2
Reactant: COC(=O)C1Cc2ccc(OC)cc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(CO)C2
Yield: 86.9 %

Procedure:
Combine 5-Methoxy-indan-2-carboxylic acid methyl ester (Intermediate 28, 1.90 g, 9.21 mmol), LiAlH4 (0.70 g, 18.43 mmol), and THF anhydrous (60 ml). After the reaction stirs under a nitrogen atmosphere at room temperature for 2 hours, quench the reaction mixture with 5 mL of deionized water. Filter the mixture through a pad of Celite using EtOAc eluent, and wash the organic layer with brine, and dry over Na2SO4. After concentrating under reduced pressure, the flash chromatograph the mixture to afford 1.43 g, 8.0 mmol (87% yield) of the title compound as a clear oil: 1H NMR (500 MHz, CDCl3); 1.4-1.6 (1H, br s), 2.6-2.8 (3H, m), 2.9-3.2 (2H, m), 3.6-3.7 (2H, m), 3.8 (3H, s), 6.7-6.8 (2H, m), 7.1-7.2 (1H, m); TLC 1:1 Hexanes:Ethyl acetate Rf:=0.4.
Reaction SMILES: [C:1]([CH:5]=[CH:6][CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:9]([CH:11]=[CH2:12])=[O:10].C(C1CCC(C=O)CC=1)(C)(C)C>>[C:1]([C:5]1[CH2:12][CH:11]([CH:9]=[O:10])[CH2:8][CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC=CC(C)(C)C
Reactant: C=CC=O
Agent: CC(C)(C)C1=CCC(C=O)CC1
Product: CC(C)(C)C1=CCCC(C=O)C1
Yield: 30 %

Procedure:
Molar amounts of tert.-butylbutadiene and acrolein are refluxed for 6-8 hours. A mixture of about 70% of 4-tert.-butyl-cyclohex-3-ene-1-carboxaldehyde and about 30% of 3-tert.-butyl-cyclohex-3-ene-1-carboxaldehyde is obtained in a yield of about 80%. Boiling point: 112° C./28 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2cc(OCCCCCC(=O)O)nc(-c3ccccc3)c2)cc1

Procedure:
The procedure in Example 4 is followed but using ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]-oxy}hexanoate (3.9 g), potassium hydroxide pellets (0.81 g) dissolved in distilled water (10 cc), and ethanol (150 cc). The reaction mixture is refluxed for 2 hours. The product is purified by recrystallization in toluene (70 cc) to obtain 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoic acid as yellowish crystals; (m.p.=131°-133° C.)
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[O:5][C:6]=1[CH3:7].P(Cl)(Cl)([Cl:21])=O.N>C(Cl)(Cl)Cl>[Cl:21][CH2:1][C:2]1[N:3]=[C:4]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(-c2ccc3ccccc3c2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Temperature: 0 °C

Procedure:
40 g of 4,5-dimethyl-2-naphthalen-2-yloxazole 3-oxide are dissolved in 200 ml of chloroform, 16.7 ml of phosphorus oxychloride are added and the mixture is heated under reflux for 30 minutes. The reaction mixture is cooled to 0° C., a slightly alkaline pH is established using ammonia and the mixture is extracted three times with in each case 500 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=80:1=>5:1. This gives 10.6 g of 4-chloromethyl-5-methyl-2-naphthalen-2-yloxazole as a colorless solid. C15H12ClNO (257.72), MS(ESI): 258 (M+H+).
Reaction SMILES: [NH2:1][C:2](=[O:39])[CH2:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[CH2:6][CH2:7]C1C(C(F)(F)F)=CN=C(NC2C=CC(C(NC(=O)OC(C)(C)C)C)=CC=2)N=1.[Cl:40][C:41]1[N:46]=[C:45](Cl)[C:44]([Cl:48])=[CH:43][N:42]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:40][C:41]1[N:46]=[C:45]([C:7]#[C:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[CH2:3][C:2]([NH2:1])=[O:39])[C:44]([Cl:48])=[CH:43][N:42]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1Cl
Temperature: 70 °C

Procedure:
To a solution of 18 (0.75 g, 4.7 mmol) and 2,4,5-trichloropyrimidine (0.70 mL, 6.1 mmol) in 1,4-dioxane (10 mL) and Et3N (2.6 mL, 19 mmol) containing CuI (0.018 g, 0.094 mmol) was added PdCl2(PPh3)2 (0.033 g, 0.047 mmol). The reaction mixture was heated at 70° C. for 2 hours under a nitrogen atmosphere. The solvent was removed in vacuo and the residue was diluted with 20% diethyl ether in cyclohexane. The precipitate was filtered, washed with water and dried in vacuo to give the title compound (A138) as a light brown solid (1.22 g, 85%). LCMS-C: rt 4.88 min; m/z 306 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:5][CH:6]=1.[OH-].[K+].Br[CH2:23][CH2:24][O:25]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[N:5]([CH2:23][CH2:24][OH:25])[CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
A suspension of tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (36.0 g, 109.02 mmol) in dry DMSO (400 mL) was treated with KOH (36.0 g, 641.60 mmol, 4.5 eq), and the contents became a clear-yellow solution after 20-30 min. After 90 min, the solution was treated with 2-(2-bromoethoxy)terahydropyran (36.0 g, 172.18 mmol, 1.2 eq). The reaction was deemed complete after 4 h by LCMS data, so the contents were diluted with ethyl acetate (800 mL) and washed with brine (3×800 mL). The organics were dried over sodium sulfate and concentrated to an oil with an approximate 8:1 ratio of regioisomers and the major isomer is the desired one. The oil was redissolved in methanol (400 mL) and treated with p-toluenesulfonic acid monohydrate (32.11 g, 168.80 mmol, 1.5 eq). The contents were stirred at room temp for 20 min, poured into ethyl acetate (500 mL) and washed with aqueous potassium carbonate (400 mL), followed by brine (2×400 mL). The organics were dried over sodium sulfate and concentrated to a colorless oil that was further dried under vacuum for 60 min. The resultant, thick oil was suspended in diethyl ether (200 mL) and rolled in an ice-water-salt bath for 90 min. A white solid precipitated, which was filtered and dried under vacuum for 30 min to give the title compound (25.15 g, 67.20 mmol, 62%, >96% by NMR and LCMS data).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[CH:28]=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Se](=O)=[O:31].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[CH:28]=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(Cc2ncc(C=O)c3cc(OC4CCCC4)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc(C(=O)c2ncc(C=O)c3cc(OC4CCCC4)c(OC)cc23)c1
Temperature: 120 °C
Yield: 64.1 %

Procedure:
To a stirred solution of 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (300 mg, 0.77 mmol) in acetic acid (7 μL) was added selenium dioxide (255 mg, 2.30 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde as a yellow solid (200 mg, 64% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:66]([NH2:69])(=[O:68])[CH3:67].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:9]1[N:8]=[C:7]([S:22][CH3:23])[C:6]2[C:11](=[C:2]([NH:69][C:66](=[O:68])[CH3:67])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(N)=O
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(NC(C)=O)cccc12
Temperature: 90 °C
Yield: 47.6 %

Procedure:
To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (200 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol), acetamide (89 mg, 1.5 mmol) and Cs2CO3 (230 mg, 0.7 mmol) was added dioxane (4 mL). The reaction vessel was evacuated and flushed with argon (3×), and the mixture was heated at 90° C. overnight. The mixture was diluted with DCM and concentrated under reduced pressure onto Celite. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)acetamide (90 mg, 48%). LC-MS (ESI) m/z 379 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].C(OC([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[C:22]([C:31]#[N:32])=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1)=O)(C)(C)C.ClCCl>CN(C=O)C>[NH:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[C:22]([C:31]3[NH:32][N:3]=[N:2][N:1]=3)=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2C#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1cc2c(-c3nnn[nH]3)c(OC3CCNCC3)ccc2cn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 13.5 %

Procedure:
Under argon atmosphere 78 mg (1.2 mmol) of NaN3 and 64 mg (1.2 mmol) of NH4Cl were added to a solution of 35 mg (0.1 mmol) 4-(5-Cyano-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (15) in 1 mL of DMF. The mixture was heated to approximately 160° C. and 7 bar pressure for 3 h in a microwave reactor (CEM Discovery). After cooling to room temperature aqueous NH4Cl-solution and dichloromethane was added. The mixture was filtered through a phase separation cartridge and the aqueous layer was washed twice with dichloromethane. The organic layers were combined and the solvents were distilled off. The remainder was subjected to preparative HPLC to yield 4 mg (8%) of compound 32 as trifluoroacetate. LCMS Method # 3, retention time 0.90 min, detected mass 297.04 [M+H]+
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1([C:46]2[CH:51]=[CH:50][C:49]([O:52]C)=[CH:48][CH:47]=2)[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]2[C:10](=[CH:11][C:12]([O:44]C)=[CH:13][CH:14]=2)[S:9][CH2:8]1)[CH3:6].O>ClCCl>[CH2:5]([C:7]1([C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:40])([F:39])[F:41])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]2[C:10](=[CH:11][C:12]([OH:44])=[CH:13][CH:14]=2)[S:9][CH2:8]1)[CH3:6]
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(OC)cc2SCC1(CC)c1ccc(OC)cc1)CCCCCCC(F)(F)C(F)(F)F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2SCC1(CC)c1ccc(O)cc1)CCCCCCC(F)(F)C(F)(F)F
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of boron tribromide in dichloromethane (1.0 M, 8.82 ml, 8.82 mmol) was added dropwise to a solution of ethyl 10-[(3RS,4RS)-3-ethyl-7-methoxy-3-(4-methoxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate (1.05 g, 1.47 mmol) in dichloromethane (15 ml) at −78° C. under argon atmosphere. The reaction mixture was warmed with stirring up to 10° C. over 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue was dissolved in ethanol (5 ml) and mixed with concentrated sulfuric acid (1 drop), followed by heating under reflux for 12 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=2/1) to give ethyl 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate (550 mg, Yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:19]
Reactant: COc1ccccc1N
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccccc2OC)c1
Yield: 100 %

Procedure:
Using o-anisidine (1.0 ml, 8.55 mmol) and m-anisoyl chloride (1.2 ml, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.2 g (100%) of the title compound in the form of brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])=[C:4]([CH3:16])[CH:3]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(F)ccc1CC(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)ccc1CC(=O)O
Reaction time: 16 h

Procedure:
The pure ester was dissolved in 60 ml of CH2Cl2 was added 6 drops of anisole and 60 ml of CF3CO2H and the solution was atirred at rt for 16 hr. Upon removal of volatiles, the residue was dried three times by dissolving in toluene to afford 20.02 g of the title compound. 1H-NMR (CDCl3): δ 2.35 (s, 3H), 3.67 (s, 2H), 6.92-6.95 (m, 2H), 7.19 (d of d, 1H, J=8.2, 5.7 Hz) ppm.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=2[NH:11][C:10]1=[O:19])(=O)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:6][CH2:7][CH2:8][N:9]3[C:13]4[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=4[NH:11][C:10]3=[O:19])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:27]=1
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCCOS(C)(=O)=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
A mixture of 5.68 parts of 3-(2,3-dihydro-5-methyl-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate, 4.8 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 3.7 parts of sodium carbonate and 45 parts of N,N-dimethylformamide is stirred for 1 hour at 50°-60° C. The reaction mixture is cooled to room temperature and poured onto water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized twice from 4-methyl-2-pentanone, yielding 0.5 parts (6.5%) of 1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-2H-benzimidazol-2-one; mp. 149° C.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:26])[C:8]2[N:9]=[CH:10][N:11]([CH2:14][CH2:15][O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C:12]=2[N:13]=1)(=O)C>CN.C(OCC)(=O)C>[CH2:24]([O:23][P:18]([CH2:17][O:16][CH2:15][CH2:14][N:11]1[CH:10]=[N:9][C:8]2[C:7](=[O:26])[NH:6][C:5]([NH2:4])=[N:13][C:12]1=2)([O:20][CH2:21][CH3:22])=[O:19])[CH3:25]
Reactant: CCOP(=O)(COCCn1cnc2c(=O)[nH]c(NC(C)=O)nc21)OCC
Agent: CN
Solvent: CCOC(C)=O
Product: CCOP(=O)(COCCn1cnc2c(=O)[nH]c(N)nc21)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
2-N-Acetyl-9-(2-(diethylphosphonomethoxy)ethyl)guanine (1.42 g, 3.68 mmol) was dissolved in 50 mL of 40% aqueous methylamine and the solution was stirred at rt for 45 min. The reaction mixture was concentrated in vacuo and evaporated three times with toluene to give a gummy, white solid. The crude material was stirred in hot ethyl acetate for 1 h, then cooled to rt, and the product collected by filtration to provide 1.19 g of 9-(2-(diethylphosphonomethoxy)ethyl)guanine
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:37])=[N:4][CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1ncc(N[C@@H](C(N)=O)c2ccccc2)nc1Nc1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H](C(N)=O)c2ccccc2)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-2-phenylacetamide (15 mg, 0.037 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 414.3 (M+H); UV 201.1, 265.8, 297.2, 358.5 nm; t 0.445 min.