Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCc1ccncc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCc3ccncc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 4-(2-aminoethyl)pyridine (0.012 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-(pyridin-4-yl)ethyl)aminomethyl]indol-2-yl)isoindolinone.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3]1.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O>[CH2:23]([O:22][C:20]([O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)=[O:21])[CH3:24]
Reactant: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Oc1cc(C)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To the suspension of crude 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid (250 mg, 1.126 mmol) in 2 ml H2O was added NaOH (90 mg, 2.25 mmol) in 6 ml H2O, followed by ethyl chloroformate (134.4 mg, 1.24 mmol) dropwise. The reaction mixture was stirred at room temperature for 20 min and acidified by 1N HCl to pH=5.0. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as an off-white powder (120.5 mg, yield: 34%, two steps). 1H NMR (400 MHz, DMSO) δ 12.37-12.36 (t, J=3.6 Hz, 1H), 9.29 (s, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 5.53-5.50 (m, 1H), 4.28-4.22 (m, 2H), 3.10-3.05 (m, 1H), 2.31 (s, 3H), 2.11-2.17 (m, 1H), 1.32-1.27 (m, 3H); MS (ESI) m/z=285 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]([C:20]([O:22]C)=[O:21])[CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16].[OH-].[K+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[C:12]([CH:11]=1)[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2cc(OC)ccc2Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(=O)O)cc(-c2cc(OC)ccc2Cl)c1
Yield: 83.5 %

Procedure:
A mixture of dimethyl 5-(2-chloro-5-methoxyphenyl)-isophthalate (1.20 g) and potassium hydroxide (0.23 g) in methanol (60 ml) and 1,4-dioxane (20 ml) was refluxed for 48 hours. The mixture was evaporated in vacuo and to the residue was added ethyl acetate and water. Two layers were separated and the aqueous layer was acidified with hydrochloric acid solution. The product was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 5-(2-chloro-5-methoxyphenyl)-3-methoxycarbonylbenzoic acid (0.96 g, 83.5%).
Reaction SMILES: Br[C:2]1[O:3][C:4]([Si](C)(C)C)=[C:5]([Br:7])[CH:6]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.COCCOC.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>[Br:7][C:5]1[CH:6]=[C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[O:3][CH:4]=1
Reactant: C[Si](C)(C)c1oc(Br)cc1Br
Reactant: OB(O)c1ccncc1
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: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Brc1coc(-c2ccncc2)c1
Yield: 42.9 %

Procedure:
2,4-Dibromo-5-(trimethylsilyl)furan (8.97 g), pyridine-4-boronic acid (1.85 g, 15.1 mmol), potassium carbonate (6.24 g, 45.2 mmol) and tetrakis(triphenylphosphine)palladium (0) (435 mg, 0.38 mmol) were heated under refluxed in ethanol/1,2-dimethoxyethane (1:4 v/v; 100 mL) at 100° C. for 6 h. The solution was allowed to cool, and was then filtered and evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in hexane to give the title compounds as a pale brown solid (1.45 g), m/z 224, 226 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:27]=[CH:26][C:25]=1[S:40](Cl)(=[O:42])=[O:41]>C1COCC1.CN(C=O)C>[CH2:3]([O:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]([S:40]([C:25]3[CH:26]=[CH:27][C:28]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])=[CH:29][C:24]=3[O:23][CH3:22])(=[O:42])=[O:41])[C:11](=[O:19])[N:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=1)[CH3:4]
Reactant: CCOc1ccc2[nH]c(=O)n(C3CCCCC3)c2c1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Yield: 80.7 %

Procedure:
0.5 g of sodium hydride as a 60% dispersion in oil was added in small portions, at room temperature, to a solution of 2.4 g of 5-ethoxy-3-cyclohexyl-1,3-dihydro-2H-benzimidazol-2-one in 50 ml of THF and 50 ml of DMF and the mixture was stirred for half an hour, still at room temperature. 3.4 g of 2-methoxy-4-benzyloxycarbonylbenzenesulfonyl chloride were then added and the reaction medium was stirred for 4 hours at room temperature. It was concentrated under vacuum to remove the residual THF and the residue was taken up with water. It was then extracted with AcOEt and washed with water and the organic phase was dried over sodium sulfate and concentrated under vacuum. The residue obtained was then purified by chromatography on silica using DCM as the eluent. 4.2 g of the expected product were obtained in the form of a white solid by crystallization from iso ether. M.p.=131° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([NH2:9])=[CH:7][C:6]([CH3:10])=[N:5]2)[CH2:3][CH2:2]1.[CH:11]1([C:14](=O)[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1>C(O)(=O)C>[CH:1]1([N:4]2[C:8]3[N:9]=[C:14]([CH:11]4[CH2:12][CH2:13]4)[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]=3[C:6]([CH3:10])=[N:5]2)[CH2:3][CH2:2]1
Reactant: Cc1cc(N)n(C2CC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CC1

Procedure:
1-cyclopropyl-3-methyl-1H-pyrazol-5-amine (300 mg, 2.187 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (403 mg, 2.187 mmol) and acetic Acid (40 mL) were heated at reflux for 2 hours. The solvent was removed in vacuo and the crude residue was purified via silica gel chromatography (eluent: 0 to 11% EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05-1.13 (m, 4 H), 1.16-1.21 (m, 2 H), 1.25-1.30 (m, 2 H), 1.46 (t, J=7.20 Hz, 3 H), 2.16-2.31 (m, 1 H), 2.63 (s, 3 H), 3.78 (m, J=7.26, 7.26, 3.79, 3.66 Hz, 1 H), 4.47 (q, J=7.24 Hz, 2 H), 7.40 (s, 1 H). LCMS(ES) [M+H]+ 286.2
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>ClCCl>[F:1][C:2]1[C:3]([C:4]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:6])=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc(C(=O)O)c1F
Reactant: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCCCC2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
162 g (1.47 mol, 1.05 eq) of N-methylmorphorine was added to the mixed solution of 278 g (1.4 mol, 1.0 eq) of 2-fluoro-3-(methoxycarbonyl)benzoic acid obtained from the Step 2 and 2.7 l of dichloromethane, and then stirred for 30 minutes at 0° C. 191 ml (1.47 mol, 1.05 eq) of isobutyl chloromate was slowly added, and then stirred for 1 hour at 0° C. 139 ml (1.4 mol, 1.0 eq) of piperidine was slowly added, and then stirred for 1 hour at a room temperature. After completing the reaction, the reaction solution was washed with 560 ml of a saturated sodium bicarbonate aqueous solution, 560 ml of a saturated ammonium chloride aqueous solution, and 1 l of distilled water in order. A obtained organic layer was dehydrated with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure to obtain 371 g of methyl 2-fluoro-3-(piperidine-1-carbonyl)benzoate in a red-yellow oil phase
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]2[C:16]=1[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=1)[CH3:3].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]3[C:16]=2[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH3:3])[C:30]=1[C:31]#[N:32]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COC(=O)c1cccc2nc([C@H](C)N)c(-c3cncc(F)c3)n12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)c(-c3cncc(F)c3)n12

Procedure:
A solution of (S)-methyl 2-(1-aminoethyl)-3-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine-5-carboxylate (0.151 g, 0.480 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.089 g, 0.576 mmol) and DIEA (0.252 mL, 1.441 mmol) in n-butanol (2.40 mL) was stirred at 110° C. for 2 h. The mixture was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-7% MeOH in DCM) to afford the methyl 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(5-fluoro-3-pyridinyl)imidazo[1,2-a]pyridine-5-carboxylate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.65 Hz, 3H) 3.33 (s, 3H) 5.41 (quin, J=6.65 Hz, 1H) 7.16 (d, J=7.24 Hz, 1H) 7.23 (br. s., 2H) 7.38-7.50 (m, 2H) 7.75-7.90 (m, 2H) 7.95 (dd, J=8.61, 1.57 Hz, 1H) 8.42 (br. s., 1H) 8.62 (d, J=2.74 Hz, 1H). LC-MS (ESI) m/z 433.1 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:34])([CH3:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:24])=[CH:16]/[C:17]([O:19]CCCC)=[O:18])=[C:11]([CH3:25])[CH:10]=1)=[O:7].[OH-].[K+].Cl>O1CCCC1>[CH3:32][Si:29]([CH3:30])([CH3:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:1])([CH3:33])[CH3:34])[CH:28]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:24])=[CH:16]/[C:17]([OH:19])=[O:18])=[C:11]([CH3:25])[CH:10]=1)=[O:7]
Reactant: CCCCOC(=O)/C=C(\C)c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C/C(=C\C(=O)O)c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.8 %

Procedure:
Compound 5c (304 mg) was dissolved in tetrahydrofuran (12 ml) and a 4.4% potassium hydroxide solution (8 ml) was added to the obtained mixture. The mixture was stirred at room temperature for 12 hours, and was further stirred under heating at 50° C. for 3 hours. The reaction mixture was allowed to cool, and a 2N hydrochloric acid aqueous solution was added thereto. The mixture was separated with ethyl acetate and water. The organic layer was sequentially washed once with a saturated sodium bicarbonate aqueous solution and once with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized with a mixed solvent of diethyl ether and n-hexane to obtain Compound 5 (164 mg, 61%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:45])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:42][CH3:43])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[C:25]([CH3:41])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:44])=[CH:12][CH:13]=1)C.Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[CH:9][C:8]([CH2:7][C:6]([OH:45])=[O:5])=[CH:13][CH:12]=2)=[C:15]([CH3:44])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:32]([F:34])([F:35])[F:33])[C:36]([F:39])([F:37])[F:38])=[C:25]([CH3:41])[CH:24]=1)[CH2:42][CH3:43])[CH3:22]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cn2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.03 mL) was added to a solution of [6-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester (Example 74-(2); 8.4 mg, 0.014 mmol) in methanol (0.2 mL) at room temperature, and the mixture was stirred at room temperature for three hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (8 mg, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C:19]1[CH2:20][N:21](CC2C=CC=CC=2)[CH2:22][CH2:23][CH:24]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C:19]1[CH2:20][N:21]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:22][CH2:23][CH:24]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2[nH]cc(CC3=CCCN(Cc4ccccc4)C3)c2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC=C(Cc2c[nH]c3ccc(OC)cc23)C1
Temperature: 75 °C

Procedure:
Ethyl chloroformate (5.74 ml; 0.060 mol) was added to a mixture of 5-methoxy-3-(N-benzyl-1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole (4 g; 0.012 mol) in toluene (430 ml). The reaction mixture was heated at 75° C. for 3 hours. The reaction mixture was then cooled and the desired compound was obtained after evaporation of the solvent. The compound was used as such without further purifiction.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C@H:15]([O:25]C(=O)C2C=CC=CC=2)[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:9][C:8]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C@H:15]([OH:25])[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[CH:9][C:8]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc(CC[C@@H](CCCC2CCCCC2)OC(=O)c2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(CC[C@H](O)CCCC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Yield: 46.4 %

Procedure:
5 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 460 mg (0.70 mmol) of (R)-N-[2-t-butyl-5-(6-cyclohexyl-3-benzoyloxyhexyl)phenyl]-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (i) above] in 40 ml of ethanol, and the resulting mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was first diluted with ethyl acetate and then acidified with 2N aqueous hydrochloric acid. The organic phase was separated and then washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The mixture was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from diisopropyl ether, to give 180 mg (yield 47%) of the title compound as crystals, melting at 128°-129° C.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:7]=[CH:6][CH:5]=1>C(O)(=O)C.S([O-])(O)(=O)=O.[K+]>[Br:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[S:12][C:13]([Br:1])=[CH:14][N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Nc2nccs2)n1
Reactant: BrBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: Brc1cccc(Nc2ncc(Br)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of bromine (1.1 mL, 20.9 mmol) in acetic acid (15 mL) was added dropwise to a solution of 2-[(6-bromo-2-pyridinyl)amino]thiazole (2.68 g, 10.46 mmol) in acetic acid (23 mL) at 40° C. After addition, the mixture was stirred at rt. for 3 h. The mixture was diluted with aqueous potassium hydrogen sulfate solution (60 mL) at 0° C. and stirred for several min. The precipitated solid was filtered, washed several times with water and dried in vacuo over P2O5 to obtain the titled compound (3.28 g, 94%) as an off-white solid.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([F:42])[CH:36]=1)[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[CH3:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:42][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[CH3:41])[CH2:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[CH2:28][C@@H:9]([OH:8])[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[CH3:13]
Reactant: COC(=O)C(C)(C)Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of methyl 3-{2-[(1R)-1-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}-2,2-dimethylpropanoate (308 mg, 0.51 mmol), which had been obtained in Example 179 (179c), in THF (3.1 mL) was added with 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.72 mL, 0.72 mmol), and stirred at room temperature. After stirring for 2 hours, a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.5 mL, 1.50 mmol) was added and further stirred for 48 hours. Upon the completion of the reaction, water (5 mL) was added and the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified silica gel chromatography (n-hexane/ethyl acetate=3/7) to give the title compound as a pale yellow oily substance (206 mg, yield 83%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:40][S:41]([NH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(CN)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cc(CNS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 48.7 mg of 5-[6-(aminomethyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide and 26.1 mg triethylamine in 1 ml anhydrous dichloromethane is stirred at room temperature. Under nitrogen atmosphere, 14 mg methanesulfonyl chloride is added. The reaction mixture is stirred at room temperature for 14 h. The solvent is removed under pressure and the residue is purified by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 97/3 to 0/100 (v/v)) to obtain the title product.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13](O)[CH2:14][CH2:15][CH3:16])[CH3:6].N1C=CC=CC=1>ClCCl>[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([Cl:3])[CH2:14][CH2:15][CH3:16])[CH3:6]
Reactant: CCCC(O)CCCCC(=S)OCC
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(Cl)CCCCC(=S)OCC
Reaction time: 1 h
Yield: 89.5 %

Procedure:
89.25 grams (0.7 mole) of thionyl chloride at +5° C. were slowly dropped into a solution of 137.0 grams (0.59 mole) of 6-hydroxy-8-methylthiooctanoic acid ethyl ester (VIb) and 1 ml of pyridine in 300 ml of dichloromethane. After stirring for 1 hour at +10° C. the mixture was heated for 3 hours at reflux and subsequently concentrated in a vacuum. The residue was treated with 200 ml of water and extracted with dichloromethane. After drying the combined extracts with sodium sulfate the solvent was removed in a vacuum. By fractional distillation there were obtained 125.1 grams (84% of theory) of 6-chloro-8-methylthiooctanoic acid ethyl ester as a colorless oil having a boiling point of 135° C. to 145° C. at 1 mbar.
Reaction SMILES: C([N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29]C(=O)OC(C)(C)C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH:38]([C:40]1[O:41][C:42](=[O:56])[C:43]2[C:48]([C:49]=1[C:50]1[CH2:51][CH2:52][O:53][CH2:54][CH:55]=1)=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:39].[H-].[Na+]>CN(C=O)C>[N:24]1[C:25]([NH:29][CH:38]([C:40]2[O:41][C:42](=[O:56])[C:43]3[C:48]([C:49]=2[C:50]2[CH2:51][CH2:52][O:53][CH2:54][CH:55]=2)=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH3:39])=[C:26]2[C:21]([NH:20][CH:28]=[N:27]2)=[N:22][CH:23]=1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1C1=CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Nc1ncnc2[nH]cnc12)c1oc(=O)c2ccccc2c1C1=CCOCC1
Yield: 5.8 %

Procedure:
The title compound was made in a similar way as that of the compound of example 21, from tert-butyl 9-trityl-9H-purin-6-ylcarbamate (214 mg, 0.449 mmol) and 3-(1-bromoethyl)-4-(3,6-dihydro-2H-pyran-4-yl)-1H-isochromen-1-one (intermediate C19, 94 mg, 0.280 mmol) and 50% dispersion in mineral oil NaH (18 mg, 0.34 mmol) in DMF. This was purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%). Fractions containing the required product were collected, 1 M HClaqueous (5 ml) was added and concentrated under reduced pressure to give the title compound (6.3 mg, 5.8%) as colourless solid.