Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[S:41][C:42]([Sn](CCCC)(CCCC)CCCC)=[CH:43][C:39]=2[C:38]([CH3:57])=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:41][C:40]3[N:36]([CH3:35])[N:37]=[C:38]([CH3:57])[C:39]=3[CH:43]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(C)nn(C)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2sc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc12
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (120 mg, 0.240 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[2,3-c]pyrazole (212 mg, 0.481 mmol) and tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.120 mmol) in toluene (3 mL) was heated to 120° C. in a Biotage Initiator microwave for 30 minutes. The mixture was concentrated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a white solid (89 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.73 (m, 5H), 1.83-1.97 (m, 3H), 2.35 (s, 3H), 3.78-3.79 (m, 1H), 3.86 (s, 3H), 4.26-4.27 (m, 1H), 4.43 (d, J=4.88 Hz, 2H), 7.02-7.04 (m, 1H), 7.81-7.82 (m, 2H), 8.51 (s, 1H), 9.16 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H23FN6OS, 415. found, 415.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([C:7]1[C:15]2[CH:14]=[CH:13][C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[S:9][C:8]=1[C:23]#[N:24])=[O:6].[OH-:28].[Na+].Cl>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([C:7]1[C:15]2[CH:14]=[CH:13][C:12](=[O:16])[N:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[S:9][C:8]=1[C:23]([NH2:24])=[O:28])=[O:6]
Reactant: Cc1cccc(C(=O)c2c(C#N)sc3c2ccc(=O)n3-c2ccccc2)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C(=O)c2c(C(N)=O)sc3c2ccc(=O)n3-c2ccccc2)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A mixture of Example 5 (127 mg, 0.34 mmol) and 0.25M sodium hydroxide(aq) (1.36 ml, 0.34 mmol) was heated to reflux in EtOH (20 ml) for 45 minutes. The solution was cooled to room temperature, 2M HCl(aq) (100 ml) added and the aqueous extracted with DCM (2×100 ml). The combined DCM extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (0-10% EtOAc in DCM) to give the title compound as a white solid (125 mg, 95%). δH (CDCl3) 7.70 (1H, br s), 7.59-7.32 (8H, m), 7.05 (1H, d, J 9.7 Hz), 6.44 (1H, d, J 9.7 Hz), 2.37 (3H, s). LCMS (ES+) RT 3.00 minutes, 389 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23](=[O:34])[C@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[NH2:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23](=[O:34])[C@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH3:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To a solution of 1 (250 mg, 0.9 mmol) in 20 mL of DCM were added tert-butyl [(2R)-1-hydrazinyl-1-oxopropan-2-yl]carbamate 274 (275 mg, 1.35 mmol), HOBt (183 mg 1.35 mmol), DMAP (162 mg, 1.35 mmol) and EDCI (260 mg, 1.35 mmol). The mixture was stirred at room temperature for 48 h and purified by column to afford compound 275 as foam (400 mg, 95%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].[Na+].[CH2:19](I)[CH3:20].O>C1COCC1>[CH2:19]([O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (500 mg) was dissolved in THF (5 ml), and NaH (174 mg) was added thereto under ice-cooling, and subsequently, ethyl iodide (680 mg) was added thereto, followed by elevating the temperature to room temperature and stirring overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5% to 20% EtOAc/hexane) to obtain tert-butyl 4-(2-ethoxyethyl)piperidine-1-carboxylate (496 mg).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>C(OCC)(=O)C>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:12][CH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:22]
Reactant: COc1cc(CCO)ccc1O
Reactant: CC(C)CCCCCCC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CCOC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 93.4 %

Procedure:
Homovanillyl alcohol (769 mg, 4.57 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, ethyl acetate (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Ethyl acetate (50 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2), saturated brine (25 ml), 5% aqueous sodium hydrogen carbonate solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (preparative thin layer chromatography) (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give homovanillyl 8-methylnonanoate (1.31 g, yield 93.2%) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:11][N:10]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:9]1=[O:30])(C)(C)C.C[Si](I)(C)C>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:14][CH2:13][C@@H:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:11][N:10]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:9]1=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN(Cc2cccnc2)C1=O
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C(=O)N(Cc2cccnc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To a stirred solution of [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-carbamic acid tert-butyl ester (5.0 g, 11.1 mmol) in CH2Cl2 (50 mL) at −78° C. is added trimethylsilyl iodide (2.8 g, 14.0 mmol) neat. After 30 min the reaction solution is warmed to 0° C. and stirred for 15 min. The reaction is quenched with a solution of CH3OH (25 mL) and NH4HCO3 (10 mL, saturated in H2O), and partitioned with H2O/CH2Cl2. The CH2Cl2 fraction is dried over Na2SO4 and evaporated to a gum and chromatographed on silica (95% CH2Cl2/5% CH3OH) to give 3.6 g (92.6%) of (3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1-pyridin-3-ylmethyl-azepan-2-one as a white solid. MS (ESI) 350.2 (M+H)+
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]([C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:49]=1[OH:50])[C:44](O)=[O:45])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:51]([C:48]1[CH:47]=[C:43]([CH:42]=[C:41]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:49]=1[OH:50])[C:44]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[O:45])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and 3,5-di-t-butyl-4-hydroxybenzoic acid (204 mg) in anhydrous N,N-dimethylformamide (8 ml) were added triethylamine (0.32 ml) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (153 mg). The mixture was stirred at room temperature for 1 hour and then allowed to stand at room temperature overnight. To the reaction mixture was further added triethylamine (0.10 ml) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (134 mg) and this mixture was stirred at room temperature for 8 hours and allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→3:1 as the eluant to afford the title compound (176 mg, mp 160-162° C.).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH3:16])=[C:12]([CH2:14]Cl)[N:13]=2)=[CH:5][CH:4]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)C.O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:14][C:12]3[N:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=4)[NH:10][C:11]=3[CH3:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1ccc(-c2nc(CCl)c(C)[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)c(C)[nH]2)cc1

Procedure:
50 Grams (0.2 mol) of 2-(4-methylphenyl)-4-chloromethyl-5-methyl-1H-imidazole hydrochloride dissolved in 200 ml of a mixture of ethanol:water 6:4 were added dropwise to a refluxing solution of 55 grams (0.2 mol) of N-(diphenylmethyl)piperazine and 24 grams (0.6 mol) sodium hydroxide in 200 ml of a mixture of ethanol:water 6:4. After 2 to 3 hours 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine precipitated from the reaction mixture. After having left the crystals standing at room temperature, they were removed by filtration and recrystallized from methanol to give the free base which melted at 220°-222° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.CN([CH:35]=[O:36])C.Cl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:35]=[O:36])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: CN(C)C=O
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C=O)n2C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 2-chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purine (500 mg, 1.67 mmol) and TMEDA (419 μL, 2.80 mmol) in THF (10 mL) at −78° C. was added n-BuLi (1.12 mL, 2.80 mmol, 2.5M solution in hexanes). The resulting mixture was allowed to warm to −40° C. and stir for 30 min then cooled back to −78° C. before the addition of DMF (435 μL, 5.61 mmol). The reaction mixture was allowed to stir at −78° C. for 30 min then poured onto 1M HCl. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-50%) affording the title compound as a white solid (450 mg, 81%). LCMS (method H): RT 3.28 min [M+H]+ 296.3
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:3]2[C:2]([C:34]3[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][C:35]=3[Cl:37])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:24][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
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: O
Solvent: C1COCCO1
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)cn12
Yield: 50 %

Procedure:
The title compound (5.5 mg, 50%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2,4-dichlorophenylboronic acid (7.5 mg, 0.039 mmol, K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethylpyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time=2.04 min, [M+H]+=547.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (4.3 g) in methylene chloride (50 ml) was added a solution of (R)-(+)-1,1,1-trifluoro-2-octanol (2.9 g) ([α]D22.5 =+20.1, optical purity 96.3 % ee), dimethylaminopyridine (0.6 g) and triethylamine (1.7 g) in methylene chloride (50 ml) under ice-cooling. The mixture was left to stand at the room temperature for 24 hours before being poured in ice water. The methylene chloride layer separated was washed with diluted hydrochloric acid, water, 1N aqueous sodium carbonate solution and water in this order before being dried over magnesium sulfate. After distillation was over purification by toluene/silica gel chromatography and recrystallization from ethanol gave the titled compound (3.8 g).
Reaction SMILES: [CH2:1]([C:5]([CH3:26])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[N-:27]=[N+:28]=[N-:29].[Na+]>>[N:27]([CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:13][CH:14]=1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC(C)(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)OCC
Agent: [Na+]
Product: CCCCC(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)C(=O)OCC
Yield: 102.4 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-butyl-3-[4-(2-methanesulfonyloxyethoxy)phenyl]-2-methylpropionate (3.17 g), which is the product of Reference example 10(e), and sodium azide (1.60 g) and the reaction mixture was treated to afford the desired compound (2.80 g) as a syrup.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C>C1(C)C(C)=CC=CC=1>[O:6]1[C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]3)=[CH:9][C:8]=2[CH:4]=[CH:5]1
Reactant: CCOC(COc1ccc(C2(C(=O)O)CC2)cc1)OCC
Solvent: Cc1ccccc1C
Product: O=C(O)C1(c2ccc3occc3c2)CC1
Temperature: 140 °C
Yield: 11.4 %

Procedure:
To a suspension of 1-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (20 g, ˜65 mmol) in xylene (100 mL) was added PPA (22.2 g, 64.9 mmol) at room temperature. The mixture was heated at reflux (140° C.) for 1 hour before it was cooled to room temperature and decanted from the PPA. The solvent was evaporated under vacuum to obtain the crude product, which was purified by preparative HPLC to provide 1-(benzofuran-5-yl)cyclopropanecarboxylic acid (1.5 g, 5%). 1H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H), 7.95 (d, J=2.8 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.47 (d, J=11.6 Hz, 1H), 7.25 (dd, J=2.4, 11.2 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 1.47-1.44 (m, 2H), 1.17-1.14 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[N:8]=[C:9]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:10]2[S:15][C:14]([CH:16]=O)=[CH:13][C:11]=2[N:12]=1>>[Cl:6][C:7]1[N:8]=[C:9]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:10]2[S:15][C:14]([CH2:16][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:13][C:11]=2[N:12]=1
Reactant: COCCN
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: COCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
Reaction of 2-methoxyethylamine with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 using standard reductive amination conditions yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methoxy-ethyl)-amine, which was reacted with 1-isopropyl-4-piperidone using the standard reductive amination conditions to yield (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-isopropyl-piperidin-4-yl)-(2-methoxyethyl)amine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:16][C:17]1[S:18][C:19]([CH2:22]Br)=[CH:20][N:21]=1>>[Br:16][C:17]1[S:18][C:19]([CH2:22][N:10]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][N:21]=1
Reactant: BrCc1cnc(Br)s1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Product: O=[N+]([O-])c1ccc(N(Cc2cnc(Br)s2)n2cnnc2)cc1

Procedure:
Starting Compounds: 4-(4-nitrophenyl)amino-4H-1,2,4-triazole and 2-bromo-5-(bromomethyl)thiazole
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](O)(=[O:18])[C:16]#[CH:17]>ClCCl.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[C:16]#[CH:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: C#CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.b. from 4′-chlorobiphenyl-4-ylamine and propynoic acid. Yield: 0.4 g (29.2% of theory); C15H10ClNO (M=255.70); calc.: molecular ion peak (M+H)+: 256/258; found: molecular ion peak (M+H)+: 256/258; Rf value: 0.35 (silica gel, dichloromethane/ethanol 20:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:30][N:29]=[CH:28][CH:27]=4)([N:11]=[C:12]([NH:17]C(=O)C4C=CC=CC=4)[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[OH-].[Li+].Cl>CO.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:26]4[S:30][N:29]=[CH:28][CH:27]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(NC1=N[C@@]2(c3ccns3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC1=N[C@@]2(c3ccns3)CN(c3ncc(F)cn3)C[C@H]2CS1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
N-[(4aR,7aR)-6-(5-Fluoropyrimidin-2-yl)-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (5 g, 11.5 mmol) is added to lithium hydroxide (530 mg, 12.6 mmol) in methanol (50 mL) at 22° C. The reaction mixture is refluxed for 3 hours and then cooled to 22° C. Hydrogen chloride, 2 M in water (20.3 mL) is added and then solvent is evaporated. The solution is washed with MTBE (50 mL). The aqueous solution is treated with charcoal (500 mg) and stirred 30 minutes at 22° C. The mixture is filtered over diatomaceous earth and the pH of the filtrate is adjusted to pH=9 with sodium hydroxide (2M aqueous solution). A white solid precipitates and is collected. The solid is dried under vacuum to a constant weight to give the title compound (1 g, 30%). ES/MS (m/e): 337 (M+H).