Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[NH:36][CH:35]=[CH:34]2.CC(N(C)C)=O>ClCCl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:41])[F:42])[NH:36][CH:35]=[CH:34]2
Reactant: Oc1cc2cc[nH]c2cc1C(F)(F)F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3C(F)(F)F)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (276 mg, 2.0 mmol) and 5-hydroxy-6-trifluoromethylindole (110 mg, 0.55 mmol) and DMA (4.0 ml) were stirred at 95° C. for 1.5 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (89/10/1) to give a partially purified oil. This oil was further purified by high performance column chromatography on octadecylsilane reverse phase silica eluting with acetonitrile/water/trifluoroacetic acid (60/39.8/0.2) to give an oil which was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The dichloromethane layer was evaporated to give 6-methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quinazoline (62 mg, 25%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:23]3[CH:24]=[N:25][S:26][CH:27]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:23]3[CH:24]=[N:25][S:26][CH:27]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cnsc2)c1OC
Solvent: CO
Product: COc1c(-c2cnsc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Example 3, starting from crude methyl 6-(benzenesulphonylmethyl)-3-(isothiazol-4-yl)-2-methoxybenzoate (Intermediate 57) using methanol in place of dioxane.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9](SC)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Ni]>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)cc2n1
Agent: [Ni]
Solvent: CCO
Product: c1ccc(-c2cc3ncnc(NC4CCCC4)n3n2)cc1
Yield: 77.8 %

Procedure:
N-Cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine (300 mg, 0.92 mmol, from Example 9) was dissolved in absolute ethanol (30 mL). To this mixture was added Raney nickel (approximately 2–3 g) and the reaction was heated at reflux for 6 hours. The Raney nickel was removed by filtering the reaction mixture through a Celite pad, and the Celite was washed with ethanol (150 mL). The combined organic phase was concentrated to dryness. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane 1:1) to give 200 mg (78%) of N-cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a yellow foam. 1H-NMR (CDCl3): δ 8.24 (s, 1H), 7.98 (m, 2H), 7.51 (m, 3H), 6.75 (s, 1H), 6.67 (d, 1H), 4.60 (m, 1H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H); MS m/z 280 (M+1).
Reaction SMILES: ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:23]1([C:26]([OH:28])=O)[CH2:25][CH2:24]1.[NH2:29][C@@H:30]([CH3:50])[C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][C:41]2[C:42]([NH2:49])=[N:43][C:44]([CH3:48])=[N:45][C:46]=2[Cl:47])[CH2:35][CH2:34]1)=[O:32]>C1COCC1.CCOC(C)=O>[NH2:49][C:42]1[C:41]([CH2:40][CH2:39][CH:36]2[CH2:35][CH2:34][N:33]([C:31](=[O:32])[C@@H:30]([NH:29][C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:28])[CH3:50])[CH2:38][CH2:37]2)=[C:46]([Cl:47])[N:45]=[C:44]([CH3:48])[N:43]=1
Reactant: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)N)CC2)c(Cl)n1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(N)c(CCC2CCN(C(=O)[C@H](C)NC(=O)C3CC3)CC2)c(Cl)n1
Yield: 78.9 %

Procedure:
Add 1-hydroxy-7-azabenzotriazole (281 mg, 2.03 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (430 mg, 2.21 mmol) to a slurry of cyclopropanecarboxylic acid (161 μL, 2.03 mmol), (2S)-2-amino-1-[4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5-yl)ethyl]-1-piperidyl]propan-1-one (600 mg, 1.84 mmol) in anhydrous THF (12 mL). Then add TEA (770 μL, 5.52 mmol) and stir the resulting mixture at RT for 12 h. Dilute the reaction mixture with EtOAc (10 mL), filter over diatomaceous earth, and concentrate the filtrate in vacuo. Purify the resulting residue by mass-guided HPLC reverse phase chromatography (Agilent® 1200 LCMS and MSD mass spectrometer, 75×30 mm Phenomenex Gemini-NX®, 5μ particle size column with a 10×20 mm guard, 12-46% ACN in 10 mM aqueous ammonium bicarbonate solution, pH 10, gradient over 9 min) to obtain the title compound as a colorless glass (572 mg, 78%). LC-ESMS m/z (35Cl/37Cl) 394.2/396.2 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:13][N:14]=[C:15]1[CH2:20][NH:19][C@H:18]([C:21]#[N:22])[CH2:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[K+]>C(OCC)(=O)C>[CH2:6]([O:13][NH:14][CH:15]1[CH2:20][NH:19][C@H:18]([C:21]#[N:22])[CH2:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#C[C@@H]1CCC(=NOCc2ccccc2)CN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCC(NOCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Sulphuric acid (11.7 ml, 0.217 mol) was slowly added to a stirred solution of (2S)-5-[(benzyloxy)imino]-2-cyanopiperidine (IX) (10 gm, 0.0436 mol, prepared according to the procedure described in step 6) in ethyl acetate (150 ml) at −10° C. After 10 minutes of stirring, sodium triacetoxy borohydride (NaHB(OOCCH3)3) (11.7 gm, 0.0519 mol, 95% purity) was added in small portions while maintaining temperature below −5° C. After completion of the addition, stirring was further continued for 2 hour at the same temperature. The pH of the reaction mixture was adjusted to about pH 7 by using 30% aqueous potassium hydrogen carbonate solution. The mixture was allowed to warm to 25° C. and the reaction mixture was filtered under suction. The organic layer was separated and the aqueous layer extracted with fresh ethyl acetate (50 ml). The combined organic layer was washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure to obtain 8.88 gm of (2S)-5-[(benzyloxy)amino]-2-cyanopiperidine (X) as an oil, in 88% yield. This was used as such for the next step without further purification.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:4]=1.[CH:25]1([C:28](Cl)=O)[CH2:27][CH2:26]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:19][C:18]([CH3:20])([CH3:21])[CH2:17][CH2:16][C:15]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:4]=[C:3]([C:2]3[N:1]=[C:28]([CH:25]4[CH2:27][CH2:26]4)[O:24][N:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:10][CH2:11]1)=[O:22]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)CCC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CCC(=O)N1CCN(c2cc(-c3noc(C4CC4)n3)ccn2)CC1

Procedure:
1-{4-[Amino(hydroxyimino)methyl]pyridin-2-yl}-4-(4,4-dimethylpentanoyl)piperazine (235 mg) obtained in Example 56-1) was dissolved in pyridine (1 mL), then cyclopropanecarbonyl chloride (0.065 mL) was added thereto and heated under reflux for 90 minutes. The reaction liquid was diluted with ethyl acetate, washed with water, aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 187 mg of the entitled compound as a colorless solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[N:35]1([CH2:40][CH2:41]O)[CH:39]=[N:38][CH:37]=[N:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:41][CH2:40][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: OCCn1cncn1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1cncn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
The starting material was prepared as follows Diethyl azodicarboxylate (1.1 ml, 7 mmol) was added dropwise to a solution of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one-(1.7 g, 5.55 mmol), 2-(1,2,4-triazol-1-yl)ethanol (791 mg, 7 mmol), (Ann. Pharm. Fr. 1977,35,503-508) and triphenylphosphine (1.8 g, 7 mmol) cooled at 5° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The mixture was poured directly on to a column of silica and eluted with methylene chloride/methanol (95/5) to give 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.64 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][C:3]=12.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:28](O)=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[C:10]([CH:28]=[O:29])[C:3]=12
Reactant: COCCCn1ccc2c(F)ccnc21
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COCCCn1cc(C=O)c2c(F)ccnc21

Procedure:
A solution of 4-fluoro-1-(3-methoxypropyl)-1H-pyrrolo[2,3-b]pyridine (520 mg) and hexamethylenetetramine (700 mg) in trifluoroacetic acid (9.1 ml) was stirred at 80° C. for 4 hours. After evaporation of the solvent in vacuo, the resulted residue was dissolve in ethyl acetate. The solution was poured slowly into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=60/40 to 20/80) to give 4-fluoro-1-(3-methoxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-carbaldehyde (260 mg) as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[F:10][C:7]1[CH:6]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:30]([O:31][CH3:32])=[O:33])[CH:4]=[C:3]([F:2])[C:8]=1[F:9]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cc(F)c(F)c(F)c2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
Methyl 2-(3,4,5-trifluorophenyl)piperidine-4-carboxylate hydrochloride (2.75 g, 8.88 mmol) was dissolved into DCM (50 mL), then DIPEA (3.88 mL, 22.20 mmol) was added. Methyl carbonochloridate (0.979 mL, 12.43 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h. The mixture was washed with HCl (0.1 M, 100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(3,4,5-trifluorophenyl)piperidine-1,4-dicarboxylate (2.77 g, 94%) as an orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Na+].[I-:12].CN[C@@H]1CCCC[C@H]1NC.C[Si](C)(C)N[Si](C)(C)C.Cl>[Cu]I.O1CCOCC1>[I:12][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: [I-]
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1COCCO1
Product: O=C(O)c1cccc(I)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 89.5 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), 3-bromobenzoic acid (210 mg, 1.00 mmol), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), 1,1,1,3,3,3-hexamethyldisilazane (211 μL, 1.00 mmol), and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting suspension was allowed to reach room temperature, poured into 10% aq HCl (20 mL), and extracted with dichloromethane (3×15 mL). The combined organic phases were dried (Na2SO4) and concentrated. The residue was dissolved in dichloromethane (50 mL) and washed with an aqueous solution of 1% HCl and 1% Na2SO3. The aqueous phase was extracted with with dichloromethane (2×20 mL). The organic phases were combined, dried (Na2SO4) and concentrated. The solid residue was washed with hexane (3×15 mL) and dried to provide 3-iodobenzoic acid (222 mg, 90% yield) as white, fine needles.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][NH:12][CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:23][CH:24]=3)[CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3]
Reactant: BrCc1ccc(-c2ccccn2)cc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg, 0.45 mmol), 2-(4-(bromomethyl)phenyl)pyridine (160 mg, 0.65 mmol) and potassium carbonate (120 mg, 0.87 mmol) in anhydrous DMF is stirred at room temperature overnight. After routine workup, the obtained crude product is purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 389.2 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].O[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][C:28]=1[O:41][CH3:42].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][C:28]=3[O:41][CH3:42])[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: COc1cc(-c2ccccc2C#N)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4′-(hydroxymethyl)-3′-methoxybiphenyl-2-carbonitrile (1.7 g), 1,1′-(azodicarbonyl)dipiperidine (2.2 g), tributylphosphine (2.2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (1.9 g, 80%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH2:26][CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=3)[C:13]([C@@H:15]([O:22]C(=O)C)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:14])=[CH:9][CH:10]=2)[C:5]([CH3:38])=[N:4]1)[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH2:26][CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=3)[C:13](=[O:14])[C@@H:15]([OH:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:9][CH:10]=2)[C:5]([CH3:38])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)c2cc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)[C@@H](OC(C)=O)c3ccccc3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1nc(C)c2cc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)[C@@H](O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of acetic acid (S)-{(1-ethyl-3-methyl-1H-indazol-5-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-carbamoyl}-phenyl-methyl ester (150 mg, 0.286 mmol) in tetrahydrofuran (2.0 mL) were added 1.0 mL water and 20.0 mg (0.84 mmol) lithium hydroxide monohydrate. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 89 mg (65%) of the title compound as a colourless oil. MS(m/e): 483.1 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=1.[Si:12]([C:16]#[CH:17])([CH3:15])([CH3:14])[CH3:13].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[F:9][C:8]([F:11])([F:10])[CH2:7][N:5]1[CH:6]=[C:2]([C:17]#[C:16][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=[N:4]1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)Cn1cc(I)cn1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn(CC(F)(F)F)c1
Temperature: 60 °C
Yield: 97.6 %

Procedure:
4-Iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (Preparation 146, 970 mg, 3.51 mmol) was dissolved in DMF (4.9 mL) and TMS-acetylene (0.7 ml, 486 mg, 4.96 mmol) was added; followed by di-isopropylamine (0.65 mL), copper(I) iodide (44 mg) and triphenylphosphine (184 mg). The reaction was flushed with nitrogen. Palladium acetate (52.5 mg) was added and the reaction flushed again with nitrogen (×3) before heating at 60° C. for 60 minutes. The reaction was cooled and added to water (50 mL). The product was extracted with ether (3×25 mL). The combined organic layers were washed with water (3×20 mL) and brine, then dried (MgSO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 1:2 ethyl acetate:cyclohexane to afford the title compound (844 mg, 97%). 1H-NMR (CDCl3, 500 MHz): δ 0.24 (s, 9H), 4.68 (q, J=8.20, 2H), 7.66 (s, 1H), 7.67 (s, 1H).
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[CH3:13][C:14]([CH3:25])([CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[CH:15]=O.C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)C>[CH3:13][C:14]([CH3:25])([C:15]#[CH:1])[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CC(C)(C=O)COC1CCCCO1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#CC(C)(C)COC1CCCCO1
Reaction time: 8 h
Yield: 47.7 %

Procedure:
(1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (486 mg, 2.54 mmol) was added to a stirred suspension of 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionaldehyde (315 mg, 1.69 mmol) and K2CO3 (700 mg, 5.07 mmol) in methanol (20.0 mL) at room temperature. After overnight stirring, the reaction was diluted with diethyl ether, washed with sat. NaHCO3, brine, dried over Na2SO4 and concentrated to provide a crude oil. Purification by flash column chromatography on silica gel using 20% ethyl ether in hexanes provided 2-(2,2-dimethyl-but-3-ynyloxy)-tetrahydro-pyran (147 mg, 48%) as a pale liquid.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])[CH3:8])=[N:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:4]2[CH:3]=[C:2]([I:1])[N:6]=[C:5]2[CH:7]([CH3:9])[CH3:8])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)c1ncc(I)[nH]1
Product: CC(C)c1nc(I)cn1-c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=331.1 (M+H+), was prepared in accordance with the general method of example 7 from 5-iodo-2-isopropyl-1H-imidazole and 4-fluorobenzene boronic acid.
Reaction SMILES: C([NH:8][CH2:9][C:10]1[N:14]2[C:15]3[C:20]([N:21]=[C:22]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:13]2=[N:12][CH:11]=1)=[CH:19][C:18]([C:28]([F:31])([F:30])[F:29])=[CH:17][CH:16]=3)C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:9][C:10]1[N:14]2[C:15]3[C:20]([N:21]=[C:22]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[C:13]2=[N:12][CH:11]=1)=[CH:19][C:18]([C:28]([F:29])([F:31])[F:30])=[CH:17][CH:16]=3
Reactant: [H][H]
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(CNCc3ccccc3)cnc12
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NCc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Yield: 47.2 %

Procedure:
To a solution of 3-({1-[(benzylamino)methyl]-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl}amino)propan-1-ol (23 mg, 0.05 mmol) in methanol (600 μL) were added 5% Pd/C (21 mg, 0.01 mmol) and para-toluenesulfonic acid (2 mg, 0.01 mmol). The mixture was stirred under one hydrogen atmosphere for 4 days at room temperature. The reaction mixture was filtered on Celite and rinsed with methanol and dichloromethane. The crude product was purified by preparative TLC (dichloromethane/methanol 9/1) to give the title compound (8 mg, 43%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1.[F:16][C:17]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH2:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:16][C:17]([F:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Reactant: NCC(F)(F)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)cnc(NCC(F)(F)c2ccccc2)c1=O
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a stirred suspension of 3-bromo-1-(ethoxycarbonylmethyl)-6-methylpyrazinone (750 mg, 2.75 mmol), as prepared in step 5 of Example 2, in toluene (30 mL) was added 2,2-difluoro-2-phenylethylamine (900 mg, 5.75 mmol), as prepared in the preceding step. The mixture was refluxed for two days under nitrogen. The solution was allowed to cool to room temperature, and ethyl acetate (50 mL) was added. The diluted reaction mixture was washed with 10% HCl (2×20 mL) and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (50 mL), brine, and dried over Na2SO4. After evaporating the solvent, the solid was collected and washed with 15% ethyl acetate in hexane to give the title compound as an off-white solid (730 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2 H), 7.43 (m, 3 H), 6.67 (s, 1 H), 6.14 (s(br), 1 H), 4.70 (s, 2 H), 4.24 (q, 2 H, J=7.1 Hz), 4.09 (td, 2H, J=14.3, 6.5 Hz), 2.11 (s, 3 H), 1.29 (t, 3 H, J=7.1 Hz).