Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:24][CH2:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[N:50]=[CH:49][C:48]2[C:43](=[C:44]([F:55])[CH:45]=[C:46]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:47]=2)[C:42]1=[O:56])(=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[C:51]([C:46]1[CH:47]=[C:48]2[C:43](=[C:44]([F:55])[CH:45]=1)[C:42](=[O:56])[N:41]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[N:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:26]=1[CH2:25][OH:24])[N:50]=[CH:49]2)([CH3:54])([CH3:52])[CH3:53]
Reactant: Cn1nc(Cl)cc(Nc2cnc(C(F)(F)F)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCCCO
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cnc(C(F)(F)F)cn2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
A solution of 6-chloro-2-methyl-4-(5-(trifluoromethyl)pyrazin-2-ylamino)pyridazin-3(2H)-one (109 mg, 0.36 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (264 mg, 0.54 mmol), potassium phosphate (189 mg, 0.89 mmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (17.0 mg, 0.04 mmol) in n-butanol (4 ml) and water (1 ml) was bubbled argon gas for 10 min. To this solution was added bis(dibenzylideneacetone)dipalladium(0) (10.3 mg, 0.02 mmol) was added and the resulting mixture heated to 100° C. for 2 hr. The mixture was cooled and then poured into a saturated ammonium chloride solution. The resulting mixture was extracted with methylene chloride (2×100 ml). The organic phases were combined and dried over MgSO4. The mixture was filtered and evaporated and the residue dissolved in dioxane (10 mL). To this solution was slowly added a 2 M lithium hydroxide solution (0.5 mL) and the resulting mixture stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution. The mixture was extracted with methylene chloride (2×150 ml). The organic phases were combined and dried over MgSO4. The mixture was filtered and evaporated and the residue purified via automated flash chromatography (Analogix, SF15-24 g column, 1%-10% methanol/dichloromethane gradient) to give a light yellow solid which was recrystallized from methanol/dichloromethane to give 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[1-methyl-6-oxo-5-(5-trifluoromethyl-pyrazin-2-ylamino)-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one (65 mg, 31%) as a white solid: Mp 250-254° C.; LC/MS m/e calculated for C29H25F4N7O3 [M+H]+ 596.20, observed 596.3; 1H NMR (DMSO-d6) δ: 10.38 (s, 1H), 8.71-9.08 (m, 2H), 8.43-8.66 (m, 2H), 7.68-8.02 (m, 2H), 7.38-7.65 (m, 3H), 4.54-4.76 (m, 1H), 4.40 (br. s., 2H), 3.82 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH2:18]O)([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.N1C(C)=CC(C)=CC=1C.[F:42]C(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH2:18][F:42])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CO)C3)n1
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CF)C3)n1
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (227) (62 mg, 0.140 mmol) and 2,4,6-collidine (0.0359 mL, 0.271 mmol) in dry CH2Cl2 was added trifluoromethanesulfonic acid anhydride (0.0365 mL, 0.217 mmol) at 0° C. The mixture was stirred at 0° C. to room temperature for 1 hr. TLC indicated that the reaction was complete. The reaction was quenched with 0.5 N aqueous HCl, extracted with 3×CHCl3, dried over Na2SO4, and concentrated. The residue was dissolved in anhydrous CH2Cl2(3 mL), and TBAF (1 mL, 1 M in THF) was added. The resulting mixture was stirred at room temperature for 1.5 hr, quenched with H2O, and extracted with 3×CHCl3. The combined organic layer was dried over Na2SO4, concentrated, and purified by column chromatography eluting with 50-65% EtOAc in hexanes to give a white solid (18 mg, 28% yield). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1 H) 7.84-7.96 (m, 2 H) 7.25-7.31 (m, 2 H) 7.02-7.15 (m, 3 H) 6.72-6.83 (m, 1 H) 4.26-4.54 (m, 2 H) 3.79 (s, 3H) 3.20 (d, J=16.67 Hz, 1H) 3.08 (s, 3 H) 2.89 (dd, J=16.67, 1.77 Hz, 1 H) 1.52 (s, 3 H); LCMS for C22H22FN3O5S m/z 460.00 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]4[CH:25]=[C:24]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)[CH:23]=[CH:22][C:21]=4[NH:31]C(=O)OC(C)(C)C)=[O:18])[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)Cl.FC(F)(F)C(O)=O.[OH-].[K+]>C(Cl)Cl.[Cl-].[Na+].O>[NH2:31][C:21]1[CH:22]=[CH:23][C:24]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[CH:25][C:20]=1[NH:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[CH2:12][CH2:13]1)=[O:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(-c2cccs2)cc1NC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Yield: 64.5 %

Procedure:
A solution of compound 315 (165 mg, 0.31 mmol) in a mixture DCM-trifluoroacetic acid (3 mL, 2:1 ratio) was stirred at room temperature for 1.5 h; diluted with DCM and washed with a solution of KOH (830 mg, 15 mmol) in brine (15 mL), then brine, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (elution with 5% to 10% MeOH in DCM) gave title compound 316 (87 mg, 0.20 mmol, 64% yield) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26]Br)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][N:6]1[CH2:7][CH2:8][C:3]([C:1]#[N:2])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:4][CH2:5]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Cc1ccccc1C1(C#N)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1C1(C#N)CCN(CCCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-cyano-4-(o-tolyl)piperidine (5.00 g, 24.9 mmol) and 1-(tert-butoxycarbonylamino)-3-bromopropane (16, 6.55 g, 27.5 mmol) in DMF (100 mL) was treated with diisopropylethylamine (4.50 mL, 25.8 mmol) at room temperature. The resulting mixture was stirred at room temperature (3 d). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (5% methanol/dichloromethane) afforded the title compound (25).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH3:22][CH:23]1[CH2:27][C:26]2[CH:28]=[C:29]([CH2:32][CH2:33][O:34]S(C3C=CC(C)=CC=3)(=O)=O)[CH:30]=[CH:31][C:25]=2[O:24]1>O>[CH3:22][CH:23]1[CH2:27][C:26]2[CH:28]=[C:29]([CH2:32][CH2:33][O:34][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:30]=[CH:31][C:25]=2[O:24]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CC(C)O3)cc1
Reactant: CON(C)C(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Nc1ccccc1OCCc1ccc2c(c1)CC(C)O2
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
2.0 g of 1-(3-hydroxyphenyl)-3-methoxy-3-methylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.4 g of 60% sodium hydride was added thereto. After the mixture was stirred for 30 minutes, 3.3 g of 2-(2,3-dihydro-2-methyl-5-benzofuranyl)ethyl-p-toluene sulfonate was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 3.3 g of Compound No. 49 shown in Table 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=3)[N:11]=2)[N:8]=1.CC(O)=O>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH:13]=3)[NH2:19])[N:11]=2)[N:8]=1
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(C)c(N)c3)cn2n1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
To a stirred solution of 6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.5 g, 1.75 mmol) in ethanol (20 mL) and water (5 mL) containing AcOH (10.5 mmol) is added iron (0.491 g, 8.79 mmol). The mixture is heated at 80° C. for 4 hours, cooled, concentrated under reduced pressure, and sat. aqueous NaHCO3 (100 mL) is added. The mixture is extracted with EtOAc (3×50 mL), the organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford the title compound (0.328 g, 73%) as a light yellow solid: Rf 0.21 (EtOAc); LCMS (m/z)=255.5 [M+H]+, tR=4.89 min. (10 min run).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C(O)CC>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(N)=O)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: CCCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C(N)=O)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-carbamoyl-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 200 mg, 0.430 mmol) in 6 mL of DCM was added 2 mL of TFA. After stirring at RT for 3 h, the mixture was treated with 20 mL of n-propanol and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (4-6% MeOH/DCM) to afford 88.0 mg (61%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.41 (d, 1H, J=8.6 Hz), 8.03 (s, 1H), 7.81 (dd, 1H, J=8.6, 2.3 Hz), 7.74 (d, 1H, J=2.3 Hz), 5.89 (m, 1H), 2.20-2.38 (m, 4H), 1.71-1.95 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C18H17N5O2, 336.1 (M+H), found 336.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[C:16]=2[CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:40]2[C:41]([C:47]([F:50])([F:49])[F:48])=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:40]4[C:41]([C:47]([F:50])([F:49])[F:48])=[N:42][C:43]([NH2:46])=[N:44][CH:45]=4)=[N:18][C:17]=3[C:16]=2[CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)nc2C(F)(F)F)OC1(C)C
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3C(F)(F)F)nc12

Procedure:
4-(2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (200 mg), prepared as in Example 118, was coupled to 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-pyrimidin-2-ylamine via General Procedure A to yield 30 mg of 4-[2-(2-Amino-4-trifluoromethyl-pyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C1COCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.Cl>O.CCOC(C)=O>[F:9][C:8]([F:11])([F:10])[C:16]1([OH:20])[CH2:17][CH2:18][CH2:19][O:14][CH2:15]1
Reactant: O=C1CCCOC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCCOC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
To a round-bottom flask equipped with a stir bar and placed under N2 atmosphere was added THF (50 mL), then trimethyl(trifluoromethyl)silane (1.03 mL, 6.99 mmol). The solution was cooled to 0° C. and to the solution was added dihydro-2H-pyran-3(4H)-one (500 mg, 4.99 mmol). The solution was stirred for 5 minutes at 0° C. and then was allowed to warm to room temperature with stirring for 30 minutes. The solution was cooled to 0° C. and to the solution was added aq 1M HCl (50 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with water and EtOAc and was transferred to a separatory funnel. The organic phase was isolated; washed with brine; dried over MgSO4, filtered; then concentrated in vacuo to afford 3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol as a colorless oil (0.40 g, 47%). 1H-NMR (400 MHz, CDCl3) δ 4.01-3.93 (m, 1H), 3.82 (dd, J=11.8, 2.5 Hz, 1H), 3.60 (d, J=12.0 Hz, 1H), 3.41 (td, J=11.8, 2.5 Hz, 1H), 2.10-2.08 (m, 2H), 1.97-1.90 (m, 1H), 1.82 (dd, J=12.9, 4.4 Hz, 1H), 1.65-1.55 (m, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1)[C:2]#[CH:3].[CH:21]([C:23]1[N:24]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:25]=[CH:26][N:27]=1)=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CO.O>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:24]1[CH:25]=[CH:26][N:27]=[C:23]1[CH2:21][N:10]([CH2:9][C:8]1[CH:19]=[CH:20][C:5]([O:4][CH2:1][C:2]#[CH:3])=[CH:6][CH:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)Cn1ccnc1C=O
Reactant: C#CCOc1ccc(CNCCCCCC(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#CCOc1ccc(CN(CCCCCC(=O)O)Cc2nccn2CC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A solution of 6-((4-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid (0.4125 g, 1.50 mmol), tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (0.315 g, 1.50 mmol) and AcOH (0.05 mL) in DCE (40 mL) at 0° C. was treated with NaBH(OAc)3 (0.636 g, 3.0 mmol). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for overnight and decomposed with water and methanol. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by Biotage SP4 over silica gel to afford 6-(((1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-(prop-2-yn-1-yloxy)benzyl)amino)hexanoic acid (0.268 g, 38%). MS (ESI), 470.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:10][CH:9]=2)[C:5]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:6]1[C:24]([OH:26])=[O:25])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1C(c1ccccc1)c1ccccc1
Product: CS(=O)(=O)Nc1ccc2c(c1)c(-c1ccccc1)c(C(=O)O)n2C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzhydryl-3-phenyl-1H-indole-2-carboxylate and methanesulfonyl chloride followed the procedure of Example 1 Step 3 as an off-white solid: 1H NMR (DMSO-d6) δ 2.85 (s, 3H, 6.79 (d, J=9.0 Hz, 1H, 6.95 (dd, J=9.0, 2.0 Hz, 1H, 7.19 (d, J=7.4 Hz, 4H, 7.30-7.50 (m, 12H, 7.91 (s, 1H, 9.37 (s, 1H, 13.21 (br s, 1H; MS (ESI) m/z 495 [M-H]−; HRMS calcd for C29H25N2O4S: 497.1533; found (ESI+): 497.1522; Anal. calcd for C29H24N2O4S.0.7H2O: C, 68.41; H, 5.03; N, 5.50. Found: C, 68.32; H, 4.91; N, 5.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:25]([N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:15]=[CH:16][C:17]=2[CH2:23]1)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2ccncc2)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a mixture of N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (94.8 mg, 0.30 mmol) and isonicotinoyl chloride hydrochloride (56.1 mg, 0.32 mmol) in THF (2.0 mL) at room temperature was added N,N-diisopropylethylamine (0.157 mL, 0.90 mmol). After stirring for 3 hours at room temperature, an additional 21 mg of isonicotinoyl chloride hydrochloride was added and the reaction continued for 17 hours. The reaction was quenched with H2O, then treated with an EtOAc/saturated NaHCO3(aq) solution work-up to give an off-white solid. The solid was recrystallized from EtOAc/hexane to afford a white solid (115 mg, 91%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[C:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].N1CCCC1>CO>[C:19]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:2][C:1](=[O:3])[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:11]4[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=4)[C:17]#[N:18])[CH:5]=3)[O:10]2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cc(-c2cccc(C#N)c2)ccc1O
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: CC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 3′-acetyl-4′-hydroxybiphenyl-3-carbonitrile (0.802 g, 3.38 mmol) and 1-acetylpiperidin-4-one (0.477 g, 3.38 mmol) in MeOH (50 mL) was added pyrrolidine (0.4 mL). The resulting solution was heated to reflux for 1.5 h. The reaction mixture was cool down to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with aqueous 1 M HCl, aqueous 1 M NaOH, and brine successively. Solvent was removed under reduced pressure after dried over anhydrous Na2SO4, to yield 0.768 g of 3-(1′-acetyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)benzonitrile as a light brown solid. It was used for next step without further purification. MS ESI +ve m/z 361 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:3]1.C([Li])CCC.[Si:18]([O:25][C:26]1[C:27]([F:36])=[C:28]([CH:31]=[C:32]([CH2:34][CH3:35])[CH:33]=1)[CH:29]=[O:30])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][C:26]1[C:27]([F:36])=[C:28]([CH:29]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)[OH:30])[CH:31]=[C:32]([CH2:34][CH3:35])[CH:33]=1)([C:21]([CH3:22])([CH3:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: Cn1cnc(-c2ccccc2)n1
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)nn2C)c1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
To a solution of 1-methyl-3-phenyl-1H-1,2,4-triazole (310 mg, 1.95 mmol, see J. Chem. Soc., 1954, 3319-3322) in THF (25 mL) cooled to −78° C. was added 1.6 M n-butyl lithium (1.33 mL, 2.12 mmol) dropwise and stirred for 15 min. Next a solution of Intermediate 368.2 (500 mg, 1.77 mmol) in THF (5 mL) was added dropwise and stirred for 5 min before allowing the mixture to warm to 23° C. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc (3×50 mL). The organic layer was washed with H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 440 mg of Example 368.3. HPLC (2 min gradient) RT=2.42 min.
Reaction SMILES: [N:1]1([C:7](OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:20]=[CH:19]C(F)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:31]>CN(C=O)C.CCOCC.CO>[ClH:31].[Br:14][C:15]1[CH:20]=[CH:19][C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1N1CCNCC1
Yield: 99 %

Procedure:
Using similar reaction conditions as described in (step i of Intermediate-2), tert-butyl piperazine-1-carboxylate (1.5 g, 6.81 mmol) was reacted with 4-bromo-1-fluoro-2-nitrobenzene (1.28 g, 6.81 mmol) in DMF (25 ml) and potassium carbonate (2.35 g, 17.02 mmol) to afford crude product. Using similar reaction conditions as described in Step-ii of example-7, above crude was deprotected in HCl in ether/methanol (10/10 ml). This afforded 2.0 g (99% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](I)[CH2:8][CH3:9].Cl.[CH3:12][N:13]1[C:21]2[C:16](=[C:17]([C:22]3([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>CN(C)C=O.O>[CH2:7]([N:24]1[CH2:25][CH2:26][CH2:27][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[CH:14][N:13]3[CH3:12])([OH:28])[CH2:23]1)[CH2:8][CH3:9]
Reactant: Cn1ccc2c(C3(O)CCCNC3)cccc21
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCCC(O)(c2cccc3c2ccn3C)C1
Reaction time: 20 h

Procedure:
14.5 g of sodium carbonate and 6 ml of propyl iodide were added to a mixture of 12 g of 3-(1-methyl-1H-indol-4-yl)-3-piperidinol hydrochloride in 240 ml of dimethylformamide and the mixture was stirred for 20 hours and then was diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure. The 11 g of residue were chromtographed over silica gel and eluted with a 9-1 cyclohexane-triethylamine mixture to obtain 8.2 g of 1-propyl-3-(1-methyl-1H-indol-4-yl)-3-piperidinol) with an Rf=0.2.