Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[O:7]([C:15]1[CH:16]=[C:11]([Cl:10])[N:12]=[CH:13][N:14]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cc(Oc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of phenol (1.1 g) in dimethylformamide (20 mL) was slowly added sodium hydride (60%, 805 mg) at 0° C. After the resultant mixture was stirred at 0° C. for 30 minutes, 4,6-dichloropyrimidine (1.5 g) was added, followed by stirring at 25° C. for 1 hour and then addition of saturated aqueous ammonium chloride solution (20 mL). Then, the obtained mixture was diluted with ethyl acetate (50 mL) and washed three times with brine (30 mL each time). An organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The title compound (1.2 g) was obtained by silica gel column chromatography (ethyl acetate/n-hexane=1/10).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.[CH:27]([N:30](C(C)C)CC)(C)C.CN>S(Cl)(Cl)=O.C1COCC1.CCOC(C)=O>[CH3:27][NH:30][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:16][N:15]=[CH:14]3)[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
4-Methyl-3-(1-morpholinophthalazin-6-yl)benzoic acid (100 mg, 286 μmol) was dissolved in thionyl chloride (5.7 mL) and heated to 65° C. for 1 h. The reaction was then concentrated in vacuo, dissolved in tetrahydrofuran 99.9% (5.7 mL) and diisopropylethylamine (150 μL, 859 μmol) and methylamine, 2.0 m solution in THF (0.7 mL) were added. The reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layers were washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated via rotovap to give a crude product. After purification by chromatography, the title compound was obtained. Found MS (ES+): 363(M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH3:15].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=1>>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C@H:10]([CH3:15])[CH2:11]2)=[O:22])=[C:19]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:18]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNC[C@H]2C)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)C[C@H]2C)c(C)c1
Yield: 73.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 67 and using (R)-1-(2,4-dimethylphenyl)-2-methylpiperazine (1.2 g) and 4-bromo-2-methanesulfonylbenzoic acid (1.7 g), (4-bromo-2-methanesulfonylphenyl)[(R)-4-(2,4-dimethylphenyl)-3-methylpiperazin-1-yl]methanone (2.0 g) was obtained.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:4]=[C:5]([C:9](=[CH2:14])[C:10]([O:12]C)=[O:11])[CH:6]=[CH:7][CH:8]=1>[OH-].[Li+].O.C(#N)C.CCCCCCC>[OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[CH:4]=[C:5]([C:9](=[CH2:14])[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(C(=O)OC)c1cccc(C(O)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCCCCCC
Product: C=C(C(=O)O)c1cccc(C(O)c2ccccc2)c1

Procedure:
A mixture of 2.40 g (8.96 mmol) of methyl 2-(3-(hydroxy-phenyl-methyl)-phenyl)-propenoate (product from Example 15a) in 1.76 g of lithium hydroxide, 16 ml of water, 18 ml of acetonitrile and 18 ml of heptane is treated overnight with intensive stirring using a mechanic stirrer. The acetonitrile/water phase is then separated and concentrated. The resulting residue is taken up in ethyl acetate and extracted with sodium hydroxide solution. The basic extract is acidified using hydrochloric acid and extracted with ethyl acetate, dried and concentrated. Yield: 1.87 g (7.36 mmol) (82.1% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][N:4]=1.Cl[CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:7]2[S:8][CH:13]=[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:9]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COc1ccc(C(N)=S)cn1
Product: COC(=O)Cc1csc(-c2ccc(OC)nc2)n1

Procedure:
This material was prepared according to the procedure described for Example 24(a) using 6-methoxythionicotinamide (Maybridge) (1.68 g, 10.0 mmol) and methyl 4-chloroacetoacetate (1.42 g, 10.0 mmol). Chromatography (gradient elution: 0-20% EtOAc in hexanes) of the crude material afforded the compound as an off-white solid. MS m/z: 265 (M+1). Calc'd for C12H12N2O3S: 264.06.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:19]3)[CH:12]=[C:7]12.[CH2:26]([Zn]CC)[CH3:27]>O1CCOCC1.CCOC(C)=O.Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:26]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:19]3)[CH:12]=[C:7]12)[CH3:27]
Reactant: CC[Zn]CC
Reactant: CC(C)c1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cccc2c1CCN1C(=O)CN=C(n3cnc(C(C)C)c3)C=C21
Temperature: 80 °C
Reaction time: 0.02 h
Yield: 31.9 %

Procedure:
To a degassed solution of 9-iodo-2-(4-isopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (20 mg, 0.045 mmol) and PdCl2(dppf)-CH2Cl2 adduct (2 mg, 2.24 μmol) in dioxane (1 mL) was added diethylzinc (135 μL, 0.135 mmol, 1M in hexane) and the mixture was heated in the microwave at 80° C. for 44 h. The reaction mixture was allowed to warm to rt and then diluted with AcOEt and 2M aqueous HCl. The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by SFC (column: Diol 5 μm, 250×30 mm, 60A, Princeton; eluent: 7% MeOH/CO2 for 1 min, then from 7% MeOH/CO2 to 12% MeOH/CO2 in 6 min; flow 100 mL/min; UV detection at 220 nm) to yield the title compound (5 mg). UPLC-MS: MS 349.2 (M+H+); UPLC rt 1.01 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.21-1.28 (m, 9H) 2.72 (q, J=7.4 Hz, 2 H) 2.85-2.92 (m, 1 H) 2.96 (t, J=6.2 Hz, 2 H) 3.91 (t, J=6.3 Hz, 2 H) 4.35 (br. s., 2 H) 6.61 (s, 1 H) 7.18 (s, 1 H) 7.27-7.38 (m, 2 H) 7.52 (d, J=7.3 Hz, 1 H) 7.93 (s, 1 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][O:6][C@@H:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@@H:3]1[OH:21].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:8]([C@H:5]1[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:7][O:6]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(CN[C@H]2CO[C@@H](C(c3ccccc3)c3ccccc3)C[C@@H]2O)cc1

Procedure:
(2R, 4S, 5S)-5-amino-2-benzhydryl-tetrahydropyran-4-ol 31b (0.02 g, 0.07 mmol) was reacted with 4-hydroxybenzaldehyde (0.009 g, 0.071 mmol), glacial acetic acid (0.004 g, 0.071 mmol) and NaCNBH3 (0.005 g, 0.085 mmol) (Procedure H) to give (2R, 4S, 5S)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydropyran-4-ol, (+)-32a, 0.023 g (85%, [α]D=(+)72.4, c=1, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH3:22])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:11]([CH2:21][CH3:22])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: CCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole (230 mg, 0.66 mmol) from Step A (higher Rf isomer) in THF (4 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.500 mL, 0.80 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.130 mL, 1.3 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (3×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: COC1C=CC([CH2:7][C:8]([O:13][C:14](=[O:30])[C@H:15]([CH:27]([CH3:29])[CH3:28])[NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])(C)[C:9]([O-:11])=[O:10])=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:15]([C:14]([O:13][CH:8]([CH3:7])[C:9]([OH:11])=[O:10])=[O:30])[CH:27]([CH3:28])[CH3:29])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: COc1ccc(CC(C)(OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxybenzyl-2-(N-CBZ-L-valyloxy)-propionate (7.8 g, 17.5 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml) and the solution was stirred for one hour at room temperature. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography. Yield: 5.0 g 1H-NMR (CDCl3) 0.94 (m, 6H) 1.56 (d, 3H) 2.30 (m, 1H) 4.42 (m, 1H) 5.12-5.30 (m, 4H) 7.28 (m, 5H)
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].Br[C:24]1C=CC(OC(F)F)=C(C=1)C(NC)=O>>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:21])([CH3:20])[O:14]2)=[CH:9][C:5]=1[C:6]([NH:8][CH3:24])=[O:7]
Reactant: CNC(=O)c1cc(Br)ccc1OC(F)F
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(C(N)=O)c2)OC1(C)C
Product: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(F)F

Procedure:
2-Difluoromethoxy-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide was prepared in a similar way as 2-Difluoromethoxy-5-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-benzamide using 5-bromo-2-difluoromethoxy-N-methyl-benzamide as the starting material.
Reaction SMILES: [NH2:1][C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>O1CCCC1.O>[CH:36]1([C:39]([NH:1][C:2]2[N:28]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[CH:13][C:14]([CH3:27])=[C:15]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:40])[CH2:38][CH2:37]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)nn4c3)ccc2C)n(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)n(C)n1
Yield: 60 %

Procedure:
To a solution of N-{5-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (158 mg, 0.419 mmol) and triethylamine (63.8 μL, 0.461 mmol) in tetrahydrofuran (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (41.9 μL, 0.461 mmol), and the mixture was stirred at room temperature for 1 hr. Cyclopropanecarbonyl chloride (83.8 μL, 0.922 mmol) was further added and the mixture was stirred for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, sodium carbonate (200 mg), methanol (3 mL) and water (100 μL) were added to the residue, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate to give the title compound (112 mg, 60%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>CN(C=O)C.C(Cl)Cl>[CH2:16]([C:7]1([CH2:5][CH2:4][CH2:3][CH:11]=[CH2:10])[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCCC1(CCCC=C)Cc2cc(OC)ccc2C1=O
Reaction time: 6 h

Procedure:
To a solution of 5-methoxy-1-indanone (2.5 g, 15.4 mmol) in DMF (20 mL) at rt was added NaH (1.8 g, 61% in oil, 46.2 mmol) and 5-bromo-1-pentene (5.48 mL, 46.2 mmol). After 6 h at rt, the solution was diluted with CH2Cl2 and quenched with saturated aqueous NH4Cl. The slurry was dried with MgSO4 and filtered through a plug of silica and rinsed with 10% EtOAc in hexanes. The filtrate was concentrated and provided crude 2,2-di(4-pentenyl)-5-methoxy-1-indanone.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]2[CH2:41][O:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[O:27])=[CH:21][CH:20]=1)=[O:18]>CO>[ClH:1].[ClH:1].[CH3:15][NH:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH:29]2[CH2:41][O:42][C:43]2[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=2)=[O:27])=[CH:23][CH:24]=1)=[O:18]
Reactant: CNC(=O)c1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(NC(=O)N2CCNCC2COc2cccnc2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-(methylcarbamoyl)phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (103 mg, 0.177 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 42.8 mg (55%) of the title compound as a white solid. LC-MS: RT=2.22 min, [M+H]+=370.1.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])=[C:15]([O:30]C)[CH:14]=1.Br.C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:12][C:13]2[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:18])=[C:15]([OH:30])[CH:14]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: COc1cc(N)ccc1C(=O)NCc1ccc(C)nc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(CNC(=O)c2ccc(Nc3ncc(Br)n4ncnc34)cc2O)cn1

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (285 mg, 1.03 mmol) and 4-amino-2-methoxy-N-[(6-methylpyridin-3-yl)methyl]benzamide (280 mg, 1.03 mmol) are stirred in iPrOH (5 mL) and HBr (48% aq., 380 μL) is added. The mixture is heated at reflux for 24 hours. The cooled suspension is poured into NaHCO3 (sat. aq., 25 mL) and water (25 mL) and extracted with CHCl3 (4×30 mL). The extracts are dried over MgSO4 and evaporated. The residue is purified by column chromatography, eluting with 10% CH2Cl2/MeOH. The product-containing fractions are evaporated and the residue is triturated with MeOH to afford the title compound as a brown solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:13])([F:12])[O-:11].CN([S+](N(C)C)N(C)C)C>C(#N)C>[F:9][C:10]([O:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([F:13])[F:12]
Reactant: [O-]C(F)(F)F
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Product: FC(F)(F)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
Benzyl bromide, 12.47 g (0.073 mol), was added dropwise at 25° to a solution of 0.081 mol of tris(dimethylamino)sulfonium trifluoromethoxide (prepared as in Example 1) in 75 mL of acetonitrile. The reaction mixture was stirred at 25° for 18 h and then poured into ice-water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and distilled to give 10.55 g (85%) of benzyl trifluoromethyl ether as a colorless oil: bp 45°-46° (18 mm); 1H NMR (CDCl3) δ4.93 ppm (s, 2H), 7.33 ppm (s, 5H); 19F NMR (CDCl3) δ-60.6 ppm (s). Anal. Calcd. for C8H7F3O: C, 54.55; H, 4.01; F, 32.36. Found: C, 54.76; H, 4.04; F, 32.51.
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:24][CH2:23]3)=[CH:16][CH:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[CH:7][CH:8]=2)[C:3]1=[O:27].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH3:1][N:2]1[C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:24])[CH2:23][NH:31][CH:28]([CH3:30])[CH3:29])=[CH:16][CH:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[CH:7][CH:8]=2)[C:3]1=[O:27]
Reactant: COc1ccc2cc(CCc3ccc(OCC4CO4)cc3)n(C)c(=O)c2c1
Reactant: CC(C)N
Product: COc1ccc2cc(CCc3ccc(OCC(O)CNC(C)C)cc3)n(C)c(=O)c2c1
Yield: 77 %

Procedure:
2-Methyl-3-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example 1b from 2-methyl-3-[4-(2,3-epoxypropoxy)-phenethyl]-7-methoxy-isoquinolin-1(2H)-one and isopropylamine.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[C:20]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1

Procedure:
8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 3-(methanesulfonyl)phenyl boronic acid (1.0 g, 5.0 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.99 g, 73%). MP=173-183° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.64-8.60 (m, 1H), 8.59 (t, J=1.6 Hz, 1H), 8.50-8.46 (m, 1H), 7.98-7.94 (m, 1H), 7.86-7.83 (m, 1H), 7.78 (dd, J=7.8, 7.8 Hz, 1H), 7.02 (dd, J=7.1, 7.1 Hz, 1H), 6.18 (s, 1H), 3.29 (S, 3H). MS=289 (MH)+. 13b) [8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine and [8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-phenyl-amine were prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (90.0 L, 0.434 mmol) in a manner analogous to Step 2d. The title compound 8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine was isolated as a yellow foam (0.047 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.66 (t, J=1.7 Hz, 1H), 8.47-8.44 (m, 1H), 8.39-8.35 (m, 1H), 8.01-7.97 (m, 1H), 7.26 (dd, J=7.8, 7.8 Hz, 1H), 7.68-7.65 (m, 1H), 7.54-7.48 (m, 2H), 6.99 (dd, J=7.0, 7.0 Hz, 1H), 6.96-6.92 (m, 2H), 6.91 (s, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.13 (s, 3H), 2.91 (t, J=6.1 Hz, 2H), 2.68-2.58 (m, 4H), 1.85-1.78 (m, 4H). MS=478 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(O)COCCOC2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2COCCOC2)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 6-(4-methoxyphenyl)-[1,4]-dioxepan-6-ol (6.20 g, 0.028 mol) in CH2Cl2 was added triethylsilane (3.53 g, 0.031 mol) and trifluoroacetic acid (35.1 g, 0.31 mol). The reaction mixture was allowed to stir overnight. The reaction was made basic with K2CO3 solution until pH=10. The organic layer was dried (MgSO4), filtered and evaporated to dryness to give the desired product as a red oil (5.84 g, 100%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20].C(N(C(C)C)CC)(C)C>ClCCCl>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 75 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (3.03 g, 12.2 mmol) and 4-nitrobenzene-1-sulfonyl chloride (2.99 g, 13.5 mmol) in 1,2-dichloroethane (60 mL) was added diisopropylethylamine (6.6 mL, 4.90 g, 37.9 mmol). The mixture was stirred at 75° C. for 15 hours. The mixture was quenched by addition of saturated aqueous sodium bicarbonate (80 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (30% EtOAc/hexane) to give tert-butyl 1-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (4.6 g).