Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+:6]=[N-:7])([CH3:4])[CH3:3].C([Li])CCC.[C:13]([C:15]1[CH:16]=[C:17]([C:21]2([CH3:34])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH:22]2[CH3:33])[CH:18]=[CH:19][CH:20]=1)#[N:14]>O1CCCC1>[CH2:27]([N:24]1[CH2:25][CH2:26][C:21]([CH3:34])([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13]3[N:14]=[N:7][NH:6][C:5]=3[Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:16]=2)[CH:22]([CH3:33])[CH2:23]1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCN1CCC(C)(c2cccc(C#N)c2)C(C)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCN1CCC(C)(c2cccc(-c3nn[nH]c3[Si](C)(C)C)c2)C(C)C1
Reaction time: 0.33 h

Procedure:
To a solution of (trimethylsilyl)diazomethane (2.0 M in hexane, 400 μL, 0.80 mmol) in tetrahydrofuran (10 mL) at 0° C. under an atmosphere of nitrogen was added n-butyllithium (2.5 M in diethyl ether, 320 μL, 0.80 mmol) dropwise. After 20 min, a solution of 4-(3-cyanophenyl)-1-hexyl-3,4-dimethylpiperidine (Preparation 6, 200 mg, 0.67 mmol) in tetrahydrofuran (5 mL) was added such that the internal temperature remained at 0° C. After stirring overnight, the reaction was quenched with saturated aqueous sodium hydrogencarbonate (25 mL) and the mixture was extracted with diethyl ether (3×25 mL). The extracts were washed with water and brine (10 mL each), dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a white foam which was used without further purification (266 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:26][C:27]1[O:28][C:29]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][C:30]=2[N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:34]3[CH:33]=[CH:32][C:30]4[N:31]=[C:27]([CH3:26])[O:28][C:29]=4[CH:35]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCCC3)nc(Cl)nc21
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 90 °C
Yield: 42 %

Procedure:
To a mixture of 2-chloro-4-(cyclopentyloxy)-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzooxazole (1 equiv), tripotassium phosphate trihydrorate (3 equiv) in 1,4-dioxane and water (8:1, 0.5 M) was added 1,1-bis(diphenylphosphion)ferrocene palladium dichloride (0.1 equiv). The mixture was refluxed at 90° C. for 2 h. Filtration and concentration gave the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (42% yield). MS (ESI) m/z 498.2 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14]S(C)(=O)=C>>[CH3:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[C:10]([F:11])([F:12])[F:13]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Reactant: C=S(C)(C)=O
Product: Cc1c([N+](=O)[O-])cccc1C(F)(F)F

Procedure:
reacting 3-nitrobenzotrifluoride with dimethyloxosulfonium methylide to produce 2-methyl-3-nitro-benzotrifluoride; and
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:20][CH:19]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([O:46]C(C)(C)C)=[O:45])[CH:39]=3)=[O:36])[C:18]2=[O:51])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:20][CH:19]([NH:34][C:35](=[O:36])[NH:37][C:38]3[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=3)[C:44]([OH:46])=[O:45])[C:18]2=[O:51])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1cccc(NC(=O)NC2CN(C3CCCCC3)c3ccccc3N(CC(=O)C3CCCCC3)C2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C(=O)O)c1)NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 1-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea (560 mg) in methylene chloride (5 ml), the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, etanol was added to the residue for crystallization, collected by filtration, to thereby obtain 330 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([O:18][CH3:19])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:28][C:24]3[CH:23]=[C:22]([CH3:21])[N:27]=[CH:26][N:25]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Cc1cc(N)ncn1
Reactant: COc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(Cl)c(-c2nc3ccnc(Nc4cc(C)ncn4)c3s2)c(Cl)c1
Temperature: 85 °C
Reaction time: 56 h
Yield: 26.2 %

Procedure:
A mixture of 4-chloro-2-(2,6-dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridine (0.113 g, 0.328 mmol), 6-methylpyrimidin-4-ylamine (0.031 g, 0.328 mmol), XantPhos (0.019 g, 0.033 mmol), Pd2(dba)3 (0.015 g, 0.0164 mmol) and Cs2CO3 (0.213 g, 0.655 mmol) in dioxane (3 mL) was degassed with a stream of argon and the reaction mixture was heated at 85° C. for 18 hours. After cooling to room temperature and standing at room temperature for 56 hours, additional XantPhos (0.019 g) and Pd2(dba)3 (0.015 g) were added. The resultant mixture was then degassed with a stream of argon and heated at 110° C. for 1 hour using microwave irradiation. Additional XantPhos (0.010 g), Pd2(dba)3 (0.008 g) and 6-methylpyrimidin-4-ylamine (0.006 g) were added and the resulting suspension was then degassed with a stream of argon and heated at 110° C. for 1 hour using microwave irradiation. The crude reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-2% MeOH in DCM followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 30 minute gradient 10-80%, 0.1% HCO2H in CH3CN/H2O) to afford the title compound as an off-white solid (36 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.73 (s, 1H), 7.36 (s, 2H), 3.92 (s, 3H), 2.49 (s, 3H). LCMS (Method D): RT=3.65 min, m/z: 418 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[OH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH2:33][CH2:32][CH2:31][CH2:30]2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:26][C:27]3[CH:36]=[CH:35][C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=3)=[CH:22][CH:23]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:9])=[O:10]
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Reactant: Oc1ccc2c(c1)CCCC2
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccc3c(c2)CCCC3)cc1)c1ccccc1Cl
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 6-hydroxy-1,2,3,4-tetrahydronaphtalene, the title compound was isolated as a yellow solid in 69% yield (99% purity by HPLC).
Reaction SMILES: [C-]#N.[Na+].[Br:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([O:11][C:12]2C=CC=[CH:14][CH:13]=2)=[O:10])=[C:7]([OH:20])[CH:6]=1>C(O)CC>[Br:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])=[C:7]([OH:20])[CH:6]=1
Reactant: O=C(Oc1ccccc1)c1ccc(Br)cc1O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCCO
Product: CCCOC(=O)c1ccc(Br)cc1O
Temperature: 25 °C
Yield: 78 %

Procedure:
Sodium cyanide was added to a solution of phenyl 4-bromo-2-hydroxybenzoate (1.45 g) in 1-propanol (10 ml). The mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and evaporated. The residue was partitioned between ether and water. The ether phase was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (Varian Bond Elut S1 silica) using 10% ethyl acetate in pentene as eluent to give n-propyl 4-bromo-2-hydroxybenzoate (1 g), NMR: 1.0(3H,t), 1.72(2H,m), 4.28(2H,t), 7.15(1H,m), 7.24(1H,m), 7.7(1H,d) and 10.7(1H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[CH:6]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:7][CH2:8][N:9]([C:11](=[O:26])[NH:12][CH2:13][CH2:14][CH2:15][C:16]3[N:21]=[C:20]4[NH:22][CH2:23][CH2:24][CH2:25][C:19]4=[CH:18][CH:17]=3)[CH2:10][C:4]=2[CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[CH:6]([CH2:27][C:28]([OH:30])=[O:29])[CH2:7][CH2:8][N:9]([C:11](=[O:26])[NH:12][CH2:13][CH2:14][CH2:15][C:16]3[N:21]=[C:20]4[NH:22][CH2:23][CH2:24][CH2:25][C:19]4=[CH:18][CH:17]=3)[CH2:10][C:4]=2[CH:3]=1
Reactant: COC(=O)CC1CCN(C(=O)NCCCc2ccc3c(n2)NCCC3)Cc2cc(Cl)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCN(C(=O)NCCCc2ccc3c(n2)NCCC3)Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirring solution of methyl 2-{8-chloro-2-[N-(3-(1,2,3,4-tetrahydropyridino[2,3-b]pyridin-7-yl)propyl)carbamoyl]-1H,3H,4H,5H-benzo[e]azepin-5-yl}acetate (1 eq) in tetrahydrofuran (0.05 M) and water (0.05 M) was added lithium hydroxide monohydrate (1.5 eq). The reaction mixture was stirred at room temperature for 10 h. 1 M of hydrogen chloride (1.5 eq) was added and the reaction solvent was evaporated in vacuo. The residue was diluted with (5% MeOH/CH2Cl2 and the precipitate was filtered. The filtrate was concentrated and dried under vacuum oven for 24 h to afford product. EI-MS m/z 457 (M+H)+; 1H NMR (CD3OD; 400 MHz): δ7.53 (d, J=7.3 Hz, 1H), 7.39 (s, 1H), 7.18 (s, 2H), 6.51 (d, 7.3 Hz, 1H), 4.56 (s, 2H), 3.80-3.45 (m, 5H), 3.21 (m, 2H), 2.80 (m, 4H), 2.75 (m, 2H), 2.00-1.50 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([NH2:20])=[O:19])=[CH:8]1.C([O-])(=O)C.[Na+].[F:26][CH2:27][C:28]([CH3:39])([OH:38])[C:29]#[C:30][Si](CC)(CC)CC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:16][C:15]1[C:2]([C:30]#[C:29][C:28]([OH:38])([CH3:39])[CH2:27][F:26])=[CH:3][C:4]2[C:5]3[N:9]([CH:10]4[CH2:17][CH:12]([C:13]=2[CH:14]=1)[CH2:11]4)[CH:8]=[C:7]([C:18]([NH2:20])=[O:19])[N:6]=3
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: CC[Si](C#CC(C)(O)CF)(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(O)(C#Cc1cc2c(cc1F)C1CC(C1)n1cc(C(N)=O)nc1-2)CF
Temperature: 100 °C

Procedure:
To a vial containing 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide (0.1 g), palladium acetate (0.05 eq), sodium acetate (4 eq) and tetrabutylammonium chloride (1 eq) was added DMF (15 mL/mmol) and 1-fluoro-2-methyl-4-triethylsilyl-but-3-yn-2-ol (2 eq) dropwise. The reaction was sealed and heated to 100° C. for 15 minutes in a biotage microwave. The reaction mixture was extracted with DCM and saturated ammonium chloride. The organic layer was dried with magnesium sulfate, filtered, concentrated to dryness and purified by reverse phase hplc to afford (±) 10-fluoro-9-(4-fluoro-3-hydroxy-3-methylbut-1-yn-1-yl)-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide. MS (Q1) 358 (M)+. 1H NMR (400 MHz, DMSO) δ 8.67 (d, J=7.6 Hz, 1H), 7.82 (s, 1H), 7.53 (s, 1H), 7.30 (d, J=10.2 Hz, 1H), 7.10 (s, 1H), 6.01 (s, 1H), 4.91 (q, J=10.6, 6.2 Hz, 1H), 4.48-4.37 (m, 1H), 4.37-4.27 (m, 1H), 3.78-3.64 (m, 1H), 3.15-2.99 (m, 2H), 1.68 (d, J=12.2 Hz, 2H), 1.50 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)[NH:8][C:7]=2[C:6](=[O:24])[N:5]([CH2:25][CH2:26][CH2:27][OH:28])[C:4]1=[O:29])[CH3:2].Cl[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[N:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=3)[N:8]([CH2:31][C:32]3[CH:37]=[N:36][C:35]([CH3:38])=[CH:34][CH:33]=3)[C:7]=2[C:6](=[O:24])[N:5]([CH2:25][CH2:26][CH2:27][OH:28])[C:4]1=[O:29])[CH3:2]
Reactant: Cc1ccc(CCl)cn1
Reactant: CCn1c(=O)n(CCCO)c(=O)c2[nH]c(Oc3cccc(OC(F)(F)F)c3)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(C)nc1
Temperature: 50 °C
Yield: 26.3 %

Procedure:
To a solution of 3-ethyl-1-(3-hydroxypropyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (110 mg, 0.22 mmol) in DMF (3 mL) was added 5-(chloromethyl)-2-methylpyridine (50 mg, 0.4 mmol), potassium carbonate (91 mg, 0.66 mmol), and TBAI (2 mg, 0.02 mmol). The reaction was heated at 50° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified by preparative HPLC to give 3-ethyl-1-(3-hydroxypropyl)-7-((6-methylpyridin-3-yl)methyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (30 mg, 44.8% yield) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][C:28]4[NH:27][N:26]=[CH:30][N:29]=4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: c1nc[nH]n1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)Cc4ncn[nH]4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with 1H-[1,2,4]triazole. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.63 (s, 3H, CH3), 5.10 (s, 2H, CH2), 7.05 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.50 (d, 2H, J=8.3 Hz, pyrimidinyl-H), 7.69 (d, 2H, J=8.9 Hz, Ph-H), 7.98 (s, 1H, Aryl-H), 8.48 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 8.53 (s, 1H, Aryl-H), 9.62 (brs, 1H, NH), 10.30 (brs, 1H, NH). MS (ESI+) m/z 406.97 (C19H18N8OS requires 406.47).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:3])[CH3:2].O[N:19]=[C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1)[NH2:21]>C1COCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[N:19]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccc(CO)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a solution of 4-isopropoxy-3-(trifluoromethyl)benzoic acid (CAS 213598-16-4)(1.04 g, 4.19 mmol) in THF (20 mL) was added CU (748 mg, 4.61 mmol). After stirring at rt for 2 h, N′-hydroxy-4-(hydroxymethyl)benzenecarboximidamide (CAS 1233243-49-6) (766 mg, 4.61 mmol) was added to the mixture and resulting solution was stirred at 50° C. for 3 h. The reaction mixture was submitted to the microwave at 150° C. for 20 min. The reaction mixture was quenched with water, extracted with EtOAc and washed with K2CO3, brine, dried over magnesium sulfate and concentrated. The crude material was purified by MPLC (1:1 ethyl acetate in hexanes) to give rise to 874 mg of the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.O(C(C)(C)C)[Na].Br[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[ClH:37]>COCCOC>[ClH:37].[O:30]([CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: BrCCOc1ccccc1
Agent: CC(C)(C)O[Na]
Agent: Cl
Solvent: COCCOC
Product: c1ccc(OCCOc2ccccc2N2CCNCC2)cc1
Temperature: 55 °C
Reaction time: 0.08 h

Procedure:
The product from Step 1 above (0.55 g, 2.0 mmol) was added to a stirred solution of NaO-t-Bu (0.55 g, 2.0 mmol) in DME (5 mL). After 5 min, β-bromophenetole (0.56 g, 2.8 mmol) was added, and the reaction was stirred at 55° C. for 15 h. 2 M HCl was added, and the reaction mixture was stirred for another 3 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 2 M NaOH/CHCl3. The aqueous phase was extracted with CHCl3 (×3). The combined organic layers were dried (MgSO4), concentrated, and the residue was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (90:10:0.4) as eluent to give the free base of the title compound. The free base was treated with HCl/ether, and the resulting hydrochloride salt was dried (80° C., 1 mmHg) to afford 0.254 g (35%) of the title compound as a light brown semi-solid material that solidified upon standing. Anal. (C18H22N2O2.HCl. H2O) H, N; C: calc, 61.27; found, 61.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCC[CH2:23]1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21][CH3:23])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: O=C(O)c1cccc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Product: COC(=O)c1cccc2cc(-c3ccc([N+](=O)[O-])cc3)oc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A diazomethane-ether solution (prepared from 5.0 g of nitrosomethylurea) is added to a solution of 6.0 g of 2-(4-nitrophenyl)benzofuran-7-carboxylic acid in 60 ml of tetrahydrofuran and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated to remove solvent and the residue is dissolved in ethyl acetate. The solution is washed with water, dried and evaporated to remove solvent. The residue is washed with ethyl acetate and dried to give 3.82 g of methyl 2-(4-nitrophenyl)benzofuran-7-carboxylate as pale brown powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH2:14][CH2:15]2)=[CH:6][C:5]=1[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc([N+](=O)[O-])c(OCC(F)(F)F)c3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCNCC3)CC2)cc1OCC(F)(F)F
Temperature: 0 °C
Yield: 82 %

Procedure:
1,1-Dimethylethyl 4-(1-{4-nitro-3-[(2,2,2-trifluoroethyl)oxy]phenyl}-4-piperidinyl)-1-piperazinecarboxylate (1.35 g, 2.76 mmol) was dissolved in 40 mL of DCM with stirring. TFA (10.0 mL, 130 mmol) was added via syringe, and the reaction was stirred for 3 h and cooled to 0° C. The reaction was quenched with 20 mL of 6N NaOH (aqueous). Saturated NaHCO3 (aqueous) was added until the pH was approximately 9. The mixture was poured into H2O and DCM. The layers were separated, and the aqueous layer was washed with 4:1 DCM/iPrOH (2×) and 4:1 EtOAc/iPrOH. The combined organic layers was dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 0.879 g (82%) of the title compound of step E. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.5 Hz, 1H), 6.63 (dd, J=9.5, 2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.88 (q, J=8.7 Hz, 2H), 4.02 (d, J=13.6 Hz, 2H), 2.84-2.98 (m, 2H), 2.56-2.67 (m, 4H), 2.26-2.49 (m, 5H), 1.96 (br. s., 1H), 1.70-1.84 (m, 2H), 1.38 (d, J=8.2 Hz, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Temperature: 60 °C
Yield: 47.1 %

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid methyl ester (1.00 g, 3.07 mmol) (1.0 g, 1.69 mmol) in ethanol (10 mL) was added aqueous sodium hydroxide (1 N, 6.2 mL). After heating at 60° C. for 30 min it was cooled to ambient temperature and aqueous sodium carbonate (2 M, 50 mL) added. Addition of aqueous sodium hydroxide (1 M, 50 mL) was followed by extraction with tert-butylmethylether. The aqueous phase was acidified with aqueous hydrogen chloride (25%) to pH=2 and extracted with tert-butylmethylether and ethyl acetate. The combined organic layers were dried over sodium sulfate and concentration afforded the title compound (450 mg, 86%) as a white foam. MS: m/e=310.5 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[CH3:7])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[CH2:7][Br:24])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1OCc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1OCc1ccccc1
Yield: 65.3 %

Procedure:
To a stirred mixture of (E)-3-(2-benzyloxy-phenoxy)-but-2-enoic acid ethyl ester (5.70 g, 0.018 mol) in carbon tetrachloride (35 mL) under a nitrogen atmosphere was added N-bromosuccinimide (4.90 g, 0.028 mol) and benzoyl peroxide (440 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-3-(2-benzyloxy-phenoxy)-4-bromo-but-2-enoic acid ethyl ester (4.60 g, 64%) as a yellow oil.