Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[N-:14]=[N+:15]=[N-:16].[Li+].O>CN(C=O)C>[N:14]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOc1ccc([N+](=O)[O-])cc1
Yield: 96.9 %

Procedure:
A solution of 1.12 g (5.55 mmol) of 4-nitro 2-chloroethyl ether (Example 212) and lithium azide (544 mg, 11.1 mmol) in 3 mL of DMF was heated at 60° C. in an oil bath overnight under nitrogen atmosphere. The reaction was poured into water and extracted with ethyl acetate. The organics were washed with water and brine and dried over anhydrous magnesium sulfate and concentrated to give 1.12 g (97%) of the product: 1H NMR (200 MHz, CDCl3) δ8.18 (d, 2H, J=9Hz), 6.96 (d, 2H, J=9Hz), 4.21 (t, 2H, J=5Hz), 3.63 (t, 2H, J=5Hz).
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:21][C:22]([Cl:26])([Cl:25])CO>>[OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]([O:6][CH2:7][C:22]([Cl:26])([Cl:25])[Cl:21])=[O:5]
Reactant: CCCCCCCCCCCCC[C@H](O)CC(=O)OC
Reactant: OCC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCC[C@H](O)CC(=O)OCC(Cl)(Cl)Cl

Procedure:
(S)-Methyl 3-hydroxyhexadecanoate and 2,2,2-trichloroethyl alcohol were reacted according to a similar manner to that of Preparation 1 to give (S)-(2,2,2-trichloroethyl) 3-hydroxyhexadecanoate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]=O.[BH4-].[Na+]>CO>[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: Cn1ccnc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ccnc1CNc1ccccc1N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 1-boc-4-(2-aminophenyl) piperazine (554 mg, 2.0 mmol, 1.0 eq.) in methanol was added (1-methyl-1H-imidazole-2-carbaldehyde (220 mg, 2.0 mmol, 1.0 eq.). The mixture was reflux for about 1 hour and then cool to about 0° C. Sodium borohydride on alumina (10 wt % on basic alumina, 1.13 g, 3.0 mmol, 1.5 eq.) was added. The solution was warmed to r.t. and then stirred overnight. The reaction mixture was filtered through celite and then concentrated. Purification by flash chromatography (35 g SiO2, 40 mL/min, linear gradient, 0-8% MeOH/CH2Cl2 for 25 minutes and then 8% MeOH for 7 minutes) afforded Boc protected title compound (176 mg, 0.47 mmol, 24%). LRMS (ESI+): 372.3 [M+1].
Reaction SMILES: C(OC(=O)[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[CH:11]=2)=[CH:20][CH:21]=1)([CH3:27])([CH3:26])[CH3:28]
Reactant: CCc1cccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cccc(CCNCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a solution of (4-tert-butyl-benzyl)-[2-(3-ethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester 66 mg, 0.166 mmol) in DCM (1 ml) was added trifluoroacetic acid (128 μl, 1.668 mmol) at 0° C. The reaction mixture was allowed to warm to RT and was stirred over night. The mixture was then basified with 1 N NaOH and extracted with DCM. The combined extracts were dried (Na2SO4) and evaporated to obtain the title compound as a colorless gum (45 mg, 92%). MS (ISP) 296.5 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]([CH:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)[CH:9]=[CH:10][C:2]1=2.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:33](C)=O.[Na+].CC(O)=O>ClCCCl.C(OCC)(=O)C.[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]([CH:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[CH3:33])[CH:9]=[CH:10][C:2]1=2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc2c(c1)CC(N(CCC1CCCCN1)c1ccc3c(c1)OCCO3)C2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN1CCCCC1CCN(c1ccc2c(c1)OCCO2)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 60 (0.5 g, 1.32 mmol) in DCE (25 mL) were added formaldehyde (35% solution in H2O, 0.17 mL, 1.98 mmol), Na(OAc)3BH (0.84 g, 3.96 mmol) and AcOH (0.2 mL) successively at 0° C. and the mixture was stirred at rt for 16 hours. The reaction mixture was dissolved in ethyl acetate and basified with 1N NaOH. The organic layer was separated and washed with water and brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatography eluting with 5-5.2% methanol-DCM to provide compound 61.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[I-].[K+]>CC(C)=O>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:8]3[CH:7]=[CH:6][C:5]([CH3:21])=[C:4]([CH:9]=3)[C:3]([O:2][CH3:1])=[O:22])=[O:20])=[CH:13][CH:14]=2)[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(NC(=O)c2ccc(CCl)cc2)ccc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)ccc1C
Yield: 55.6 %

Procedure:
A reactor is charged with 1 g (3.3 mmol) of the solid obtained in step 1, 2.28 g (16.5 mmol) of potassium carbonate, 30 ml of acetone, 0.39 g (3.96 mmol) of N-methylpiperazine and 55 mg (0.33 mmol) of potassium iodide. The mixture is heated at reflux for 6 hours. The solvent is then evaporated under reduce pressure and the residue is taken off into 100 ml of a saturated sodium bicarbonate solution. The aqueous phase is extracted by 3*30 ml ethyl acetate. The organic phases are then combined, dried on sodium sulphate and evaporated under reduced pressure. The obtained product is triturated in ethylic ester and then dried to give a white solid (700 mg, 56%).
Reaction SMILES: [OH:1][C@H:2]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:25]=[CH:24][C:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+].C(O)(=O)C>O.C(O)C>[OH:1][C@H:2]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH:27]=1)[CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:16](=[O:23])[CH2:17][C:18]([OH:20])=[O:19])=[CH:24][CH:25]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NC(=O)CC(=O)O)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a stirred solution of ethyl 3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate (which was obtained in Example 371)(0.23 g, 0.43 mmol) in distilled water (3 mL) and ethanol (2 mL) was added 1 N sodium hydroxide (2 mL). The reaction was stirred at room temperature for 1 hr. The reaction mixture was made acidic (pH 6) with glacial acetic acid, concentrated, triturated with water, ether, ethyl acetate to give the title compound as a light yellow solid (0.13 g, 59%); 1H NMR (300 MHz, DMSO-d6) δ 1.30–1.45(m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.80 (m, 5 H), 2.90 (s, 2 H), 2.91(s, 3 H), 3.45–3.60 (m, 2 H), 4.48–4.53(m, 1 H), 6.80–6.90(m, 3H), 7.00(d, J=8.3 Hz, 1 H), 7.18 (d, J=1.6 Hz, 1 H), 7.38(d, J=9.0 Hz, 2 H), 11.50–11.60(m, 1 H); MS (ES) m/z: 505.3 (M−H)−; HRMS Calcd. for C23H31N4O7S (MH+): 507.1908. Found: 507.1895.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[C:29]([F:39])=[CH:30][C:31]([F:38])=[C:32]([S:34](Cl)(=[O:36])=[O:35])[CH:33]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[S:34]([C:32]2[CH:33]=[C:28]([Cl:27])[C:29]([F:39])=[CH:30][C:31]=2[F:38])(=[O:36])=[O:35])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2ccnc(OCc3ccccc3)n2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccnc(OCc3ccccc3)n2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Yield: 61.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 86a by using the 2-(benzyloxy)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.50 g, 1.42 mmol) prepared in Example 153a, 5-chloro-2,4-difluorobenzenesulfonyl chloride (0.36 g, 1.57 mmol), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 1.71 mL, 1.71 mmol) and THF (5.0 mL), to yield the title compound (487.8 mg, 61%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[CH:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To a solution of 1.10 g of 3,5-dichloro-4-(3-hydroxypropoxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.56 g of 3-trifluoromethoxyphenol and 0.83 g of triphenylphosphine dissolved in 20 ml of tetrahydrofuran was added dropwise a solution of 0.64 g of diisopropylazodicarboxylate dissolved in 10 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 1.03 g of 3,5-dichloro-4-(3-(4-trifluoromethoxyphenoxy) propoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (64% yield), nD23.4 1.5343.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:23][CH2:22][CH2:21]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:23][CH2:22][CH2:21]2)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (6.14 g, 20 mmol), azetidine (2.33 mL, 34 mmol) and Et3N (8.4 mL, 60 mmol) in DMSO (40 mL) at 23° C. according to the general procedure C. Obtained as an orange solid (5.85 g).
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>C(Cl)Cl.O>[CH3:11][O:10][N:9]([CH3:8])[C:12](=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Pyridine (100 mL) was cooled to 0° C., and N,O-dimethylhydroxylamine hydrochloride (20.14 g, 206 mmol) was added with stirring. This solution was stirred for 10 minutes, and then a solution of butyryl chloride (19.5 ml, 20 g, 188 mmol) dissolved in 50 ml methylene chloride was added via addition funnel over 30 minutes. A precipitate formed after 5 minutes. This suspension was stirred and allowed to warm to room temperature. Stirring was continued for 2.0 hours, and the reaction was diluted with water, extracted with methylene chloride twice. The methylene chloride layers were combined and washed with 1 N HCl twice and once with brine. Diethyl ether (100 mL) was added to facilitate emulsion separation, and the organic layer was separated and washed with saturated bicarbonate solution, brine, and dried over magnesium sulfate. The solution was filtered and the solvent removed in vacuo to give N-Methoxy-N-methyl-butyramide as an oil (22.1 g, 89%).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:45]([N:44]([CH2:47][CH3:48])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH3:46]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 89.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N,N-diethylacetamide (8.1 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.2 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: COCCNc1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COCCNc1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C

Procedure:
2-Chloro-N-(2-methoxyethyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (43 mg, 0.14 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (58 mg, 0.29 mmol), cesium carbonate (94 mg, 0.29 mmol), palladium(II) acetate (5 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-biphenyl (8 mg, 0.02 mmol) and dioxane (2 mL) were mixed in a vial and kept under an atmosphere of nitrogen. The mixture was heated in a microwave reactor at 120° C. for 90 min. The reaction mixture was filtered through at pad of diatomeous earth. The filter plug was rinsed with MeOH. The solvents were removed in vacuo and the residue was purified by preparative HPLC to give the title compound as a solid, 34 mg (51%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH:26]1([Mg]Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[CH:26]1([C:11]([C:10]2[S:9][C:8]([NH:17][C:18]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[O:19])=[N:7][C:6]=2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:16])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Br[Mg]C1CCCC1
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCCC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7 %

Procedure:
Compound 98 (74.0 mg, 0.207 mmol) was dissolved in THF (1.5 mL), and a 2 mol/L solution of cyclopentylmagnesium bromide in diethyl ether (0.500 mL, 1.00 mmol) was added thereto under ice-cooling, followed by stirring at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 431 (5.60 mg, 7%) as a pale brown solid.
Reaction SMILES: CN(C)[C:3](=O)[S:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][CH:6]=1.[OH-].[K+].BrC[C:24]([O:26]C(C)(C)C)=[O:25]>CO>[N+:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([S:4][CH2:3][C:24]([OH:26])=[O:25])=[CH:6][CH:7]=1)([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)C(=O)Sc1ccc([N+](=O)[O-])c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CSc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
97 mg 19 was suspended in 1 ml methanol, to which, in Argon atmosphere, was added 1.4 ml KOH solution (1M in CH3OH). The resulting mixture was stirred at room temperature for 12 hours affording a homogenous solution. 103 μl tert butyl bromoacetate was added through syringe. The reaction solution was continued for 12 hours and concentrated. The residue was dissolved in water and acidified with solid NaHSO4. The yellow precipitate was filtered and washed with water. Dried in air, 78.8 mg (85.6%, 2 steps) yellow solid was obtained. 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=8.4 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 3.91 (s, 2H). LRMS (ES−) 218 (M—H—CO2)−; HRMS (ES−) m/z calculated for C12H8NO4S (M−H)− 262.0180, found 262.0180.
Reaction SMILES: Br[CH:2]([C:5]1[C:6]([F:20])=[C:7]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)[CH2:3][CH3:4].[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23][OH:24]>CN(C=O)C>[C:12]([C:7]1[C:6]([F:20])=[C:5]([CH:2]([NH:26][C:22]([CH3:25])([CH3:21])[CH2:23][OH:24])[CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[Cl:11])(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCC(Br)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reactant: CC(C)(N)CO
Solvent: CN(C)C=O
Product: CCC(NC(C)(C)CO)c1ccc(Cl)c(C(=O)c2ccccc2)c1F

Procedure:
Step 3 A solution of [3-(1-bromo-propyl)-6-chloro-2-fluoro-phenyl]-phenyl-methanone (50 mg; 0.14 mmol) and 2-methyl-2-aminopropanol (30 μl; 2 equiv.) in DMF (1 ml) was stirred at room temperature for 72 hours then partitioned between Et2O and brine. The Et2O later was separated, dried (Na2SO4), filtered and evaporated. The crude material was purified by flash column chromatography using gradient elution from 0-10% MeOH/DCM. Product containing fractions were combined, treated with saturated HCl/EtOAc then evaporated. The residue was triturated with Et2O, the solid collected by filtration, washed with Et2O and sucked dry to give 55 mg of 2-{[1-(3-benzoyl-4-chloro-2-fluorophenyl)-propyl]amino}-2-methylpropan-1-ol as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:20]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[CH:21]=2)[C:14](=[O:19])[CH:15]=[CH:16][CH2:17]Br)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH:37]1[CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([C:20]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:28]([N:37]4[CH2:40][CH2:39][CH2:38]4)[C:22]=3[CH:21]=2)[C:14](=[O:19])[CH:15]=[CH:16][CH3:17])=[CH:6][CH:5]=1
Reactant: C1CNC1
Reactant: COC(=O)c1ccc(OCCN(C(=O)C=CCBr)c2cc3ccccc3o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC=CC(=O)N(CCOc1ccc(C(=O)OC)cc1)c1cc2c(N3CCC3)cccc2o1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(3-benzofuran-2-yl-4-bromobut-2-enoylamino)ethoxy]benzoic acid methyl ester (300 mg, 0.654 mmol)) in dry DMF (4 ml), potassium carbonate (180 mg, 1.31 mmol) and azetidine hydrochloride (41 mg, 0.719 mmol) were added. The reaction mixture was stirred for 4 h at 50° C. The reaction mixture was diluted with ethyl acetate and the resulting suspension was washed with water and brine. After drying the organic phase over sodium sulfate, the solvent was removed under vacuum and the residue was purified by flash chromatography, using mixture of DCM/MeOH (9.5/0.5) as eluent to give 4-[2-(4-azetidin-1-yl-3-benzofuran-2-yl-but-2-enoylamino)ethoxy]benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(-c2cnc(N)cn2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 102.5 %

Procedure:
To a solution of 2-amino-5-bromopyrazine (642 mg) in dimethoxyethane (40 mL) was added 3-methoxyphenylboronic acid (560 mg), 1.5N aqueous sodium carbonate solution (4 mL) and tetrakis(triphenylphosphine)palladium (0) (86 mg). The mixture was stirred at 80° C. for 6 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethyl acetate (50 mL×3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (760 mg).