Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=1)[C:18](O)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1>C(Cl)Cl>[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([NH:38][C:18](=[O:19])[C:17]2[CH:16]=[C:15]([O:14][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:23]=[C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:21]=2)=[N:34]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
Oxalyl chloride (7.71 mL, 89.7 mmol) was added dropwise to a suspension of 3,5-dibenzyloxybenzoic acid (20.0 g, 59.8 mmol) in DCM (0.5 L) under argon. The reaction was stirred at RT for 6 hours after which time the volatiles were removed in vacuo. The residue was taken up in DCM (300 mL) and a solution of 1-methyl-1H-pyrazol-3-amine (5.81 g, 59.8 mmol) in DCM (50 mL) was added dropwise. The resulting solution was stirred for 16 hours at RT after which time a precipitate had formed. The solid was isolated by filtration and recrystallised from ethanol to give the title compound as a white solid (14.8 g). 1H NMR δ (d6-DMSO): 3.84 (3H, s), 5.17 (4H, s), 6.59 (1H, d), 6.84 (1H, t), 7.33-7.46 (12H, m), 7.62 (1H, d), 10.83 (1H, s); m/z 414 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:27]([C:31]1[N:36]=[CH:35][C:34]([C:37]2[N:38]([C:58]([N:60]3[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]3)=[O:59])[C@@:39]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=3)([CH3:50])[C@@:40]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)([CH3:42])[N:41]=2)=[C:33]([O:66][CH2:67][CH3:68])[CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[C:27]([C:31]1[N:36]=[CH:35][C:34]([C:37]2[N:38]([C:58]([N:60]3[CH2:65][CH2:64][N:63]([C:5](=[O:7])[CH2:4][CH2:3][S:2][CH3:1])[CH2:62][CH2:61]3)=[O:59])[C@@:39]([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=3)([CH3:50])[C@@:40]([C:43]3[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=3)([CH3:42])[N:41]=2)=[C:33]([O:66][CH2:67][CH3:68])[CH:32]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: CSCCC(=O)O
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CCSC)CC1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 3-(methylthio)propionic acid (30.8 mg, 0.256 mmole, Lancaster) in dimethylformamide (10 mL) were added successively 1-hydroxybenzotriazole (46.3 mg, 0.342 mmole, Chem-Impex), N,N,N′,N′-tetramethyl-O-(1H-Benzotriazol-1-yl)uranium hexafluorophosphate (130.0 mg, 0.343 mmole, Aldrich) and diisopropylethylamine (111.0 mg, 0.857 mmole). The mixture was stirred for 15 min before [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (104.4 mg, 0.171 mmole) was added. The reaction mixture was allowed to stir for 1 h before concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, brine, dried and concentrated. The crude residue was purified by flash column chromatography (silica gel, eluting with a gradient of 1-10% methanol in methylene chloride) to give the title compound (108.7 mg, 89% yield). HR-MS (ES, m/z) calculated for C37H46Cl2N5O3S [(M+H)+] 710.2693, observed 710.2691.
Reaction SMILES: [CH:1]1([C:4]([C:12](=O)[CH2:13][CH3:14])=[CH:5]N2CCOCC2)[CH2:3][CH2:2]1.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].C(O)(=O)C.N1CCCCC1>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:18]([C:16]#[N:17])[C:19](=[O:20])[NH:21][C:12]=2[CH2:13][CH3:14])[CH2:3][CH2:2]1
Reactant: N#CCC(N)=O
Reactant: CCC(=O)C(=CN1CCOCC1)C1CC1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1[nH]c(=O)c(C#N)cc1C1CC1
Yield: 81.8 %

Procedure:
A sample of 2-Cyclopropyl-1-(morpholin-4-yl)pent-1-en-3-one (2A, 2.09 g, 10 mmol), cyanoacetamide (0.92 g, 11 mmol) and piperidine acetate (4 mL) were dissolved in ethanol (30 mL) under nitrogen. The reaction mixture was heated at reflux for 24 hours. The reaction mixture was cooled and concentrated, then diluted with methylene chloride. The solution was washed with brine and dried (MgSO4), filtered and concentrated. The crude solid was chromatographed (silica, 5% methanol/methylene chloride) to afford pure title compound (3A, 1.54 g, 82%) as a crystalline solid. 1H NMR (300 MHz, CDCl3): δ0.62 (m, 2H), 0.98 (m, 2H), 1.38 (t, 3H), 1.71 (m, 1H), 2.91 (q, 2H), 7.63 (s, 1H); MS (DCI/NH3) m/e 189 (M+H)+, 206 (M+NH4)+. Anal. Calcd for C11 H12N2O: C, 70.19; H, 6.42; N, 14.88. Found C, 70.31; H, 6.49; N, 14.62.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19](=[O:24])(=[O:23])[NH:20][CH2:21][CH3:22])=[C:14]2[N:13]=[CH:12][C:11]=1[C:25]([O:27]CC)=O.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[CH2:21]([NH:20][S:19]([C:18]1[CH:17]=[N:16][N:15]2[C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[Cl:1])=[C:11]([C:25]([N:40]3[CH2:41][CH2:42][CH:37]([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=4)[CH2:38][CH2:39]3)=[O:27])[CH:12]=[N:13][C:14]=12)(=[O:24])=[O:23])[CH3:22]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCNS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)OCC)cnc12
Product: CCNS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 18.2 %

Procedure:
Using ethyl 7-(2-chloro-5-methylphenylamino)-3-(N-ethylsulfamoyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.084 g, 0.205 mmol) obtained in step 1 and 4-(4-fluorophenyl)piperidine (0.030 g, 0.183 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.019 g, 16%) was obtained.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][CH:20]([F:35])[CH2:21][NH:22][CH2:23][C:24]1[NH:25][C:26](=[O:34])[C:27]2[CH2:33][O:32][CH2:31][CH2:30][C:28]=2[N:29]=1.CC#N.O>C(O)=O>[C:1]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([N:22]([CH2:21][CH:20]([F:35])[F:19])[CH2:23][C:24]2[NH:25][C:26](=[O:34])[C:27]3[CH2:33][O:32][CH2:31][CH2:30][C:28]=3[N:29]=2)=[O:18])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(CNCC(F)F)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccccc2)CC1
Solvent: O
Solvent: O=CO
Solvent: CC#N
Product: O=C(c1ccccc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC(F)F)CC1

Procedure:
The title compound (0.07 g) was prepared following the general procedure of Example 1 from 2-(4-benzoylpiperidin-1-yl)acetic acid and 2-((2,2-difluoroethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one. 1H NMR (400 MHz, MeOD) δ ppm 7.89-8.03 (m, 2H), 7.44-7.66 (m, 3H), 5.88-6.43 (m, 1H), 4.61-4.69 (m, 1H), 4.53-4.60 (m, 1H), 4.40-4.48 (m, 1H), 3.78-4.23 (m, 5H), 3.36-3.59 (m, 2H), 3.02-3.18 (m, 1H), 2.83-2.93 (m, 1H), 2.54-2.69 (m, 3H), 2.13-2.36 (m, 2H), 1.65-1.97 (m, 3H), 1.37-1.54 (m, 1H). HRMS calculated for C24H29F2N4O4 475.2157. found (ESI, [M+H]+) 475.2180. MS (ESI) m/z 475.2. (M+H)+. Retention time: 3.04 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:14]([F:15])=[C:13]([CH2:16]Br)[CH:12]=[CH:11][C:10]=2[Cl:18])[CH:7]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CS(C)=O.CCOC(C)=O>[N:21]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([Cl:18])=[C:9]([O:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:20])[C:5]=2[Cl:19])[C:14]=1[F:15])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(Br)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.3 %

Procedure:
2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-(bromomethyl)-1-chloro-3-fluorobenzene (10.04 g, 22.47 mmol) and sodium azide (1.461 g, 22.47 mmol) were combined in DMSO (50 mL) and stirred 3 days at 25° C. The reaction mixture was diluted with EtOAc, washed 4× with water, dried over MgSO4, filtered and concentrated to dryness to give 1-(azidomethyl)-3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorobenzene (8.3 g, 20.29 mmol, 90% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49-7.66 (m, 3H), 6.80 (s, 1H), 4.61 (s, 2H).
Reaction SMILES: Br[CH:2]([C:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH:2]([C:4]3[N:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH3:3])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: CC(Br)c1ncc2ccccc2n1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(c1ncc2ccccc2n1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 2-(1-Bromo-ethyl)-quinazoline (43 mg, 0.18 mmol) and 1-(4-Bromo-benzenesulfonyl)-piperazine (67 mg, 0.22 mmol), potassium iodide (30 g, 0.18 mmol) and potassium carbonate (37 mg, 0.27 mmol) in acetonitrile (1 mL) was heated at 65° C. for 1 day. The reaction mixture was then concentrated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium thiosulphate solution, saturated sodium bicarbonate solution and then with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was dissolved in DMSO and purified by HPLC. 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.06 (m, 3H), 7.80 (t, J=7.9 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 4.86 (q, J=7.0 Hz, 1H), 3.65 (m, 2H), 3.43 (m, 6H), 1.88 (d, J=7.0 Hz, 3H) HPLC ret. time 2.45 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 461.1 (M+1)+.
Reaction SMILES: C(=O)CCC1C=CC=CC=1.[Li].C(O[PH+]([CH2:19][C:20]([O:22]CC)=[O:21])OCC)C.[Br-].Br[CH2:27]/[CH:28]=[CH:29]/[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[Na].C(OCC)(=O)CC(OCC)=O>O1CCCC1.C(Cl)Cl>[C:32]1([CH2:31][CH2:30]/[CH:29]=[CH:28]/[CH2:27][CH2:19][C:20]([OH:22])=[O:21])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C[PH+](OCC)OCC
Reactant: BrC/C=C/CCc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: O=CCCc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(=O)CC(=O)OCC
Solvent: ClCCl
Product: O=C(O)CC/C=C/CCc1ccccc1

Procedure:
E-7-Phenylhept-4-enoic acid was prepared from commercially available dihydrocinnamaldehyde in five steps. Dihydrocinnamaldehyde was combined with the lithium salt of ethyl diethoxyphosphonioacetate in tetrahydrofuran at room temperature. The resulting unsaturated ester, ethyl 5-phenylpent-2-enoate, was purified by chromatography. The unsaturated ester was then reduced to the allylic alcohol, E-5-phenylpent-2-en-1-ol, by reaction with excess diisobutylaluminum hydride in tetrahydrofuran at −78° C. The purified alcohol was then converted to the bromide, E-1-bromo-5-phenylpent-2-ene, by reaction with triphenylphosphine and carbon tetrabromide in methylene chloride at 0° C. The purified bromide was then used to alkylate the sodium salt of diethyl malonate to provide the diester, methyl E-1-carbomethoxy-5-phenylhept-4-enoate. The diester was purified by chromatography and then subjected to saponification using methanolic sodium hydroxide. The diacid was purified by acid/base extraction and then used directly in the next step of the reaction sequence. Decarboxylation was effected by heating the neat diacid at 170° C. (under Ar) for 30 minutes. The product, E-7-phenylhept-4-enoic acid, was obtained in greater than 95% purity. Any residual diacid was removed by dissolving the acid in hexane and filtering. All compounds in the reaction sequence were fully characterized by spectral analysis (infrared and nuclear magnetic spectroscopy) and new compounds were analyzed by combustion analysis.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:22])[CH:8]=2)[NH:3]1.C(N(CC)C(C)C)(C)C.[CH3:32][O:33][CH2:34][CH2:35][O:36][CH2:37]Cl>ClCCl>[O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:8]=2)[NH:3]1
Reactant: COCCOCCl
Reactant: CCOC(=O)CCCCn1c(=O)[nH]c2ccc(O)cc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCCn1c(=O)[nH]c2ccc(OCOCCOC)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
To a suspension of ethyl 2,4-dioxo-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (3.50 g, 11.8 mmol) obtained in Reference Example 149 in dichloromethane (35.0 ml), N,N-diisopropylethylamine (2.05 ml, 17.7 mmol) and 2-methoxyethoxymethyl chloride (2.02 ml, 17.7 mmol) were added dropwise with cooling on ice, and the reaction mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure to give the title compound (3.68 g, 79%). Recrystallization from ethyl acetate-ethyl ether yielded a colorless crystal having a melting point of 105 to 107° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:13][C:10]1[C:9]([NH:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:25]([OH:27])=[O:26])[CH:33]=3)=[CH:3][CH:4]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)CCc1ccccc1
Reactant: O=C(O)c1cccc(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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(-c2ccc(-c3cccc(C(=O)O)c3)cc2)c1NC(=O)CCc1ccccc1
Temperature: 88 °C
Reaction time: 1 h

Procedure:
N-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-phenyl-propionamide (0.100 g, 0.26 mmol), 3-carboxyphenylboronic acid (0.052 g, 0.31 mmol), tetrakis(triphenylphosphine)palladium(0) (0.030 g, 0.03 mmol), and potassium carbonate (0.072 g, 0.52 mmol) were combined in 2:1 DME:H2O. The mixture was purged with N2 and stirred at 88° C. in a sealed container for 1 hour. After aqueous workup the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]([O:4][O:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[C:8]([Br:23])[C:7]=1[CH2:24][CH3:25])(=[O:3])[CH3:2].C(O)C>C(OC(=O)C)C.Cl[Zn]Cl>[C:1]([O:4][O:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[C:8]([Br:23])[C:7]=1[CH2:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CCc1c(OOC(C)=O)cc(Br)c(Oc2ccc([N+](=O)[O-])cc2)c1Br
Agent: Cl[Zn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1c(OOC(C)=O)cc(Br)c(Oc2ccc(N)cc2)c1Br
Temperature: 25 °C
Yield: 88.9 %

Procedure:
Ethyl(3,5-dibromo-4-[4-nitrophenoxy]phenoxy) acetate (2.4 g), zink chloride (5.7 g), ethylacetate (30 mL) and ethanol (30 mL) was heated at reflux for two hours. After cooling down to room temperature, the reaction mixture was diluted with ethylacetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and the organic phase dried over potassium carbonate. After concentration, 2.0 g of ethyl(3,5-dibromo-4-[4-aminophenoxy]phenoxy) acetate was obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (139.8 mg, 0.340 mmol) in pyridine (0.8 mL) was added acetic anhydride (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (123.2 mg, 0.272 mmol, 80%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:36]1([OH:40])[CH2:39][CH2:38][CH2:37]1>>[CH:36]1([O:40][C:2]2[N:7]=[CH:6][C:5]([C:8]3([OH:35])[CH2:13][CH2:12][CH:11]([N:14]4[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=5)=[O:20])[CH2:17]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Reactant: OC1CCC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(OC4CCC4)nc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 6a and cyclobutanol (Aldrich) using the procedure described in Example 8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[NH:16][C:15](=[O:20])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH:7]=[N:6][CH:5]=1.[H-].[Na+].[CH3:24]I.O>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[N:16]([CH3:24])[C:15](=[O:20])[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: CI
Reactant: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cncc(-c2ccc3c(n2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a stirred solution of 5-(6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (430 mg, 1.52 mmol) in THF (15.0 mL) was added 60% NaH (91 mg, 2.28 mmol) at 0° C. and the reaction mixture was stirred at 2-5° C. for 0.5 h before CH3I (0.3 mL, 4.56 mmol) was added. After stirring overnight at RT, it was poured into water (5.0 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 5-(5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridin-2-yl)-nicotinic acid methyl ester (383.7 mg, 85%) as a light yellow solid. MS: 298.1 (M+H+).
Reaction SMILES: ClC1C=CC(N)=CC=1C1C=CC=CN=1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:45])[C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=2)=[CH:30][C:29]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1.[Sn](Cl)Cl>Cl.CCO>[NH2:42][C:39]1[CH:40]=[CH:41][C:36]([C:35]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[C:29]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:30]=2)=[O:45])=[CH:37][CH:38]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Temperature: 55 °C

Procedure:
300 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 270 mg of 4-nitrobenzoic acid via Procedure G. To 520 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-nitrobenzamide in 2.5 mL of HCl in 10 mL of EtOH was added 1.3 g of Tin (II) Chloride and stirred at 55° C. Upon completion, the reaction was concentratd and extracted with Ethyl Acetate in water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 4-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 100 mg of 4-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 30 μL of Methanesulfonyl Chloride and 90 μL DIPEA in 500 μL DCM. The reaction mixture was evaporated, subjected to basic workup conditions and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylamide)benzamide. MS (Q1) 402 (M)+.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH:13]2[N:26]([C:29](=[O:49])[CH:30]([NH:35][C:36](=[O:48])[CH:37]([N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH3:40])[CH3:38])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:28][CH:12]12)=O)C1C=CC=CC=1>CO.[Pd]>[C:44]([O:43][C:41](=[O:42])[N:39]([CH:37]([C:36](=[O:48])[NH:35][CH:30]([C:29]([N:26]1[CH2:27][CH2:28][CH:12]2[NH:11][CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH:13]12)=[O:49])[C:31]([CH3:33])([CH3:34])[CH3:32])[CH3:38])[CH3:40])([CH3:45])([CH3:46])[CH3:47]
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
A solution of carbamate 83 (546 mg, 0.8 mmol) in MeOH (15 mL) was treated with 10% Pd/C (wet, 208 mg) and subjected to H2 (50 psi) using a Parr apparatus. After 2.5 h, the reaction mixture was filtered through a filter disc (Acrodisc®, PSF—0.45 μM) with MeOH and concentrated to afford amine 84 (443 mg) as a light yellow-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.07 (app q, J=9.6 Hz, 1H), 6.89-6.82 (m, 1H), 6.72-6.68 (m, 1H), 4.72-4.69 (m, 1H), 4.56 (d, J=9.3 Hz, 1H), 4.45 (dd, J=2.1, 6.0 Hz, 1H), 4.25-4.11 (m, 4H), 3.90-3.81 (m, 1H), 3.47-3.36 (m, 1H), 3.30-3.24 (m, 1H), 2.79 (s, 3H), 2.46-2.38 (m, 1H), 2.26-2.17 (m, 1H), 1.48 (s, 9H), 1.30 (d, J=6.9 Hz, 3H), 0.99 (s, 9H) ppm. Mass spectrum, m/z [553.7] (M+H)+.