Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:14])[C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:16])([CH3:15])[CH:6]=[C:5]2[CH:17]([CH3:19])[CH3:18].C([Li])(C)(C)C.B(OC)(OC)OC.B(O)O.I/[C:36](/[CH3:40])=[CH:37]/[CH2:38][OH:39].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1(C)C=CC=CC=1.CO.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>[Cl:14][C:10]1[C:11]([O:12][CH3:13])=[C:2](/[C:36](/[CH3:40])=[CH:37]\[CH2:38][OH:39])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:16])([CH3:15])[CH:6]=[C:5]2[CH:17]([CH3:19])[CH3:18]
Reactant: C/C(I)=C\CO
Reactant: COc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1c(/C(C)=C\CO)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromene (Compound 19, 334 mg, 0.97 mmol) in THF (25 mL) at −78° C. tert-butyllithium (1.7 M in pentane, 1.1 mL, 1.93 mmol) was added dropwise. After stirring for 30 min, trimethyl borate (0.2 mL, 1.93 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with diethyl ether. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude boronic acid was treated with 3-iodo-but-2E-en-1-ol (334 mg, 1.93 mmol), 2 M sodium carbonate (2 mL), and tetrakis(triphenylphosphine)palladium (0) (30 mg) in toluene (101 mL) and methanol (1 mL). The reaction mixture was degassed via bubbling argon for 5 min. After heating to 100° C. for 6 h, the black solution was cooled to room temperature and quenched with a saturated solution of NH4Cl and extracted with diethyl ether. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography (silica gel, 5% to 20% ethyl acetate in hexanes) gave rise to the title compound as a brown oil.
Reaction SMILES: [CH3:1]OB(O)O.C([O-])([O-])=O.[Na+].[Na+].[NH2:12][C:13]1[C:45]([Cl:46])=[CH:44][C:16]([CH2:17][C@@H:18]([CH2:23][C:24](=[O:43])[N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:37][CH2:36][C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[NH:33][C:32]3=[O:42])[CH2:27][CH2:26]2)[C:19]([O:21][CH3:22])=[O:20])=[CH:15][C:14]=1Br>O1CCOCC1.CO.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]>[NH2:12][C:13]1[C:14]([CH3:1])=[CH:15][C:16]([CH2:17][C@@H:18]([CH2:23][C:24](=[O:43])[N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[CH2:37][CH2:36][C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[NH:33][C:32]3=[O:42])[CH2:27][CH2:26]2)[C:19]([O:21][CH3:22])=[O:20])=[CH:44][C:45]=1[Cl:46]
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(N)c(Br)c1
Reactant: COB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C)c(N)c(Cl)c1

Procedure:
Under a nitrogen atmosphere 0.99 g (16.0 mmol) methylboric acid, 15.5 mL 2 M Na2CO3 solution and 1.02 g (1.40 mmol) Pd(dppf)Cl2 were added to a solution of 8.40 g (14.5 mmol) methyl (S)-2-(4-amino-3-bromo-5-chloro-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoate in 50 mL 1,4-dioxane and 3 mL MeOH and the reaction mixture was refluxed overnight. The reaction solution was filtered while hot and the filtrate was combined with EtOAc. The organic phase was washed several times with semisaturated NaHCO3 solution and dried over Na2SO4. It was filtered through activated charcoal and evaporated down i.vac. The residue was taken up in a little DCM and purified by chromatography (silica gel, gradient DCM to DCM/MeOH/NH3 90:10:1). The fractions containing the product were combined, evaporated down i.vac., triturated with DIPE, suction filtered and dried.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[CH2:10]([O:17][C:18](=[O:30])[CH2:19][N:20]1[C:25]([CH3:26])=[C:24]([Cl:27])[N:23]=[C:22](Cl)[C:21]1=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[CH2:10]([O:17][C:18](=[O:30])[CH2:19][N:20]1[C:25]([CH3:26])=[C:24]([Cl:27])[N:23]=[C:22]([NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:21]1=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: NCCc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NCCc2ccccc2)c(=O)n1CC(=O)OCc1ccccc1

Procedure:
2-Phenethylamine (0.38 ml, 3.0 mmol) was added to a stirred mixture of (3,5-dichloro-6-methyl-2-oxo-2H-pyrazin-1-yl)acetic acid benzyl ester (327 mg, 1.00 mmol) in EtOAc (2 ml) and the resulting mixture was heated to reflux under argon. After 2 h the reaction was cooled, diluted with EtOAc (the product is sparingly soluble), washed with 10% citric acid solution and brine, dried (Na2SO4) and evaporated in vacuo to give 1-3 as a crystalline solid. 1H NMR (CDCl3) δ2.21 (s, 3 H, CH3), 2.93 (t, J=7.1 Hz, 2 H, PhCH2), 3.67 (q, J=7.1 Hz, 2 H, CH2NH), 4.79 (s, 2 H, CH2), 5.21 (s, 2 H, CH2), 6.10 (br t, 1 H), 7.20-7.39 (m, 10 H, 2 Ph).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cc(F)ccc4F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,5-difluorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 555.3 ([M+H]+)
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]=1[N:16]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:16]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[C:6]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:35])=[O:2])(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc(CN2CCCC2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(CN3CCCC3)cccc2C(=O)O)cc1
Yield: 67.6 %

Procedure:
To a solution of 0.754 g (1.523 mmol) of the product of Example 318 in 15 mL of THF/Methanol (1:1) was added 7.6 mL of 1.0N sodium hydroxide solution. The resulting mixture was heated to reflux for 15 h and then concentrated in vacuo. The residue was diluted with water, neutralized with 5% HCl solution and exited with dichloromethane. The organics were dried over Na2SO4, filtered and concentrated in vacuo to provide 0.496 g (67%) of the product as a tan solid. Electrospray Mass Spec: 482.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[O:23]=[C:24]1[C:29]2=[CH:30][NH:31][C:32]([CH:33]=O)=[C:28]2[CH2:27][CH2:26][O:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:22])[S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:33][C:32]2[NH:31][CH:30]=[C:29]3[C:24](=[O:23])[O:25][CH2:26][CH2:27][C:28]=23)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1cccc(Cl)c1)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: CN(c1cccc(Cl)c1)S(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCOC3=O)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-methyl-amide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]3=[C:5]([C:17]([F:20])([F:19])[F:18])[C:4]=2[CH:3]=1.[Li][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.CN(CCN(C)C)C>[CH2:22]([C:5]1([C:17]([F:18])([F:20])[F:19])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[NH:8][C:7]2[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]1=2)[CH2:23][CH2:24][CH3:25]
Reactant: [Li]CCCC
Reactant: O=c1[nH]cnc2c(C(F)(F)F)c3cc(Cl)ccc3nc12
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CCCCC1(C(F)(F)F)c2cc(Cl)ccc2Nc2c1nc[nH]c2=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
8-Chloro-10-(trifluoromethyl)pyrimido[5,4-b]quinolin-4(3H)-one (7, 87 mg, 0.290 mmol) was suspended in anhydrous THF-TMEDA (10:1, 2 mL) and cooled to −78° C. under a nitrogen atmosphere. n-BuLi (1.6M 0.73 mL, 4 equiv) was added dropwise over 10 minutes. After the addition was complete, the reaction was stirred for 20 minutes at −78° C. and then warmed to rt over 45 minutes. The reaction was quenched with sat. NH4Cl solution and then partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc (2×) and Et2O (2×). The combined organic phases were dried over Na2SO4 and concentrated. Chromatography (SiO2, 50% EtOAc-hexane) afforded the desired material 8 as a tan solid (35.4 mg, 34%). Rf 0.34 (50% Ethyl acetate-hexane). 1H NMR (CDCl3, 300 MHz) δ 11.42 (br s, NH), 7.78 (s, 1H), 7.30 (m, 1H), 7.18 (dd, J=2.2, 8.5 Hz, 1H), 6.95 (br s, NH), 6.77 (d, J=8.5 Hz, 1H), 2.75 (m, 1H); 2.12 (m, 1H), 1.28 (m, 2H), .0.95 (m, 2H), 0.79 (t, J=7.4 Hz, 3H). ESI-HRMS 358.0935 (M++H, C16H15ClON3F3 requires 358.0934).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[OH:2][CH2:3][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1cccnc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1cccnc1CO
Temperature: 20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution prepared by dissolving 29.5 g, of 2,3-dimethoxycarbonylpyridine in 200 ml of ethylether was added dropwise to a solution prepared by suspending 10 g of lithium aluminum hydride in 300 ml of dried ethylether at 0° C. This mixed solution was stirred at 20° C. for 3 hours and 30 ml of water was slowly added thereto at 0° C. The resulting solution was stirred for 5 hours at the room temperature and solid was filtered through celite. The filtrate was evaporated under reduced pressure and then the residual product was purified by a silica gel column chromatography (chloroform : methanol (10:1)) to give 10.4 g of the above title compound (yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:27]2[O:26][CH2:25][C:21]3([CH2:24][O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:28][CH3:29])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:27]2[O:26][CH2:25][C:21]3([CH2:24][O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:28][CH3:29])=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(COC1)CO2
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(COC1)CO2

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (169 mg, 1.04 mmol) with compound 514 (224 mg, 0.8 mmol) in THF (4 mL) in the presence of LiHMDS (2.4 mL, 2.4 mmol) afforded compound 121 as a white solid material after purification by column chromatography (65-80% EtOAc in light petroleum). LC-MS: RT=3.24 min.; m/z 410.07 (M+H)+, 408.19, 410.22 (M−H)−. 1H NMR (DMSO-d6): δ 8.66 (2H, s), 7.45 (1H, d, J 8.9), 6.91 (1H, d, J 9.0), 4.66 (2H, s), 4.57 (2H, s), 4.50 (2H, d, J 6.5), 4.46 (2H, d, J 6.5), 4.36 (2H, s), 3.85 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[C@H:6]([CH3:19])[CH2:5][CH2:4]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH:3]1[CH2:8][NH:7][C@H:6]([CH3:19])[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: COC1CC[C@@H](C)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1CC[C@@H](C)NC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To benzyl (2R)-5-methoxy-2-methylpiperidine-1-carboxylate (345 mg, 1.31 mmol) dissolved in ethyl acetate (6.5 mL) was added palladium on carbon (139 mg, 0.13 mmol). Hydrogen gas was added via balloon, and the reaction was stirred at room temperature for 3 hours. The mixture was filtered over celite and concentrated under reduced pressure to afford (2R)-5-methoxy-2-methylpiperidine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCN(C)C)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CN(C)CCCOc1cccc2cc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)oc12
Agent: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: CN(C)CCCOc1cccc2cc(C(=O)Nc3ccccc3N)oc12

Procedure:
was prepared from (2-{[7-(3-Dimethylamino-propoxy)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (18) in an analogous manner to that described for the preparation of (1) example 1, step 5; exact MW [M+H] calc'd: 354.18; MW found [M+H]: 354.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][N:2]=1.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.[ClH:54].C(N=C=NCCCN(C)C)C>ClCCl>[ClH:54].[ClH:54].[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[N:2][CH:3]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1ccnnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccnnc3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
0.25 g of 4-pyridazine-carboxylic acid (2.01 mmol) and 0.7 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.01 mmol) were dissolved in 25 ml of dichloromethane. 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) were added at 0° C. and the reaction mixture was stirred for 16 h at room temperature. 0.09 g of hydroxybenzotriazole and 0.23 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred 5 h. 25 ml of dichloromethane were added, the organic layer was washed with aqueous saturated sodium chloride, the aqueous phase re-extracted once with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (10%). Fractions containing the product were combined, the solvent evaporated, and the residue re-dissolved in 20 ml of ethyl acetate. Treatment with 3.3 ml of 1 N hydrochloride acid in diethyl ether yielded 0.69 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O.S(Cl)(Cl)=O.[SH:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>ClCCl.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][S:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1
Reactant: Sc1ncc[nH]1
Reactant: COCCCNc1ccccc1CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: COCCCNc1ccccc1CSc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a solution of 2.9 g (14.8 mmol) of 2-(3-methoxypropyl) aminobenzyl alcohol in 29 ml of dichloromethane was dropwise added a solution of 1.3 ml (17.8 mmol) of thionyl chloride in 3 ml of dichloromethane under chilling with ice for a period of 5 min. The resulting mixture was stirred for 15 min. at room temperature. The solvent was distilled off under reduced pressure at room temperature. To the residue was added 10 ml of dichloromethane. The obtained dichloromethane solution was little by little added to a solution of 2.22 g (22.2 mmol) of 2.mercaptoimidazole in 22 ml of ethanol, and then the mixture was stirred for 15 min. at room temperature. Ethanol was distilled off under reduced pressure. To the residue were added ice and saturated aqueous sodium hydrogencarbonate. The resulting mixture was treated with ether for extraction. The organic portion was collected and sequentially washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2.7 g of the desired compound as a pale yellow oil. (Yield: 65.8 %)
Reaction SMILES: Cl[C:2]([F:28])([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:4]=1[C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH2:21]([N:18]([CH2:19][CH3:20])[C:5]1[C:4]([C:23]([O:25][CH3:26])=[O:24])=[C:3]([CH:2]([F:27])[F:28])[N:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:22]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N(CC)CC
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N(CC)CC
Yield: 68.2 %

Procedure:
A mixture of 2.5 g (0.006 mol) of product of Example 53, 0.61 g (0.006 mol) of triethylamine and 0.12 g of Pd/C (10%) in 35 ml of ethanol was hydrogenated at 50° C. under 480 kPa of hydrogen pressure for 45 minutes. Reaction mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in ether, washed with 10% HCl and the aqueous 10% HCl layer was extracted with chloroform. The combined organic layers were dried (MgSO4) and concentrated in vacuo to 1.91 g. Crude was kugelrohr distilled at 109 Pa, pot temperature 99° C., affording 1.63 g (68.2%) of this product as a yellow oil, nD25 1.4682.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].C1(C=CC(O)=CC=1)O>>[CH2:19]([O:21][CH:22]([N:6]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[C:2]1[CH3:1])[CH3:23])[CH3:20]
Reactant: C=COCC
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: Oc1ccc(O)cc1
Product: CCOC(C)n1c(C)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 180 °C
Yield: 68.3 %

Procedure:
A mixture of 2-methyl-4,5-diphenylimidazole (3.00 g, l3 mmol), ethyl vinyl ether (9.23 g, l2.30 mL, l30 mmol) and hydroquinone (0.l4 g, l.2 mmol) was heated at 180° C. in a sealed vessel for 17 hours. The excess ethyl vinyl ether was evaporated and the residue chromatographed on a column of silica gel using a mixture of diethyl ether and hexanes (3:2) as eluent. Elution gave 1-(1-ethoxyethyl)-2-methyl-4,5-diphenyl-1H-imidazole (2.68 g, 68%), mp 87°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1.Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][N:6]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: Clc1ccc(CNCc2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: N#CCCCBr
Product: N#CCCCN(Cc1ccc(Cl)c(Cl)c1)Cc1ccc(Cl)c(Cl)c1

Procedure:
Using a procedure analogous to Example 6, Bis-(3,4-dichlorobenzyl)amine (2.71g, 8.09mM) was reacted with 4-bromobutyronitrile (0.81ml) to give the title compound as an oil 1.97g. Ir (film) CN 2230cm-1.
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:28])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)=[N:16][S:15](=[O:27])(=[O:26])[NH:14]2)=[CH:9][N:8]=1>C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@:13]2([CH3:28])[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[NH:16][S:15](=[O:26])(=[O:27])[NH:14]2)=[CH:9][N:8]=1
Reactant: CC1(c2ccc(Cl)nc2)NS(=O)(=O)N=C1c1ccc(Cl)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@]1(c2ccc(Cl)nc2)NS(=O)(=O)N[C@H]1c1ccc(Cl)c(F)c1
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Sodium borohydride (1.00 g, 26.4 mmol) was gradually added to an ethanol (63 ml) solution of the compound (7.13 g, 19.1 mmol) obtained in Step 7 above under ice cooling and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and then the residue obtained was diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=1:2 (v/v)] to give the title compound (4.36 g, 59%) as a pale yellow solid.
Reaction SMILES: C(OC(NC(C)(CC1C=CC=CC=1)COCC1C=C(C=C(N(S(C)(=O)=O)CCC)C=1)C(O)=O)=O)(C)(C)C.C(C1CCCN1)CC.[NH2:46][C:47]([CH3:85])([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[CH2:48][O:49][CH2:50][C:51]1[CH:52]=[C:53]([N:70]([CH2:75][CH2:76][CH3:77])[S:71]([CH3:74])(=[O:73])=[O:72])[CH:54]=[C:55]([C:57]([N:59]2[CH2:63][CH2:62][CH2:61][CH:60]2[C:64]2C=CC=[CH:66][CH:65]=2)=[O:58])[CH:56]=1>>[NH2:46][C:47]([CH3:85])([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[CH2:48][O:49][CH2:50][C:51]1[CH:52]=[C:53]([N:70]([CH2:75][CH2:76][CH3:77])[S:71]([CH3:74])(=[O:72])=[O:73])[CH:54]=[C:55]([C:57]([N:59]2[CH2:63][CH2:62][CH2:61][CH:60]2[CH2:64][CH2:65][CH3:66])=[O:58])[CH:56]=1
Reactant: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(C(=O)N2CCCC2c2ccccc2)c1)S(C)(=O)=O
Agent: CCCC1CCCN1
Agent: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Product: CCCC1CCCN1C(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(N(CCC)S(C)(=O)=O)c1

Procedure:
N-{3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(2-propylpyrrolidin-1-yl)carbonyl]phenyl}-N-propylmethanesulfonamide was prepared from 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI) and 2-propylpyrrolidine following a similar procedure as described for the preparation of N-{3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(2-phenylpyrrolidin-1-yl)carbonyl]phenyl}-N-propylmethanesulfonamide. HRMS (ES, M+H) calculated for C29H43N3O4S: 530.3047, found: 530.3045.