Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:30])[CH2:25][O:26]C(=O)C)[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1>C(=O)([O-])[O-].[Na+].[Na+].CO.O>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:30])[CH2:25][OH:26])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)COC(C)=O)cccn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)CO)cccn12
Reaction time: 4 h
Yield: 98.1 %

Procedure:
8-[2Methyl-6-(2-acetoxyacetyl)aminobenzylamino]3-(2-propynyl)-2 -methylimidazo[1,2-a]pyridine (0.33 g) was dissolved in a mixture of an aqueous solution (0.7 ml) of sodium carbonate (0.0118 g) and methanol (6.6 ml) at room temperature and then the mixture was stirred for 4 hours. The mixture was diluted with water and the resultant solid was collected to give 8-[2-methyl- 6-(2-hydroxyacetyl)aminobenzylamino]-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.29 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[ClH:19]>C(O)C>[ClH:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH:13]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C1=CCN(C)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc(N)cc1C1=CCN(C)CC1
Yield: 99 %

Procedure:
A solution of 4-(2-methoxy-5-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (D37) (570 mg, 2 mmol), in ethanol (35 ml), was warmed to 60° C. and treated dropwise with a solution of stannous chloride (2 g) in conc. hydrochloric acid (4 ml). The mixture was heated for a further 2 h after addition, and allowed to cool. The precipitate was filtered off, and washed with ethanol to give the title compound (D39) as a pale yellow powder (580 mg, 99%). MH+=219.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][N:6]([C@@H:9]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[N:5]=1)([O-])=O.O.NN>CO.[Pd]>[NH2:1][C:4]1[CH:8]=[N:7][N:6]([C@@H:9]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[N:5]=1
Reactant: O=[N+]([O-])c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Yield: 106.4 %

Procedure:
A solution of 15 (2.46 g, 0.01 mol) in methanol (50 ml) and 5% palladium-on-carbon catalyst (500 mg) was stirred at room temperature while a solution of 99% hydrazine hydrate in methanol (1:3, v/v) was added dropwise until evolution of nitrogen ceased. The catalyst was removed by filtration through Celite and the solvent was removed by evaporation in vacuo to give 2.30 g of syrup. The syrup was dissolved in methanol and absorbed on 5 g of silica gel. The methanol was removed and the mixture was added to a dry packed silica gel column (2.5 × 28 cm). The column was eluted with chloroform (0.2 liter), chloroform-ethyl acetate (1:1, 0.2 liter), ethyl acetate (0.2 liter), and ethyl acetate-methanol (9:1, 0.5 liter); 20 ml fractions were collected. Fractions 30-35 provided 2.0 g (93%) of 17 as a syrup: nmr (DMSO-d6) δ 5.62 (d, 1, J1',2' 4.0 Hz, 1'--H), 7.03 (s, 1, 5--H).
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[C:16]([N:17]4[N:21]=[CH:20][CH:19]=[N:18]4)=[CH:15][CH:14]=[CH:13][C:12]=3F)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[F:23]C1C=CC=C(N2N=CC=N2)C=1C(O)=O>>[C@H:1]12[N:8]([C:9]([C:11]3[CH:12]=[C:13]([F:23])[CH:14]=[CH:15][C:16]=3[N:17]3[N:21]=[CH:20][CH:19]=[N:18]3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: O=C(c1c(F)cccc1-n1nccn1)N1C[C@H]2CCNC[C@H]21
Product: O=C(c1cc(F)ccc1-n1nccn1)N1C[C@H]2CCNC[C@H]21

Procedure:
The title compound was prepared in a manner analogous to Intermediate 28, substituting 5-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid for 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. C15H16FN5O, 301.32; m/z found 302.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Br[CH2:13][CH2:14][CH2:15]CBr.C(O[K])(C)(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]1([CH2:15][CH2:14][CH2:13]1)[CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: BrCCCCBr
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Br)cc2CC12CCC2
Temperature: 130 °C

Procedure:
100 mg of 5-bromo-1-oxoindane was dissolved in 10 ml of toluene, 0.3 ml of 1,4-dibromobutan and 132 mg of tert-butoxypotassium were added, and the mixture was stirred all night by heating at 130° C. under reflux. The reaction solution was cooled down to room temperature, the solvents were distilled outunder reduced pressure and the residues were separated and purified by silicagel chromatography (ethyl acetate/hexane=1/2) to obtain 71 mg of the above compound as a yellow oily matter.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[CH2:23]([N:31]=[C:32]=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:32]([NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: O=C=NCCc1ccccc1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)NCCc1ccccc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using phenethyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:33])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:33])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 150 mg (0.5 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 90 mg (0.5 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.2 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 230 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 4 ml (4 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) yields 42 mg of product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:29][O:30]CC=C)[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:28])=[CH:5][CH:4]=1)#[N:2]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:29][OH:30])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:28])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCOCC1(c2ccc(C#N)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 433 mg of 4-[4-(4-cyanophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in Step 5 in DCM (5 mL), 600 μL of boron trifluoride-dimethyl sulfide complex is added. The mixture is stirred 8 hours at rt, diluted with DCM, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane: 0/100 to 50/50) to give the desired compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:28])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH2:27])[CH:21]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:15][O:16][C:17](=[O:28])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: COC(=O)C=Cc1ccc(F)c(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(F)c(NC(=O)c2ccc(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-phenyl-2-furoic acid (36) (18 mg, 0.15 mmol) was coupled to aniline (43) (30 mg, 0.15 mmol) using Method B, except that DIPEA (40 mg, 0.31 mmol) and DMF (2 mL) were used and the reaction was stirred at ambient temperature for 2.5 hours, then at 40° C. for 24 hours. Further TBTU (1 eq) and acid (1 eq) were added and the reaction heated at 60° C. for a further 6 hours to give the crude title compound after work-up. The residue was purified using column chromatography eluting with 20% EtOAc in heptane to give the title compound. Yield: 18 mg, 32%; LC-MS tr 1.55 min; HPLC Purity: 83%; MS (ES+) m/z 366 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. HR-MS (ES, m/z) calculated for C31H30N4O3F3Cl2 [(M+H)+] 633.1642, observed 633.1638.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[OH-].[NH4+:15]>O1CCCC1.C(N(CC)CC)C>[NH2:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=S)c1cnc(C)nc1N
Reaction time: 16 h
Yield: 94 %

Procedure:
A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (1450 g, 6.23 mole) (Aldrich Chemical Co., Milwaukee, Wis., USA) in 2987 mL of tetrahydrofuran was cooled to 5-10° C. and treated slowly with a mixture of 2407 mL of a 37% solution of ammonium hydroxide in 2978 mL triethylamine. After stirring for 16 hours, the reaction mixture was concentrated in vacuo to approximately 5L and filtered. The filter cake was washed with hexanes and dried in a vacuum oven at 60-65° C. The filtrate was evaporated under reduced pressure to give 1314 g (94%) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid. m.p. 130.1-130.7° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C.[CH3:35][NH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][C:42]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)([OH:45])[CH2:41][CH2:40]1>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:36]([CH2:37][CH2:38][N:39]2[CH2:40][CH2:41][C:42]([OH:45])([CH2:46][C:47]3[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=3)[CH2:43][CH2:44]2)[CH3:35])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CNCCN1CCC(O)(Cc2ccc(C)cc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CCN(C)C(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
A mixture of 4-benzyloxy benzoic acid (265 mg, 1.16 mmol), 1,1 '-carbonyl-diimidazole (197 mg, 1.21 mmol) and DMF (7 ml) was stirred at 50° C. for 1 h. After cooling to r.t., 1-(2-methylamino-ethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (335 mg, 1.27 mmol) was added and stirring was continued for 1 h. After the addition of water, the mixture was extracted with ether. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, dichloromethane-methanol 95:5) to give 4-benzyloxy-N-[2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl]-N-methyl-benzamide (226 mg) as a pale yellow oil. MS: me/e=473 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([N:9]([CH3:36])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[N:13]=1)=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[O:11])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>ClCCl>[C:5]([N:9]([CH3:36])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[N:13]=1)=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:1](=[O:3])[CH3:2])=[C:21]([O:29][CH3:30])[CH:20]=3)=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OCCN)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1OCCNC(C)=O)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetyl chloride (10.2 μl) was added dropwise to a mixture of the product of example 31 (50 mg) and DIPEA (55 μl) in dichloromethane (2 ml). After stirring at room temperature for 18 h, the reaction mixture was diluted with dichloromethane and washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0→100% acetonitrile).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:22][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]=2[CH:12]=1
Reactant: c1ccc(-c2oc3ccccc3c2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(-c3ccccc3)c(-c3ccccc3)oc2c1
Temperature: 70 °C
Yield: 72 %

Procedure:
43.2 g of 2,3-diphenylbenzo[b]furan, 31.3 g of N-bromosuccinimide, and 400 mL of N,N-dimethylformamide were loaded into a flask, and the mixture was stirred under heat at 70° C. for 8 hours. After having been cooled to room temperature, the reaction solution was poured into 2 L of water. The precipitated crystal was separated by filtration, washed with methanol, water, and methanol in the stated order, and purified by silica gel column chromatography, whereby 40.2 g of a pale yellow crystal were obtained (72% yield).
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[S:8].[CH2:15](I)[CH3:16]>>[CH2:15]([S:8][CH:7]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])[NH:6][C:2]1[S:1][CH:5]=[N:4][N:3]=1)[CH3:16]
Reactant: CCI
Reactant: CCOC(=O)NC(=S)Nc1nncs1
Product: CCOC(=O)NC(Nc1nncs1)SCC

Procedure:
[(1,3,4-Thiadiazol-2-ylamino)thioxomethyl]-carbamic acid, ethyl ester (6.96 g) was reacted with 4 ml of ethyl iodide according to the procedure of Prepartion 7 to give 1.83 g of [(ethylthio) (1,3,4-thiadiazol-2-ylamino)methyl]carbamic acid, ethyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH:16]([C@@H:18]1[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][N:20]([C@H:29]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[C:30]([O:32]CC2C=CC(OC)=CC=2)=[O:31])[CH2:19]1)=O>>[CH:9]1[N:8]=[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:16][C@@H:18]3[C@@H:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][N:20]([C@H:29]([CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[C:30]([OH:32])=[O:31])[CH2:19]3)[CH2:6][CH2:5]2)[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=12
Reactant: c1ccn2c(C3CCNCC3)ncc2c1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(c3ncc4ccccn34)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 3-(piperidin-4-yl)imidazo[1,5-a]pyridine (from Step B) and 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, (4-methoxy)benzyl ester (Aldehyde 5) using procedures analogous to those described in Example 95 (Steps C and D). ESI-MS 501 (M+1); HPLC A: 1.20 min.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:20]1[C:24](B(O)O)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:24]2[O:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Product: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2cc3ccccc3o2)C1=O
Yield: 23.1 %

Procedure:
200 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-iodo-3(2H)-furanone was coupled with 99 mg of benzo[b]furan-2-boronic acid by following a procedure similar to Step 4 of Example 22 to give 45 mg of 5-{4-(aminosulfonyl)phenyl}-4-(2-benzo[b]furanyl)-2,2-dimethyl-3(2H)-furanone as a solid. mp: 143-145° C. NMR: δ1.60 (s, 6H), 4.92 (br s, 2H), 7.23 (m, 3H), 7.72 (m, 2H), 8.02 (m, 4H), IR (cm−1): 3384, 3245, 1698, 1510, 1253, 1161, 793.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:24]3[CH2:26][CH2:25]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH:24]3[CH2:25][CH2:26]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][N:15]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC(c1cn(-c2ccc(C(F)(F)F)cn2)nc1C1CC1)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2C2CC2)C2CCCCC2)cc1
Yield: 24.6 %

Procedure:
Using cyclohexyl{3-cyclopropyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized in Example 9(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.34 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.19 g, 25%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([N+:29]([O-])=O)[CH:5]=1>[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([NH2:29])[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(C(=O)OC)c1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
A mixture of 3.55 g of 3-nitro-5-(octadecyloxy)benzoic acid methyl ester and 0.75 g of 10% palladium on carbon in 100 ml of THF was shaken under an initial hydrogen pressure of 52 psi until uptake ceased after 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to give 3.28 g of pure 3-amino-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:8][S:9]([O:13][CH2:14][C@H:15]([NH:20][C:21]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:27])[CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triethylamine (59 ml) and methanesulfonylchloride (25 ml) were added to a THF solution (200 ml) containing (R)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (46.2 g) in an ice bath, followed by stirring for 0.5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. A white solid of (R)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (60 g) was thus obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:37])[CH3:36])[CH2:30]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:29]3[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:37])[CH3:36])[CH2:30]3)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: CC(=O)N[C@H]1CCNC1
Product: CC(=O)N[C@H]1CCN(C2CCN(C(=O)c3c(C)nn(-c4cccc(C(F)(F)F)c4)c3C3CC3)CC2)C1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (S)—N-pyrrolidin-3-yl-acetamide in direct analogy to the general procedure used in example 129. MS: 504.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([F:12])([F:23])[F:24])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1C(F)(F)F
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1C(F)(F)F
Yield: 52.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-trifluoromethyl phenyl isocyanate (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (180 mg, 52%). EI-MS m/z 342 (M+H)+