Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([NH:17][C@H:18]([C:25]([NH2:27])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)=O>CO>[NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([NH:17][C@H:18]([C:25]([NH2:27])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Agent: O=C=O
Solvent: CO
Product: CC(C)C[C@H](N)[C@@H](O)CC(=O)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
240 mg of Z-Sta-β-Ala-His-NH2 are hydrogenated in 10 ml of 95% strength methanol with 50 mg of Pd-on-carbon (10% Pd) with CO2 -absorption until saturation. The catalyst is filtered off, the filtrate is concentrated to dryness and the solid amorphous residue is pulverised and then dried in a high vacuum, yielding H-Sta-β-Ala-His-NH2 ; Rf (E)=0.11; Rf (M)=0.26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([O:18]C)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:20])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:20])=[CH:6][CH:7]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccc(F)cc1
Yield: 84.2 %

Procedure:
By the method used in Example 1, Part D, 1.1 g (4.1 mmol) of 1-[(4-fluorophenyl)methyl]-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 16.4 mL of 1M BBr3/CH2Cl2 to give 881 mg (84% yield) of crude 1-[(4-fluorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[K+]>CC(C)=O>[C:18]([O:21][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
A mixture of 4-chloromethyl-2,6-di-t-butylphenol (2.55 g) and potassium acetate (0.98 g) in acetone (30 mL) was stirred at 20° C. for 24 hours. After evaporation of the solvent the residue was partioned between water and n-hexane. The hexane extract was concentrated and the residue slurried in n-hexane (6 mL) at about 0° C. The crystals were collected via filtration and dried to give 1.54 g, 45% yield, of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[S:11])[CH:7]2[CH3:12].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:13][C:7]1([CH3:12])[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]1=[S:11]
Reactant: Cc1cccc2c1NC(=S)C2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1NC(=S)C2(C)Cl

Procedure:
A solution of 7-methyl-3-methylthiooxindole (1 g, 0.0052 mol) and N-chlorosuccinimide (0.7 g, 0.0052 mol) in chloroform (100 ml) was stirred at room temperature for 1 hour. The solution was evaporated, yielding crude 3-chloro-7-methyl-3-methylthiooxindole, and the residue was dissolved in a minimum amount of tetrahydrofuran (ca. 10 ml) and added to a vigorously stirred slurry of red mercuric oxide (1.13 g, 0.0052 mol) and boron trifluoride ethereate (0,75, 0.0054 mol) in 50 ml of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for 1 hour, 150 ml of ether was added, the reaction mixture was filtered through a pad of Celite, and the organic phase of the filtrate was separated, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The red residue was recrystallized from methanol to give 0.6 g (71%) 7-methylisatin, mp 267°-269°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:18][C:19]1[CH:20]=[C:21]([C:2]3[C:11]4[C:6](=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])[CH:22]=[CH:23][CH:24]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])#[N:17]
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1Cl
Product: N#Cc1cnc2c(C(F)(F)F)cccc2c1Nc1cccc(-c2c(C#N)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 4-chloro-8-(trifluoromethyl)quinoline-3-carbonitrile and 3-aminophenylboronic acid according to the procedure of Example 1 as a side product. MS (ES) m/z 531.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](O)(=O)[CH2:21][OH:22].[OH-].[NH4+]>Cl>[C:14]1([CH2:13][N:12]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=[C:20]2[CH2:21][OH:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CO
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: OCc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 150 °C
Yield: 82 %

Procedure:
3-amino-4-(benzylamino) quinoline (9.5 g; 0.038 mol) and glycolic acid (6.8 g; 0.089 mol) were mixed and the mixture was heated at 150° C. for about 4 hr. The dark mixture was then dissolved in dilute hydrochloric acid with heating. Upon cooling a precipitate formed and was filtered from the mixture. The solid was dissolved in hot water. The solution was then made basic with ammonium hydroxide to precipitate the product. A second, less pure, small crop was obtained from the original filtrate by making it basic with ammonium hydroxide. The solid was triturated in ethyl acetate to give a green colored powder. Total yield was 82%. The product was recrystallized from methanol to give a pure sample m.p. 211-213° C. Analysis: Calculated: C, 74.7; H, 5.2; N, 14.5. Found: C, 74.4; H, 5.1; N, 14.4.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>ClCCl>[CH:9]1[C:10]2[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=2[CH:6]=[CH:7][C:8]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: c1ccc2c(c1)CCCC2
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available 5,6,7,8-tetrahydronaphthalene (1.45 g; 11.3 mmol) in dichloromethane (22.7 mL) cooled to 0° C. was added chlorosulfonic acid (0.9 mL; 13.5 mmol) fast dropwise. The reaction mixture was stirred overnight warming to room temperature gradually. The reaction mixture was used in the next reaction directly without purification.
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.C(OCC)(=O)C>[CH:26]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C:22](=[CH:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:27])[CH3:28]
Reactant: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C)C(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4C3=CC[C@]12C)C(C)C

Procedure:
A solution of N,N-diisopropyl-estr-1,3,5(10)-triene-3-ol-17β-carboxamide (380 mg, 1 mmol) in 10 mL dioxane is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (250 mg, 1.1 mmol) for two hours. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried, and concentrated. Chromatography of the residue yields N,N-diisopropyl estr-1,3,5(10),9(11)-tetraene-3-ol-17β-carboxamide.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:55][C:56]1[S:57][C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=1>C(Cl)Cl>[S:57]1[C:58]2[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=2[N:60]=[C:56]1[NH:55][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nc2ccccc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1
Yield: 65.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid (50 mg, 0.17 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (119 mg, 0.27 mmol), triethylamine (70 mL, 0.51 mmol), and 2-aminobenzthiazole (41 mg, 0.27 mmol) in methylene chloride (5 mL) was stirred at 25° C. under nitrogen for 2.33 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was sequentially washed with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide (48 mg, 66%) as a white solid: mp 206-209° C.; EI-HRMS m/e calcd for C22H24N2O3S2(M+) 428.1228, found 428.1233.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[CH:11]=[N:10][CH:9]=[N:8][C:7]=2[NH:6][CH:5]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:6]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[C:4]([Br:3])=[CH:5]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Brc1c[nH]c2ncncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(Br)c2cncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To suspension of NaH (60% in mineral oil, 34 mg, 0.85 mmol) in DMF (1.5 mL) at 0° C. under nitrogen atmosphere was added a solution of 5-bromo-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.71 mmol) in DMF (1.5 mL). The reaction mixture was stirred at 0° C. for 30 min and tert-butyl bromoacetate (104 μL, 0.71 mmol) was slowly added. The mixture was further stirred at RT for 30 min, then poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. MS (UPLC/MS): 312.3/314.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[C:33]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[C:33]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCOc1cc2ccccc2cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cc3ccccc3cc2OCOCC[Si](C)(C)C)C1

Procedure:
In an analogous manner to that described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethyl-3-(2-trimethylsilylethoxy-methoxy)-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[3-(2-trimethylsilyl-ethoxy-methoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a light yellow oil; MS: 523 [M-(C2H4 +CH2O)]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 13 g. of 4-[[bis(p-chlorphenyl)methyl]amino]benzoic acid, ethyl ester, 9 g. of potassium hydroxide, and 150 ml. of 95% ethanol is heated at 70° C. for 4 hours, cooled, diluted with 300 ml. of water, and adjusted to pH 6.5 with 37% hydrochloric acid. The solid is collected, dried, and crystallized from ethanol and then acetic acid, giving 5.52 g. of the desired product as yellow crystals, m.p. 245°-247° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][N:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(O)=[O:2].[CH3:23][NH:24][CH3:25]>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:25])[C:1]([C:4]1[C:5](=[O:22])[NH:6][N:7]=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:2]
Reactant: CNC
Reactant: O=C(O)c1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O

Procedure:
8.0 grams (0.0275 mole) of the acid chloride of the product of Example 2 was reacted with excess dimethylamine in 200 mls of toluene. This solution was heated on a steam bath for 2 hours. The solution was filtered and the filtrate distilled at reduced pressure. The residual solid was filtered, washed with petroleum ether and air dried. There was isolated 5.0 grams of a solid which when recrystallized from absolute ethyl alcohol gave 2.5 grams of a white solid that melted at 278° C. The infrared spectrum showed two carbonyl bands one at 6.0μ, the other a 6.1μ. Analysis calculated for C19H17N3O2.1H2O, C, 70.4; H, 5.4; N, 12.9. Found: C, 70.1; H, 5.5; N, 12.9.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:23]3[CH:28]=[CH:27][C:26](Cl)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:8]2.C12CC3CC(CC(C3)C1NC(C1C=NN(C3C=CC([C:60]([O:62][CH2:63][CH3:64])=[O:61])=CC=3C)C=1C(C)(C)C)=O)C2>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:60]([O:62][CH2:63][CH3:64])=[O:61])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:8]2
Reactant: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)c(C)c1
Product: CCOC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)cc1C(F)(F)F

Procedure:
Ethyl 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoate was prepared from N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]-5-tert-butyl-pyrazole-4-carboxamide (Intermediate #118) by the same process used for Intermediate #113.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](N2C=CN=C2)=[O:10])=[C:4]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9](=[O:10])[N:28]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:16]2([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[OH:24]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(F)cc2)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a suspension of N-[4-chloro-2-(4-fluorobenzoyl)phenyl]-1H-imidazole-1-carboxamide (63.0 g, 183.3 mmol) in THF (315 mL) was added 2,2,2-trifluoroethylamine (24.5 g, 247.4 mmol). The reaction was heated to 50° C. After 19 h at 50° C., the reaction was cooled to ambient temperature and concentrated in vacuo. The light yellow oil was partitioned between n-butyl chloride (110 mL) and aqueous 10% citric acid (60 mL) with vigorous stirring. The resulting precipitate was collected by vacuum filtration and placed under vacuum alongside P2O5 for 16 h to give 6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC(CO)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
To a solution of 2-(hydroxymethyl)-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (1.0 g, 3.81 mmol) in dichloromethane (10 mL) was added triethylamine (1.0 mL, 7.63 mmol) and methanesulfonyl chloride (0.60 mL, 7.63 mmol). The resulting mixture was stirred for 1.5 hours at room temperature. Product was collected by filtration, washed with dichloromethane (10 mL) and dried under reduced pressure to provide the product as a purple solid (1.1 g, 85%). M.p.=230-232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89 (d, J=6.8 Hz, 1H), 7.75 (m, 2H), 7.56 (m, 1H), 4.81 (m, 1H), 4.65 (m, 1H), 4.54 (m, 1H), 3.05 (m, 2H), 1.16 (m, 3H); LCMS: 341 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)(O)=[O:14].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.N(CC)(CC)CC>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][NH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CN)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
A mixture of 3,5-dimethoxybenzenemethanamine (3.34 g, 20 mmol), 4-(4-carboxyphenyl)-1-piperazinecarboxylic acid, 1-(1,1-dimethylethyl) ester (6.13 g, 20 mmol), EDCI (4.2 g, 22 mmol), HOBT (2.97 g, 22 mmol), N(CH2CH3)3 (12 ml) and DCM (80 ml) was stirred overnight at r.t. The solvent was evaporated. The residue was purified by column chromatography (eluent: petroleum ether/EtOAc 2/1). The desired fractions were collected and the solvent was evaporated. Yield: 5.3 g of 4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (58.24% yield).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (13 mg, 0.33 mmol) in anhydrous tetrahydrofuran (1 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (105 mg, 0.30 mmol) in anhydrous tetrahydrofuran (1 ml) and stirred under a nitrogen atmosphere for 1 hour. Ethyl bromoacetate (37 μl, 0.33 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (99:1) to pentane:ethyl acetate (80:20) to afford the title compound as a colourless oil (84 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH:31]1[CH2:34][CH2:33][CH2:32]1.O>CN(C=O)C>[CH:31]1([CH2:30][N:16]2[CH2:15][CH2:14][CH:13]([N:12]3[C:11]4[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=4[N:9]=[C:8]3[N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:18][CH2:17]2)[CH2:34][CH2:33][CH2:32]1
Reactant: BrCC1CCC1
Reactant: CN1CCN(c2nc3ccccc3n2C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2nc3ccccc3n2C2CCN(CC3CCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.4 %

Procedure:
A mixture of 2-(4-methylpiperazinyl)-1-(4-piperidinyl)-1H-benzimidazole (300 mg, 1 mmol), K2CO3 (165.9 mg, 1.2 mmol), and (bromomethyl)cyclobutane (178.8 mg, 1.2 mmol) in DMF (4 ml) was stirred at room temperature for 17 h. Then K2CO3 (110 mg, 0.8 mmol), and (bromomethyl)cyclobutane (119 mg, 0.8 mmol) were added to the reaction mixture. After 16 h stirring, the reaction mixture was poured into water and extracted with CH2Cl2. The extracts combined were dried (MgSO4), filtered, and concentrated in vacuo to give 369 mg of oil which was purified by preparative TLC (1 mm thick plate, CH2Cl2/MeOH:10/12 developped) to afford 147.6 mg (40%) of title compound as light brown solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]3=[O:21])=[CH:10][C:9]=2[F:22])[CH2:4][CH2:3]1.C(OP([CH:31]([C:33]#[N:34])[CH3:32])(=O)OCC)C>>[C:33]([C:31](=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]3=[O:21])=[CH:10][C:9]=2[F:22])[CH2:4][CH2:3]1)[CH3:32])#[N:34]
Reactant: NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: CCOP(=O)(OCC)C(C)C#N
Product: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Yield: 74 %

Procedure:
The compound was prepared by following the procedure of Example-1 and by using (S)-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and diethyl-(1-cyanoethyl)-phosphonate in 74% yield.