Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44]([NH2:47])([CH3:46])[CH3:45]>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][NH:47][CH:44]([CH3:46])[CH3:45])=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:32])=[O:33])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1ccccc1
Temperature: 80 °C
Reaction time: 16.5 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.444 g, 0.725 mmol) and isopropylamine (2.0 mL, 23 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 3 hours. More isopropylamine (2.0 mL, 23 mmol) was then added, and the reaction mixture was stirred at 80° C. in a sealed tube for 16.5 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 20 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-isopropyl-amine as a yellow semi-solid (0.290 g, 80.1% mmol). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacuo at 81° C. The result was the hydrochloride as a buff foam (0.273 g); Mass Spectrum (+EI, [M+H]+) m/z 500.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:13]=1[N+:19]([O-:21])=[O:20].O>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[C:13]=1[N+:19]([O-:21])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a suspension of sodium hydride (1.522 g, 38.06 mmol) in anhydrous DMF (150 mL) at room temperature was added benzyl alcohol (3.44 mL, 33.3 mmol) dropwise over 10 minutes, and stirring was continued for another 10 minutes. 2,6-Difluoronitrobenzene (5.046 g, 31.72 mmol) was added to the reaction mixture in one portion. The reaction mixture was stirred for an hour, and 100 mL water and 100 mL ethyl acetate were added. The layers were separated, and the aqueous layer was extracted with 75 mL ethyl acetate. The combined organic layers were washed with 100 mL water and 100 mL brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography (6% to 35% ethyl acetate in hexanes) to give 6.818 g (27.6 mmol, 87%) of 1-benzyloxy-3-fluoro-2-nitro-benzene as a yellow oil. MS: 248 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH:23]([F:25])[F:24])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH:23]([F:24])[F:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 70 °C

Procedure:
A solution of 18.0 g of isopropyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]- 4-fluorobenzoate in 60 ml of methylene chloride is stirred intensively for 5 minutes with 100 ml of concentrated sulphuric acid and subsequently poured onto 1 kg of ice. The resulting crystals are filtered off under suction. washed twice with 50 ml of water each time and dissolved in 300 ml of methanol. The mother liquor is extracted twice with 100 ml of methylene chloride each time and the organic phase is washed with water to neutrality and combined with the methanolic solution. This solution is dried over anhydrous sodium sulphate and evaporated to dryness. The crystalline residue is stirred with 100 ml of ethyl acetate at 70° C. and cooled to room temperature, and the crystals are filtered off under suction and washed with diethyl ether. There is obtained 2-chloro-5-[3 -difluoromethyl-3.6-dihydro-4-methyl- 2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid, m.p. 247°-248° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:4]=1.Cl>C(O)C.[Pd]>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:4]=1
Reactant: NCc1ccc(F)cc1-n1cncn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(F)cc1-n1cncn1
Reaction time: 4 h
Yield: 99 %

Procedure:
(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride): Intermediate 1,4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile, (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL). Aqueous 1N HCl (15 mL) was added followed by 10% Pd/C (200 mg). The mixture was shaken under H2 (55 psi) for 4 h., then filtered through Celite and concentrated in vacuo. The remaining residue was partitioned between ethyl acetate and water. The aqueous layer was isolated and lyophilized to give the title compound as a white powder (2.96 g, 99% yield). 1H NMR (500 MHz, CD3OD) δ ppm: 9.51 (1H, s), 8.63 (1H, s), 7.85 (1H, dd, J=8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 7.49 (1H, td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd for C9H10N4F: 193.08; found: 193.16.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([CH3:18])[CH2:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:21]([C:28]1[O:29][C:30]([CH3:35])=[C:31]([CH2:33]Cl)[N:32]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.FC(F)(F)C(C1C=C2C(=CC=1)N(CC1N=C(C=CC3C=CC=CC=3)OC=1C)C(C)C2)(O)C(F)(F)F>>[CH2:21]([C:28]1[O:29][C:30]([CH3:35])=[C:31]([CH2:33][N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:1])([F:19])[F:20])[C:4]([F:7])([F:6])[F:5])=[CH:17][CH:16]=3)[CH2:12][CH:13]2[CH3:18])[N:32]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1oc(Cc2ccccc2)nc1CCl
Reactant: CC1Cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1
Agent: Cc1oc(C=Cc2ccccc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Product: Cc1oc(Cc2ccccc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C

Procedure:
In analogy to example 75.2, from 1,1,1,3,3,3-hexafluoro-2-(2-methyl-2,3-dihydro-1H-indol-5-yl)-propan-2-ol (example 51.1) and 2-benzyl-4-chloromethyl-5-methyl-oxazole was prepared 1,1,1,3,3,3-hexafluoro-2-[2-methyl-1-(5-methyl-2-styryl-oxazol-4-ylmethyl)-2,3-dihydro-1H-indol-5-yl]-propan-2-ol, red oil, MS: 485 (MH+).
Reaction SMILES: [Cl-].[NH4+].[O:3]=[C:4]([N:24]1[CH2:29][CH2:28][N:27]([C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:39])[F:38])[CH2:26][CH2:25]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)=[CH:11][CH:10]=1)=[O:8]>C1COCC1.O.[Fe]>[O:3]=[C:4]([N:24]1[CH2:25][CH2:26][N:27]([C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:39])([F:40])[F:38])[CH2:28][CH2:29]1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(-c2ccc(C(=O)NCC(=O)N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)cc2)c1
Yield: 49.3 %

Procedure:
Ammonium chloride (74 mg, 1.4 mmol) was added to a stirred solution of 3′-nitro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (prepared by the method as described above) (123 mg, 0.2 mmol) in a mixture of THF (6 mL) and H2O (4 ml). Iron powder (77 mg) was then added and the resulting mixture at reflux temperature for 3 hrs. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc, washed with 5% aqueous NaHCO3 solution, followed by saturated brine solution. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 69 mg (49.3% yield) of 3′-Amino-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 92.88%. 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.8-7.7 (bd, 1H), 7.7-7.6 (m, 4H), 7.6-7.55 (bs, 1H), 7.4-7.3 (d, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 6.9 (t, 1H), 6.8 (d, 1H), 4.38-4.3 (m, 1H), 4.3-4.22 (m, 1H), 4.08-3.96 (bd, 2H), 3.94-3.86 (bs, 1H), 3.84-3.64 (m, 4H), 3.64-3.32 (m, 2H), 3.52-3.46 (d, 1H), 3.44-3.4 (t, 1H), 3.3-3.2 (bs, 2H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:4].[H][H]>CC(O)C.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH2:6][N:5]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:3](=[O:4])[C:2]([F:23])([F:1])[F:22])[CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)CCN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CC(C)O
Product: CS(=O)(=O)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 64 h
Yield: 93 %

Procedure:
To a suspension of 2,2,2-trifluoro-N-[2-(methylsulfonyl)ethyl]-N-[(3-nitrophenyl)methyl]acetamide (0.88 g, 2.5 mmol) in i-PrOH was added 10% Pd/C (80 mg, 0.08 mmol). A balloon filled with hydrogen gas was installed, and the reaction was stirred vigorously at rt. After 64 h, the reaction mixture was filtered through celite, adsorbed onto silica gel, and purified by column chromatography to generate the title compound in 93% yield. 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=7.5 Hz, 1H), 6.60-6.67 (m, 2H), 6.53 (s, 1H), 4.62 (s, 2H), 3.73 (t, J=6.9 Hz, 2H), 3.18 (t, J=6.8 Hz, 2H), 2.92 (s, 3H). ES-LC/MS m/z=324 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]2[C:17]3[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:26])[C:9]=2[N:27]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>N1C=CC=CC=1>[NH2:26][C:10]1[C:9]2[N:27]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:44]([NH:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:45])[N:7]([CH2:28][CH2:29][O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:8]=2[C:17]2[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc(CCCCNC(=O)Nc1ccccc1)n2CCOc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-(4-aminobutyl)-7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.40 g, 0.83 mmol) and pyridine (10 mL) was cooled to 0° C., and phenyl isocyanate (91 μL, 0.84 mmol) was added. The reaction was stirred for one hour and additional phenyl isocyanate (10 μL) was added. The reaction was stirred for one hour and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 95:5 chloroform:methanol), recrystallized from toluene, and dried in a vacuum oven to provide 150 mg of N-{4-[4-amino-7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}-N′-phenylurea as a white crystalline solid, mp 186.3-186.9° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[CH:5]=[C:4]([C:13]#[N:14])[CH:3]=1.FC1C(C#N)=CC2SC(SC)=NC=2C=1>>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[CH:5]=[C:4]([CH2:13][NH2:14])[CH:3]=1
Reactant: CSc1nc2c(Br)cc(C#N)cc2s1
Agent: CSc1nc2cc(F)c(C#N)cc2s1
Product: CSc1nc2c(Br)cc(CN)cc2s1

Procedure:
(4-Bromo-2-(methylthio)benzo[d]thiazol-6-yl)methanamine was synthesized as a clear oil (794 mg, 79%) using a procedure analogous to that described in Step 3 of Example 154, substituting 4-bromo-2-(methylthio)benzo[d]thiazole-6-carbonitrile from the previous step for 5-fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile used in Example 154. LCMS (ESI) m/z 288, 290 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Cl[CH2:25][C:26]([C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1)=[O:27]
Reactant: Cn1cccc1C(=O)CCl
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cccn2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-chloroacetyl-1-methylpyrrole (P. D. Croce et al., Synthesis, 1990, 212).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][C:6]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]1[NH:11][CH2:12][CH2:13][N:14]=1>C(Cl)(Cl)Cl>[CH3:5][C:6]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]1[N:14]([C:3](=[S:4])[NH:2][CH3:1])[CH2:13][CH2:12][N:11]=1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: CN=C=S
Solvent: ClC(Cl)Cl
Product: CNC(=S)N1CCN=C1COc1cccc(C)c1C
Temperature: 25 °C

Procedure:
A solution of methyl isothiocyanate (1.46 g; 0.20 mole) in chloroform (10 ml) was added dropwise during 10 minutes, to a stirred solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (4.08 g; 0.020 moles) prepared as in Example 1--in chloroform (50 ml) cooling to keep the reaction below 5° C. The reaction mixture was then allowed to warm to room temperature and finally refluxed for 5 hours. Chloroform was then evaporated in vacuo and the residue recrystallised from isopropanol to yield white crystals of 2-(2,3-dimethylphenoxymethyl)-1-N-methylthiocarbamoyl-2-imidazoline, m.p. ca 100° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: Brc1cnn(Cc2ccccc2)c1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(Cc4ccccc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-benzylpyrazole.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[SH:18]>CN(C=O)C.C(OCC)(=O)C>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[S:18][CH3:8]
Reactant: CI
Reactant: Fc1cc(S)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Potassium carbonate (310 mg, 2.22 mmol) and iodomethane (0.138 mL, 2.22 mmol) were added to a solution (10 mL) of 2-bromo-4,5-difluorothiophenol (400 mg, 1.78 mmol) in DMF, and stirred at room temperature overnight. After diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[C:29]1([SH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:28][C:4]1[CH:3]=[C:2]([S:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Reactant: Sc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccccc4)cc3F)cc2)COC(C)(C)OC1
Yield: 97.7 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (450 mg) of Reference Example 10, benzenethiol (121 mg), diisopropylethylamine (258 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (25.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (29.8 mg) in 1,4-dioxane (5 mL) was heated under reflux for 8 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (468 mg) as a pale-yellow oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([O:12][CH3:13])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:10]([O:12][CH3:13])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
12.92 g (40 mmols) of Z-Thr(tBu)-OMe are hydrogenated in 200 ml of glacial acetic acid and 3 g of Pd on charcoal (10%) at room temperature. The absorption of hydrogen is complete after 1 hour. The solution is freed of the catalyst by filtration and is evaporated under a waterpump vacuum at 35° C. After drying in a high vacuum at 35° C., 7.3 g of an oil result which according to a thin layer chromatogram is homogeneous and is directly used further.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([N+:25]([O-])=O)=[C:6]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:5]=1>CO.C(Cl)Cl.O.[Ni](Cl)Cl>[CH3:3][C:4]1[N:9]=[C:8]([N:10]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([NH2:25])=[C:6]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:5]=1
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(N(Cc2ccccc2)Cc2ccccc2)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(NCC(C)C)c(N)c(N(Cc2ccccc2)Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Sodium borohydride (585 mg, 16 mmole) was added to a solution of nickel (II) chloride hydrate (1.02 g, 4.3 mmole) in methanol (100 mL). The addition caused a black solid to form along with gas evolution. The resulting heterogeneous mixture was stirred at ambient temperature for 30 minutes. A solution containing 6-methyl-N4 -(2-methylpropyl)-3-nitro-N2, N2 -bis(phenylmethyl)pyridine-2,4-diamine (3.47 g, 8.6 mmole) in methylene chloride (20 mL) was added followed by the addition of sodium borohydride (1.37 g, 36 mmole). The reaction mixture was stirred at ambient temperature for about 30 minutes then eluted through a layer of silica gel with a methanol/methylene chloride mixture. The filtrate was concentrated under vacuum. The resulting residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried with magnesium sulfate and concentrated under vacuum to provide 2.74 g of the desired product as a green foam.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)[CH2:9][O:10][CH2:11][C:12]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[N:4][N:3]=[N:2]1>FC(F)(F)C(O)=O.C(Cl)Cl>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=2)[CH2:9][O:10][CH2:11][C:12]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3nnn[nH]3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)cc(-c2nnn[nH]2)c1
Reaction time: 1 h

Procedure:
tert-Butyl 4-((3-(1H-tetrazol-5-yl)-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (30.0 mg, 0.058 mmol) was dissolved in a trifluoroacetic acid/methylene chloride mixture (1:1, 1 mL) and stirred under nitrogen for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. Concentration afforded 11.0 mg (45%). LC/MS (HPLC method 3): tR=1.89 min, 418.88 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccnc(C#C[Si](C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 2-chloro-4-methoxypyrimidine (2.60 g, 17.99 mmol), ethynyltrimethylsilane (3.05 mL, 21.58 mmol), tetrahydrofuran (24 mL) and triethylamine (12.53 mL, 89.90 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then copper(I) iodide (0.14 g, 0.72 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.51 g, 0.72 mmol) were added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath at 90° C. After 16 hours, the mixture was filtered and the solvent was removed under reduced pressure. The residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated, washed with 4% aqueous sodium hydrogencarbonate solution, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (9:1 hexane/ethyl acetate) gave the title compound (2.85 g, 77%) as an oil.