Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[S:10].[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:41][CH3:42])=[C:16]([CH:40]=1)[C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([O:38][CH3:39])=[C:26]([S:30]([NH:33]C(NC)=O)(=[O:32])=[O:31])[CH:27]=2)[O:22][CH2:21]1)=[O:18].C>CS(C)=O>[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:41][CH3:42])=[C:16]([CH:40]=1)[C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][C:25]([O:38][CH3:39])=[C:26]([S:30]([NH:33][C:9]([NH:8][CH3:7])=[S:10])(=[O:32])=[O:31])[CH:27]=2)[O:22][CH2:21]1)=[O:18]
Reactant: CN=C=S
Reactant: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCC(NC(=O)c1cc(F)ccc1OC)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCC(NC(=O)c1cc(F)ccc1OC)C2
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
1.65 g (12 mmol) of powdered potassium carbonate and 0.35 g (4.8 mmol) of methyl isothiocyanate were added to 1.64 g (4 mmol) of 3-(5-fluoro-2-methoxybenzamido)-6-sulfamoyl-7-methoxychroman (Example 9) in 10 ml of dry DMSO. After the mixture had been stirred at 80° C. for 25 minutes, it was cooled, introduced into ice-water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from ethanol. The product had a melting point of 221°-222° C.
Reaction SMILES: I[Si](C)(C)C.[F:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:22][CH2:21][CH2:20][C@@H:19]3[N:14]2[C:15](=[O:23])[CH2:16][CH2:17][CH2:18]3)[CH:10]=[CH:11][CH:12]=1.CN(C)CCN(C)C.[I:32]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:22][CH2:21][CH2:20][C@@H:19]3[N:14]2[C:15](=[O:23])[CH:16]([I:32])[CH2:17][CH2:18]3)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCC[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Reactant: II
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C(I)CC[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Yield: 103.3 %

Procedure:
Iodotrimethylsilane (0.34 mL) was added to a solution of (6R*,9aS*)-6-(3-fluorophenyl) octahydroquinolizin-4-one (383 mg) and N,N,N′,N′-tetramethylethylenediamine (0.82 mL) in methylene chloride (15 mL) under ice-cooling in a nitrogen atmosphere, and the reaction solution was stirred under ice-cooling for 30 minutes. Iodine (590 mg) was added to the reaction solution under ice-cooling, and the reaction solution was stirred under ice-cooling for one hour. Ethyl acetate and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 597 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][N:12]([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I.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.[Pd].[Pd]>[CH3:18][N:12]([CH2:11][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[C:28]#[C:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=1)[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CN(C)Cc1nc2ccccn2c1I
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(C)Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
In a flask placed under an argon flow, 0.093 g (0.212 mmol) of methyl 2-(((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)acetate were dissolved in 0.5 ml of dimethylformamide with magnetic stirring. To this solution, were added: 0.004 g (0.021 mmol) of copper iodide, 0.037 ml (0.255 mmol) of 3-trifluoromethylphenylacetylene and 0.444 ml (3.18 mmol) of triethylamine. The reaction medium was degassed with argon for 10 min before adding 0.019 g (0.021 mmol) of Pd2(dba)3. The mixture was stirred at r.t. for 16 h before being treated, diluted with 15 ml of ethyl acetate and washed with 2×15 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 20 ml of ethyl acetate. The combined organic phases were dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.05 g (yield=57%) of methyl 2-(methyl((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)acetate were obtained as a pale brown solid. LC-MS: m/z=402 (MH+); UV purity at 254 nm=96%. 1H NMR (300 MHz, DMSO) δ 8.75 (d, J=6.7 Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.83-7.59 (m, 3H), 7.55-7.37 (m, 1H), 7.14 (td, J=6.8, 0.9 Hz, 1H), 3.97 (s, 2H), 3.58 (s, 3H), 3.43 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15](Cl)=[O:16]>>[CH3:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15]([N:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:16]
Reactant: C1COCCOCCOCCN1
Reactant: CCC(C)(C)C(=O)Cl
Product: CCC(C)(C)C(=O)N1CCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][OH:10])[O:7][CH2:6][CH2:5][O:4]1)C.[CH3:11][O:12]CC(=O)CC(OC)=O>>[CH3:11][O:12][CH2:1][C:3]1([CH2:8][CH2:9][OH:10])[O:4][CH2:5][CH2:6][O:7]1
Reactant: CCC1(CCO)OCCO1
Reactant: COCC(=O)CC(=O)OC
Product: COCC1(CCO)OCCO1
Yield: 50 %

Procedure:
The same procedure as in the step (39a) and (39b) of Example 39 was repeated using methyl 4-methoxyacetoacetate to obtain the title compound (5.3 g, 2 steps: 50%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][C:17](OC)=[O:18].[NH4+].[Cl-]>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][C:17]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: C1CCNC1
Reactant: COC(=O)CCCC(=O)c1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(CCCC(=O)N1CCCC1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1ml of pyrrolidine is added with stirring 0.100g (0.35 mmol) of the product of Example 3, and 5 mg of NH4Cl. The combined reagents were stirred in a sealed tube for 16 hours at room temperature. After this time, an additional 1 ml of pyrrolidine and 5 mg of NH4Cl was added and the reaction mixture was stirred an additional 16 hours. The solvent was removed under reduced pressure and the residue was flash chromatographed. Elution with diethyl ether produced 0.13 g of the titled product, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5](N)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][S:12]SC.N(OCCC(C)C)=O>>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([S:12][CH3:11])=[C:4]([CH3:10])[CH:3]=1
Reactant: CSSC
Reactant: Cc1cc(Br)c(F)cc1N
Agent: CC(C)CCON=O
Product: CSc1cc(F)c(Br)cc1C
Temperature: 75 °C
Yield: 84.9 %

Procedure:
4-Bromo-5-fluoro-2-methylaniline (5 g, 24.5 mmol) was dissolved in 1,2-dimethyldisulfane (35 mL, 394 mmol) and heated to 75° C. under nitrogen. Isoamyl nitrite (8.52 mL, 63.7 mmol) was added dropwise to the reaction via an addition funnel through a reflux condenser (˜1 drop/sec). (NOTE—a large exotherm may occur if addition is too fast.) After addition was complete, the reaction was heated to 95° C. for 1 hour and allowed to cool to ambient temperature. The reaction was concentrated and purified over silica gel (100% hexanes) to afford (4-bromo-5-fluoro-2-methylphenyl)(methyl)sulfane (4.9 g, 20.8 mmol, 85.0% yield) as an orange solid.
Reaction SMILES: [C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[C:1](=[O:19])([O:17][CH3:18])[O:2][C:3]1[CH:8]=[C:7]([N+:20]([O-:22])=[O:21])[C:6]([F:9])=[CH:5][C:4]=1[C:10]1([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 161.8 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate (21.5 g, 81 mmol) in 10 mL of concentrated sulfuric acid was added drop-wise to ice cold mixture of concentrated sulfuric acid (120 mL) and KNO3 (8.2 g, 81 mmol) at 0° C. After addition, the reaction mixture was stirred for 15 min while warming to ambient temperature, poured onto crushed ice, extracted with ethyl acetate (120 mL×3). The organic layer was washed with brine, dried over MgSO4, and evaporated under vacuum. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)-5-nitrophenyl methyl carbonate as a yellow oil (40.8 g, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=6.8 Hz, 1H), 7.34 (d, J=13.2 Hz, 1H), 3.97 (s, 1H), 2.02-1.96 (m, 2H), 1.73-1.45 (m, 8H), 1.39 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(OCC)C)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]=O)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:45]([SH:48])[CH2:46][SH:47].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]3[S:48][CH2:45][CH2:46][S:47]3)=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3ccccc3)c(C=O)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Reactant: SCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCc1nc2cc(-c3ccccc3)c(C3SCCS3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 80.3 %

Procedure:
0.1 g(0.000169 mole) of the aldehyde compound obtained in step 11 of Example 1 and 0.024 g(0.00025 mole) of 1,2-ethanedithiol were dissolved in 5 ml of benzene and to the resulting solution was added 0.01 mg of p-toluenesulfonic acid. The resultant was refluxed for 6 hours, neutralized with aqueous NaHCO3 solution and extracted with ethyl acetate(5 ml×3). The organic layer was dried over Na2SO4, concentrated under reduced pressure and evaporated under reduced pressure (1 mmHg, 80° C.) for 5 hours to remove the residual 1,2-ethanedithiol. The resultant was recrystallized from hexane-methylene chloride to obtain 80 mg of the title compound(yield 84%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.Cl.[NH:17]1[CH2:20][CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].IC.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[N:5]=[C:4]([CH3:15])[N:3]=[C:2]([N:17]3[CH2:20][CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18]3)[CH:7]=2)[N:9]=1
Reactant: COC(=O)C1CNC1
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CN(c2cc(-n3nc(C)nc3C)nc(C)n2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Intermediate 2 (0.45 g, 2.0 mmol), methyl azetidine-3-carboxylate hydrochloride (0.61 g, 4.0 mmol), and cesium carbonate (2.0 g, 6.0 mmol) were combined in degassed DMF (10 mL) and heated at 100° C. for 14 h. The mixture was cooled to room temperature and treated with iodomethane (0.13 mL, 2.0 mmol). After stirring for 1 h, the mixture was poured into sodium bicarbonate (200 mL, aqueous saturated) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/hexanes), providing 107-1 as an off-white solid. MS: m/z=303.3 (M+H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[O:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.O>CN1CCCC1=O>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: NC1CCOCC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC3CCOCC3)n2)cc1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.277 g, 0.73 mmol) in N-methylpyrrolidone (1.25 ml) was added tetrahydro-2H-pyran-4-amine (0.147 g, 2 eq.), the mixture was stirred for 1 hour and then water (1.25 ml) was added dropwise. This resulted in a precipitate being formed, which was collected by filtration, and dried in vacuo (0.258 g). This material was then purified by autopurification to give the title compound as a colourless solid (0.116 g, 40%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:25]3[CH2:24][CH2:23][NH:22][CH:21]([CH3:20])[CH2:26]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)c(F)c21
Yield: 27.8 %

Procedure:
A mixture of 1.00 g of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.10 g of 2-methylpiperazine and 10 ml of pyridine was heated for 15 minutes under reflux. The reaction mixture was evaporated and methanol was added to the residue. The precipitate was filtered and recrystallized from ethanol to give 0.36 g of the title compound as colorless needles, M.p. 239°-240.5° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16](Cl)(=[O:18])=[O:17])[C:7]=1[OH:20])(=[O:3])[CH3:2].[CH3:21][NH2:22]>CC(C)=O>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16](=[O:18])(=[O:17])[NH:22][CH3:21])[C:7]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Reactant: CN
Solvent: CC(C)=O
Product: CNS(=O)(=O)c1cc(C(C)(C)C)cc(CNC(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9 g (0.028 mole) of 2-acetamidomethyl-6-chlorosulfonyl-4-(1,1-dimethylethyl)-phenol are dissolved in 100 ml of acetone, and 4.9 ml (0.056 mole) of 40% strength aqueous methylamine solution are added dropwise, while cooling with ice. The mixture is stirred for 30 minutes at room temperature and poured into ice water. Recrystallization from n-propanol gives white crystals of melting point 173°-174° C.
Reaction SMILES: C([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([CH2:20][CH3:21])[CH:13]=1)[C:6]([O:8]CC)=[O:7])(=O)C>Cl>[NH2:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([CH2:20][CH3:21])[CH:13]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)[C@@H](Cc1ccc(CC)c(CC)c1)NC(C)=O
Agent: Cl
Product: CCc1ccc(C[C@@H](N)C(=O)O)cc1CC
Temperature: 0 °C

Procedure:
A mixture of 13.8 g (47.4 mmol) ethyl (R)-2-acetylamino-3-(3,4-diethyl-phenyl)-propionate and 160 mL 6 M HCl was refluxed in the oil bath for 3 h. The reaction mixture was cooled in the ice bath and the precipitate formed was suction filtered.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9]S(C(F)(F)F)(=O)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1([CH2:8][O:9][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH:21]=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(O)c1
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COc2cccc(C=O)c2)CCCCC1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of compound iii (0.5 mmol), 3-hydroxy-benzaldehyde (iv, 0.6 mmol) and K2CO3 (0.7 mmol) were dissolved in DMF (3 mL). The solution was heated to 80° C. for 4 hr. The solution was poured into water, extracted with ethyl acetate (10 mL) three times, and concentrated. The residue was purified by chromatography and resulted in 0.22 mmol of 3-(1-methyl-cyclohexylmethoxy)-benzaldehyde (v) with a 44% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=1)(=[O:3])[CH3:2].CC1C=CC(S(O[CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:33][CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CC(=O)OCc1cc(O)cc(C)c1-c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Temperature: 90 °C
Reaction time: 21 h
Yield: 60.1 %

Procedure:
To a solution of [4-hydroxy-3′-(hydroxymethyl)-6-methylbiphenyl-2-yl]methyl acetate (1.02 g, 3.56 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (1.25 g, 4.27 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.640 g, 4.32 mmol), and the mixture was stirred at 90° C. for 21 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0) to give the title compound (0.87 g, yield 60%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[BH4-].[Na+].C(OCC)(=O)C.O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(Cl)cc(CO)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.5 g (55.97 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate (prepared according to G. Doyle Daves, Fred Baiocchi, Roland K. Robins, and C. C. Cheng, J. Org. Chem., 26 (1961), 2755-2763) are initially charged in 450 ml of ethanol. 21.17 g (559.74 mmol) of sodium borohydride are added, and the mixture is stirred at room temperature for 2 hours. 500 ml of ethyl acetate and 500 ml of water are added, and the solution is stirred for 30 minutes. The phases are separated and the aqueous phase is extracted three times with ethyl acetate (in each case 100 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated. This gives 7.21 g (85% of theory) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:31])[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH2:24]O)=[C:22]([CH3:26])[N:21]=[C:20]1[CH2:27][N:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]1(=[O:61])[NH:55][C:54](=[O:56])[C:53]2=[CH:57][CH:58]=[CH:59][CH:60]=[C:52]12.N(C(OCC)=O)=NC(OCC)=O>>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([N:19]2[C:23]([CH2:24][N:55]3[C:51](=[O:61])[C:52]4=[CH:60][CH:59]=[CH:58][CH:57]=[C:53]4[C:54]3=[O:56])=[C:22]([CH3:26])[N:21]=[C:20]2[CH2:27][N:28]([CH3:30])[CH3:29])=[C:9]([C:8](=[O:31])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:14]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(C(F)(F)F)cc2C(=O)c2ccccc2Cl)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(C(F)(F)F)cc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 2'-chloro-5-trifluoromethyl-2-[2-[(dimethylamino)methyl]-4-methyl-5-hyroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-trifluoromethyl-2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:4]([F:29])[CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:49])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:29])[C:5]([CH:9]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:49])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3c(F)cc(Cl)cc3F)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3c(F)cc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 40 mg (0.09 mmol) of the compound from Example 285 in analogy to the synthesis of the compound from Example 296. 38 mg (92% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C1C[O:20]CC1.O>>[CH3:1][O:2][C:3]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:20])=[O:14])=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[O:16]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)c1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The product obtained from Example 193, Step C (240.0 mg, 1.0 mmol) was treated with THF/H2O (1:1, 10 ml). The mixture was stirred at 60° C. for 2 hr. The reaction mixture was extracted with EtOAc, washed with 1N HCl, H2O and brine. Reverse phase HPLC purification provided 4-(1-methoxycarbonyl-1-methyl-ethyl)-benzoic acid as white solid. MS found: (M+1)+=223.1.
Reaction SMILES: C(OC(=O)[N:7]([C:23]1[C:32]2[C:27](=[N:28][C:29]([S:33][CH2:34][CH3:35])=[N:30][CH:31]=2)[N:26]=[CH:25][N:24]=1)[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(C)(C)C.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.BrCC#N>>[CH2:37]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:23]2[C:32]3[C:27](=[N:28][C:29]([S:33][CH2:34][CH3:35])=[N:30][CH:31]=3)[N:26]=[CH:25][N:24]=2)=[CH:17][CH:18]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: CCSc1ncc2c(N(C(=O)OC(C)(C)C)c3cc(C)ccc3Sc3ccc(O)cc3)ncnc2n1
Agent: N#CCBr
Product: CCSc1ncc2c(Nc3cc(C)ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Yield: 29 %

Procedure:
The product from Example 164 was reacted with benzyl bromide according to the procedure from Example 165 substituting benzyl bromide for bromo-acetonitrile to provide the crude product which was purified by silica gel chromatography using 98/2 dichloromethane/methanol as eluent to provide the title compound (15 mg, 29%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.20 (t, J=7.35 Hz, 3H), 2.27 (s, 3H), 3.08 (q, J=7.35 Hz, 2H), 5.44 (s, 2H), 6.74 (d, J=8.46 Hz, 2H), 6.95 (m, 3H), 7.20 (d, J=8.46 Hz, 2H), 7.35 (m, 5H), 8.77 (s, 1H), 9.42 (s, 1H), 9.81 (s, 1H); MS (ESI+) m/z 512 (M+H)+.