Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[C:7]([Cl:25])=[N+:8]([O-:24])[C:9]([CH2:20][CH:21]([CH3:23])[CH3:22])=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=1)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[CH:1]([O:4][CH2:5][C:6]1[C:7]([Cl:25])=[N+:8]([O-:24])[C:9]([CH2:20][CH:21]([CH3:22])[CH3:23])=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=1)=[CH:2][CH3:3]
Reactant: C=CCOCc1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1Cl
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: CC=COCc1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1Cl
Yield: 130 %

Procedure:
To 200 mg of 3-allyloxymethyl-5-benzyloxy-2-chloro-6-isobutylpyrazine 1-oxide were added 195 μl of diisopropylethylamine, 51 mg of a Wilkinson's catalyst ##STR69## and 4 ml of water (10% volume)-ethanol. The mixture was reacted for 3 hours at 85°-90° C. The catalyst was removed by filtration to obtain 260 mg of 3-(1-propenyl)oxymethyl-5-benzyloxy-2-chloro-6-isobutylpyrazine 1-oxide (Compound B-6) [a cis/trans (about 4/3) mixture] as a colorless oily substance.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:16]([O:18][CH3:19])=[O:17]>C(Cl)Cl>[C:16](=[O:17])([O:18][CH3:19])[O:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: COC(=O)Cl
Reactant: OC1C=CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)OC1C=CCCCC1
Temperature: 10 °C
Yield: 94.9 %

Procedure:
To a solution of cyclohept-2-enol (8.3 g, 74.0 mmol) in DCM (227 ml) and pyridine (35.9 ml, 444 mmol), was added methyl chloroformate (14.24 ml, 185 mmol) with cooling in an ice bath at such a rate that T<10° C. Once addition was complete, the reaction was allowed to mix and warm to ambient temperature overnight. The reaction mixture was washed with 2×150 mL 1N aqueous hydrochloric acid. The combined washes were back-extracted with 100 mL DCM. The combined DCM layers were then washed with 150 mL of an aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (11.95 g, 70.2 mmol, 95% yield) as an oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) 5 ppm 5.83 (dddd, J=11.81, 7.03, 5.17, 2.15 Hz, 1H), 5.65 (d, J=11.71 Hz, 1H), 5.17 (d, J=6.64 Hz, 1H), 4.71 (d, J=4.30 Hz, 1H), 3.69 (s, 2H), 1.99-2.23 (m, 2H), 1.79-1.94 (m, 2H), 1.56-1.72 (m, 3H), 1.34 (d, J=3.51 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH2:10]([Si:17]1(C2C=CC=CC=2)[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:10]([Si@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=2)=[O:24])[CH2:21][CH2:22]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(Cl)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 4-chloro-3-fluorophenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]([C:41]1[CH:46]=[CH:45]C(O)=[CH:43][CH:42]=1)[CH2:38][CH2:39][CH3:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:46][C:41]([CH2:37][CH2:38][CH2:39][CH3:40])=[CH:42][CH:43]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CCCCc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCc1ccc(OC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)cc1
Yield: 15.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-butylphenol (35 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (12 mg, yield 15%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[NH2:11][OH:12]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[NH:10])[NH:11][OH:12])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: NO
Solvent: CCO
Product: N=C(Cc1ccc(F)cc1)NO
Yield: 99.9 %

Procedure:
A solution of 2-(4-fluorophenyl)acetonitrile (1.35 g, 10 mmol) and 50% aq. hydroxylamine (1.33 g, 20 mmol) in EtOH (10 mL) was stirred at 90° C. for 18 h then cooled and concentrated to afford the title compound (1.68 g, 100% yield) as white solid. 1HNMR (500 MHz, CDCl3) δ: 8.04-7.85 (1H, br s), 7.24 (2H, dd, J=8.6, 5.5 Hz), 7.01 (2H, t, J=8.6 Hz), 4.46 (2H, s), 3.43 (2H, s). LCMS (M+H): 169.14.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+].O.C(O)C>CN(C)C=O>[N:21]([CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N+:22]=[N-:23]
Reactant: Cc1c(-c2ccccc2)oc2c(CCl)cccc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(CN=[N+]=[N-])cccc2c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 22.8 g of Intermediate XIX and 6.8 g of sodium azide in 110 ml of dimethylformamide was stirred for 3 hours at 100° C. After cooling to ambient temperature, 130 ml of water and 88 ml of ethanol were added to the reaction mixture. After 1 hour, the crystals were collected by vacuum filtration, washed with water, and desiccated. Yield: 22 g of the title product. A sample recrystallized from ethanol had a melting point of 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]1[CH2:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[CH2:16]1.[C:23](OC(=O)CCC)(=[O:27])[CH2:24]CC.CN(C1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]1[CH2:20][C:19](=[O:21])[C:18]([C:39](=[N:38][O:27][CH2:23][CH3:24])[CH2:40][CH2:41][CH3:42])=[C:17]([OH:22])[CH2:16]1
Reactant: CN(C)c1ccccn1
Reactant: CCCC(=O)OC(=O)CCC
Reactant: Cc1c(Cl)c(C2CC(=O)CC(=O)C2)c(C)c2c1CC(C)(C)C2
Solvent: Cc1ccccc1
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)c3c(c(C)c2Cl)CC(C)(C)C3)CC1=O
Yield: 36 %

Procedure:
To a solution 8.02 g of the 5-(6-chloro-2,2,4,7-tetramethylindan-5-yl)-cyclohexane-1,3-dione in 100 ml of absolute toluene was added 13.4 ml of butyric anhydride. After refluxing for 4 hours, toluene and excess butyric anhydride were evaporated under reduced pressure to afford a residue. To the solution of the residue in 100 ml of toluene was added 0.61 g of dimethylaminopyridine and refluxed for 20 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 3.51 g of the title compound as yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]3[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1)#[N:2]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: NCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1
Product: N#Cc1ccccc1OCC(O)CNCCc1nc2ccc(C3=NNC(=O)CC3)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][CH2:14][CH:15]([NH2:18])[CH2:16][CH3:17]>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH3:13])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CCC(N)CC
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Product: CCC(CC)Nc1nc(SC)nc(Cl)c1C=O

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 3-pentylamine to give the title compound 4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.92 (t, 6H, J=7.3 Hz), 1.50-1.74 (m, 4H), 2.52 (s, 3H), 4.22 (m, 1H), 9.21 (br s, 1H), 10.33 (s, 1H). LC MS (m/e)=274 (MH+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]([CH3:27])=[CH:23][NH:22][C:21]2=[O:28])[CH2:13][CH2:12]1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1>>[ClH:31].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:22]2[CH:23]=[C:24]([CH3:27])[C:25](=[O:26])[N:20]([CH2:19][CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][C:2]([F:29])([F:1])[F:30])[CH2:16][CH2:15]3)[C:21]2=[O:28])=[CH:34][CH:33]=1
Reactant: Cc1c[nH]c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Reactant: ClCc1ccc(Cl)cc1
Product: Cc1cn(Cc2ccc(Cl)cc2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 3-{3-[4-(2-(2,2,2-trifluoroethoxy)phenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione and 4-chlorobenzyl chloride gave 1-(4-chlorobenzyl)-3-{3-[4-(2-(2,2,2-trifluoroethoxy)phenyl)piperazin-1-yl]-propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 170°-172° C.; Anal.: Calcd. for C27H30ClF3N4O3.HCl: C, 55.20; H, 5.31; N, 9.53%; Found: C, 55.01; H, 5.24; N, 9.56%;
Reaction SMILES: [O:1]1C=CC=[C:2]1[C@@H:6]([N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([CH3:11])[CH2:8][O:9][CH3:10].[OH2:21].C(Cl)(Cl)(Cl)Cl.CC#N>C(#N)C>[C:15]([O:14][C:13]([N:12]([CH3:20])[C@@H:6]([C@H:7]([CH3:11])[CH2:8][O:9][CH3:10])[C:2]([OH:1])=[O:21])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: O
Reactant: COC[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC[C@@H](C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a suspension of NalO4 (0.83 g, 3.87 mmol, 6.0 equiv) in water/CCl4/acetonitrile (3/2/3, 17.9 mL) was added RuCl3 (45.0 mg, 0.22 mmol, 0.34 equiv) at room temperature. After stirring for 15 minutes, a solution of compound 2.1c (0.183 g, 0.65 mmol) in acetonitrile (2.0 mL) was added. After stirring for another 15 minutes, the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.1b (0.17 g).
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[CH:33][CH:34]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 74.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-[(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)amino]benzoic acid (118 mg) as well as ethyl 3-(methylamino)propanoate (39 mg) to give the title compound (104 mg, 75%) as an amorphous compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)=[CH:5][CH:4]=1.C(Cl)Cl.[OH:26]OS([O-])=O.[K+]>CO.O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][C:17]=2[C:16]=34)=[CH:5][CH:4]=1)=[O:26]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-(4-methylsulfanyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (100 mg, 0.32 mmol) was dissolved in 10 mL 1:1 MeOH:CH2Cl2. The solution was cooled to 0° C. and oxone (259 mg, 0.42 mmol) was added dropwise as a solution in 1.5 mL H2O). The bright yellow reaction mixture was stirred at 0° C. for 15 min. Saturated Na2S2O5(aq) (4 mL) was added. The layers were separated and the aqueous layer extracted twice with 25% iPrPH/CHCl3. The combined organic layers were dried (MgSO4), concentrated in vacuo, and the two products (2-(4-methanesulfinyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 2-(4-methanesulfonyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one) separated by radial chromatography eluting with 5% MeOH/CHCl3. Each was then crystallized from CH2Cl2/MeOH. 2-(4-Methanesulfinyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 39 mg (37%), was isolated as a white solid: m.p. 316-317° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.81 (s, 3H), 3.09 (m, 2H), 3.40 (m, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.59 (dd, J=8.1, 0.9 Hz, 1H), 7.71 (dd, J=7.5, 0.9 Hz, 1H), 7.84 (m, 4H), 8.08 (br t, 1H), 11.68 (br s, 1H). MS (electrospray, MH+) 325. Anal. (C18H16N2O2S) C, H, N, S.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[O:3][CH:2]([F:13])[F:1]
Reactant: CO
Reactant: O=C(O)c1ccccc1OC(F)F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1OC(F)F
Yield: 87 %

Procedure:
2.0 g of 2-difluoromethoxy-benzoic acid (10.6 mmol, 1.0 eq) were dissolved in MeOH (15 mL) and a catalytic quantity of sulfuric acid was added; the mixture was heated at reflux overnight. The solvent was then evaporated and the residue was dissolved in DCM and washed with saturated NaHCO3. The organic phase was dried and evaporated to give 1.9 g of title product (yield 87%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[NH2:28]>>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]2[N:19]=[C:15]([CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[NH:28][C:21]=2[CH:22]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: COc1ccc2nc(Cc3nc(N4CCOCC4)cc(=O)[nH]3)[nH]c2c1
Yield: 2.3 %

Procedure:
The product is prepared according to the procedure described in Stage 3 of Example 1, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 166 mg of 1,2-diamino-4-methoxybenzene in place of the 1,2-diamino-4-fluorobenzene. After purification by silica gel column chromatography, elution being carried out with a gradient of pure CH2Cl2 to CH2Cl2/MeOH: 85/15, 8 mg of 2-[(6-methoxy-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one being obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)=O.[NH2:38][CH2:39][C@@H:40]([C:49]1[CH:50]=[CH:51][C:52]([OH:58])=[C:53]([NH:55][CH:56]=[O:57])[CH:54]=1)[O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CO>[Si:42]([O:41][C@H:40]([C:49]1[CH:50]=[CH:51][C:52]([OH:58])=[C:53]([NH:55][CH:56]=[O:57])[CH:54]=1)[CH2:39][NH:38][CH2:1][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[O:12])=[C:5]([CH3:37])[CH:4]=1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (150 mg, 0.30 mmol) and N-{5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-hydroxyphenyl}formamide (112 mg, 0.36 mmol) in a 1:1 mixture of dichloromethane and methanol (3.0 mL total) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (191 mg, 0.9 mmol) was added and the resulting mixture was stirred at room temperature overnight. Acetic acid was added to quench the reaction and the mixture was concentrated under reduced pressure to give biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-(tert-butyldimethylsilanyloxy)-2-(3-formylamino-4-hydroxyphenyl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)-ethyl]piperidin-4-yl ester, which was used without further purification. LCMS (10-70) Rt=4.55; [M+H+] found 794.6.
Reaction SMILES: C(=[O:5])C(C)C.[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15](Cl)=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1.CO>N1C=CC=CC=1.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.C1COCC1>[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15]([OH:5])=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Reactant: CC(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1-L-menthoxyacetyloxy-2-methylpropene is prepared from isobutyraldehyde, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and 1-L-menthoxyacetyloxy-2-methylpropene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl 2-L-menthoxyacetyloxy-L-3-methylbutyrate and methyl 2-L-menthoxyacetyl-D-3-methylbutyrate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-2-hydroxy-3-methylbutyric acid, methanol, and L-menthoxyacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1ccc([N+](=O)[O-])cc1
Yield: 64.6 %

Procedure:
4-Nitroaniline (25.0 g, 181mmol) and ethyl bromoacetate (10.0 ml, 90.5 mmol) were stirred at 80°-90° C. for 20 hours under a nitrogen atmosphere. Ethyl acetate (30 ml) was added to the reaction mixture and the mixture was refluxed under heating for 10 minutes. The obtained solid was collected by filtration and recrystallized from ethanol to give 13.1 g of ethyl (4-nitroanilino)acetate as a yellow solid (64%). This solid (1.00 g, 4.46 mmol) and benzyloxycarbonyl chloride (8 ml) were stirred at 80°-90° C. for 1.5 hours under a nitrogen atmosphere. Toluene (20 ml) was added to the reaction mixture and low boiling matters were distilled away under reduced pressure, which was followed by purification by silica gel column chromatography (n-hexane/ethyl acetate=5/2) to quantitatively give 962 mg of ethyl [4-nitro-N-(benzyloxycarbonyl)anilino]acetate as a yellow oil. Ethanol (100 ml) and water (30 ml) were added to the oil (716 mg, 2.00 mmol) and activated zinc (6.55 g, 100 mmol) and calcium chloride (2.22 g, 20.0 mmol) were added, which was followed by refluxing under heating for 2 hours. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure. Water (100 ml) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to give 576 mg of ethyl [4-amino-N-(benzyloxycarbonyl)anilino]acetate as a yellow oil (88%).