Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.CN([C:22]([O:26][N:27]1N=NC2C=CC=N[C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNOC.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][C:16]([N:27]([O:26][CH3:22])[CH3:28])=[O:18])=[CH:13][CH:14]=2)=[N:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Nc2ncc(Br)cn2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Cc1ccc(Nc2ncc(Br)cn2)cc1
Reaction time: 0.17 h

Procedure:
2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)acetic acid 22 (5.0 mmol) and HATU (6.0 mmol) are dissolved in dry DMF (10 mL) and stirred for 10 min. Then N,O-dimethylhydroxylamine (7.5 mmol) and diisopropylethylamine (15.0 mmol) are added to the solution. The reaction mixture is stirred for 1 h at rt. After the reaction is complete, the reaction mixture is added dropwise into water (100 mL). The precipitate is filtered and dried to yield 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)-N-methoxy-N-methylacetamide 23. 1H NMR (400 MHz, d6-DMSO) δ 9.82 (s, 1H), 8.58 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 3.67 (s, 3H), 3.34 (s, 2H), 3.10 (s, 3H). MS (m/z) (M+1)+: 351.0, 353.0.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH:22]([CH3:24])[CH3:23])[CH2:32][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: CC(C)c1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3C(C)C)CC2)c(OC)nc1C
Yield: 65 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:40][CH:41]([CH3:43])[CH3:42])=[CH:30][C:31]=3[O:33][CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[N:26]=[CH:25][N:24]=2)=[C:20]2[O:44][CH2:45][O:46][C:19]2=[CH:18][CH:17]=1.C=O.C(O)(=O)C>CO.C(Cl)Cl>[Cl:15][C:16]1[C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:40][CH:41]([CH3:42])[CH3:43])=[CH:30][C:31]=3[O:33][CH:34]3[CH2:35][CH2:36][N:37]([CH3:1])[CH2:38][CH2:39]3)[N:26]=[CH:25][N:24]=2)=[C:20]2[O:44][CH2:45][O:46][C:19]2=[CH:18][CH:17]=1
Reactant: CC(C)Oc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)Oc1cc(OC2CCN(C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Yield: 85.4 %

Procedure:
Sodium triacetoxyborohydride (0.087 g) was added portionwise to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-isopropoxy-5-piperidin-4-yloxyquinazoline (0.125 g), aqueous formaldehyde (13N, 0.042 ml), acetic acid (0.019 ml), methylene chloride (5 ml) and methanol (2 ml) and the resultant mixture was heated to reflux for 3 minutes. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to give the title compound (0.11 g); NMR Spectrum: (CDCl3) 1.42 (d, 6H), 1.95–2.1 (m, 2H), 2.15–2.25 (m, 2H), 2.3 (s, 3H), 2.3–2.4 (m, 2H), 2.7–2.8 (m, 2H), 4.6 (m, 1H), 4.72 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.75 (d, 1H), 6.82 (d, 1H), 6.99 (d, 1H), 8.52 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H+ 471 and 473.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>O>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of formic acid (2.5 mL, 88% in water) is cooled to 0° C., treated with acetic anhydride (0.82 mL, 9.0 mmol) then warmed to RT over 30 minutes. The solution is then cooled to 0° C. and 4-bromoaniline (500 mg, 3.0 mmol) added dropwise over 5 minutes. After stirring a further 16 h at RT, the reaction mixture is diluted with water (20 mL) and extracted into DCM (3×20 mL). The combined DCM phases are washed with 1 M HCl (20 mL) and aqueous NaHCO3 (20 mL), dried over Na2SO4 and reduced in vacuo. Purification by column chromatography (20% EtOAc in heptane) affords the title compound.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][CH:12]=[C:11]([C:15](Cl)=[O:16])[CH:10]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH3:18])[CH:10]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)c2cccc(C)c2)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
In sequence, 1,000 mL of carbon disulfide, 384 g (3.55 mole; 10% excess) of anisole, and 500 g (3.23 mole) of m-toluoyl chloride were placed in a 5 L flask, and the contents were cooled to about 10° C. Then 500 g AlCl3 was added in small increments with stirring over a 3 hr period. The stirred mixture was kept at room temperature for 2 days during which 500 mL more of carbon disulfide was added by maintain fluidity. After adding ice-water to decompose the complex, carbon disulfide was removed by steam distillation and the product was extracted with methylene chloride. The extract was washed with water and then distilled at 170° C./1.2 mm Hg to yield 642 g of 4-methoxy-3'-methylbenzophenone. Half of the product (1.42 mole) was mixed with 1500 mL of pyridine and a solution of 75 g sodium hydroxide in 1500 mL of water. This mixture was heated to 80°-90° C. and 500 g potassium permanganate was added stepwise over a 4 hr period. Refluxing continued one more hour. Sludge was filtered out and washed well with hot water. Acidification of the filtrate yielded a precipitate of 4-methoxy-3'-carboxybenzophenone. After recrystallization from ethanol, melting temperature was 183°-186° C. A total of 392 g (1.53 mole) of so prepared 4-methoxy-3'-carboxybenzophenone was added to a premixture of 1150 mL of 48% HBr/575 mL acetic anhydride/575 mL acetic acid, and the mixture was refluxed for 15 hr. Pouring the contents into water precipitated 4-hydroxy-3'-carboxybenzophenone which, after filtration and drying, yielded 350 g (1.45 mole) of crude product. Mixing this product with 1050 mL of acetic anhydride containing 1.5 mL of concentrated sulfuric acid and heating for 30 min at 100° C. yielded 4-acetoxy-3'-carboxybenzophenone which was isolated by precipitation in excess ice-water, filtration, and drying. Recrystallization first from dioxane and then chloroform provided 4-acetoxy-3'-carboxybenzophenone melting at 190°-193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc2cc(C)ccc2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2cc(CBr)ccc2o1
Temperature: 25 °C

Procedure:
A mixture of the ester 25 (2.26 g, 11.1 mmol), JV-bromosuccinimide (2.37 g, 13.3 mmol) and VAZO (271 mg, 1.11 mmol) was refluxed overnight in CCl4 (50 mL) under nitrogen. The reaction mixture was cooled to the room temperature, diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography (eluent 5% EtOAc in hexane) to give ethyl 5-bromomethyl-benzofuran-2-carboxylate. This compound was dissolved in dioxane (20 ml) and a solution of NaHCO3 (1.76 g, 20.9 mmol) in water (20 ml) was added. The reaction was stirred at 80° C. during 16 h. The solvent was evaporated and the product was dissolved in EtOAc and washed with brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography (eluent 20-40% EtOAc in hexane to give the title compound 26 (2.55 g, 61%) as a white solid. 1H-NMR (DMSO) δ: 7.74 (d, J=1.0 Hz, 1H), 7.71-7.70 (m, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.44 (dd, J=8.6, 1.8 Hz, 1H), 5.31 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H); 1.34 (t, J=7.0, 3H).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.[S:15](F)(F)(=[O:17])=[O:16].[OH-].[K+:21]>C(#N)C>[CH3:5][C:3]1[O:4][S:15](=[O:17])(=[O:16])[N:7]=[C:1]([O-:6])[CH:2]=1.[K+:21]
Reactant: CC(=O)CC(N)=O
Reactant: O=S(=O)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1=CC([O-])=NS(=O)(=O)O1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
10.1 g (0.1 mol) of acetoacetamide, 50.5 g (0.5 mol) of triethylamine and 100 ml of acetonitrile were introduced into a round-bottomed flask fitted with a stirrer and a solid carbon dioxide condenser, as in Example 1. 15.3 g (0.15 mol) of sulfuryl fluoride gas were passed in over a period of 20 minutes. The reaction mixture was then allowed to warm up to room temperature, with stirring. After stirring for 2 hours, 230 ml (0.46 mol) of 2N methanolic KOH were added dropwise and the product was filtered off with suction. 9.7 g (48% of theory) of Acesulfam K were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([N:28]2[CH2:35][CH2:34][CH2:33][C@H:29]2[C:30]([OH:32])=[O:31])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCC(=O)N2CCC[C@H]2C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.1 %

Procedure:
To a solution of p-nitropenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and L-proline (57 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added N-ethylmorpholine (128 μl, 1.0 mmol). The mixture was stirred at room temperature for 2 days. Thereafter, the reaction mixture was further treated in the same manner as Example 1 to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-proline (81 mg), melting at 131° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCC(Cc2ccccc2)CC1)CCC3

Procedure:
2a-(4-Bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (190 mg, 0.62 mmol), 4-benzyl-piperidine (110 mg, 0.65 mmol) and potassium carbonate (120 mg, 0.88 mmol) were stirred overnight at 60° C. in anhydrous N,N-dimethylformamide (2 ml). The solvent was removed by evaporation under a reduced pressure, and the residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and then the thus obtained material was separated and purified by a silica gel column chromatography to obtain 210 mg (1.1 mmol, 85% in yield) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[P:6]([O:10][CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])([OH:9])([OH:8])=[O:7].[CH2:17]([N:33]=[C:34]=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CNC(=O)C>[CH2:17]([NH:33][C:34](=[O:35])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[P:6]([O:10][CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])([OH:8])([OH:9])=[O:7]
Reactant: CCCCCCCCCCCCCCCCN=C=O
Reactant: CNCCO
Agent: C[N+](C)(C)CCOP(=O)(O)O
Solvent: CNC(C)=O
Product: CCCCCCCCCCCCCCCCNC(=O)N(C)CCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.5 g of 2-methylamino-ethanol-phosphocholine is dissolved in 10 ml of N-methylacetamide; the solution is mixed with 1.08 g of hexadecyl-isocyanate and stirred for 24 hours at room temperature. The solution is reduced in vacuo and the residue purified by column chromatography (silica gel//chloroform/methanol/water).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>ClCCl>[Br:23][C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[N:17]2
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C(F)(F)F)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 98.5 %

Procedure:
A solution of 8-(tert-butyldimethylsilanyloxy)-2-trifluoromethylquinoline (17.5 g) in dichloromethane (100 ml) was treated with N-bromosuccinimide (10.5 g) at 15° C. The mixture was stirred at 20° C. for 25 minutes, washed with 1% sodium sulfite solution (100 ml), and water (50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the product (21.4 g) as a dark oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:18][CH:10]1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:55])C=1>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[O:18][CH:10]1[S:11](=[O:55])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC[C@H]2OC(Sc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccccc1)C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Yield: 97.9 %

Procedure:
To a stirred cooled (-78° C.) solution of 3 (130 g, 0.2 mol) in dichloromethane (400 mL) is added dropwise over a period of 20 min a solution of mCPBA (74%, 58.31 g, 0.25 mol) in dichloromethane (300 mL). The mixture is stirred and allowed to warm up to -30° C. The mixture is then filtered. The filtrate is washed with saturated aqueous sodium bisulfite (2×300 mL), sodium bicarbonate (2×400 mL), brine (400 mL) and water (2×400 mL). The organic layer is dried (Na2SO4) and concentrated. Flash chromatography (CH2Cl2 :EtOAC=9:1) of the residue furnishes sulfoxide mixture 4 (127 g, 95%) as a white solid (mp 120°-122° C.). TLC Rf =0.3 (solvent--EtOH:CH2Cl2 =1:9). IR (KBr): 3060, 3030, 2910, 2867, 1495, 1450, 1360, 1210, 1136, 1092, 1049 cm-1. 1H NMR (CDCl3): 7.72-7.14 (m, 25H), 5.12-4.42 (m, 9H), 4.40-3.30 (m, 6H). Anal. Calc. for C40H40O6S: C, 74.04; H, 6.22; S, 4.93. Found: C, 74.10; H, 6.26; S, 4.99.
Reaction SMILES: CC(Cl)(C)CCCCCCC.[CH3:12][C:13]([CH3:21])=[CH:14][CH2:15][CH2:16][C:17]([CH:19]=[CH2:20])=[CH2:18].Cl.C([O-])(=[O:25])C.[Na+].C([O-])(=O)C.[OH-].[Na+]>>[OH:25][CH2:20]/[CH:19]=[C:17](/[CH3:18])\[CH2:16][CH2:15][CH:14]=[C:13]([CH3:21])[CH3:12]
Reactant: C=CC(=C)CCC=C(C)C
Reactant: CC(=O)[O-]
Agent: CCCCCCCC(C)(C)Cl
Agent: Cl
Agent: [Na+]
Product: CC(C)=CCC/C(C)=C\CO

Procedure:
The dimethyloctyl chloride is then obtained by reacting the myrcene hydrochloride (neryl/geranyl chloride) with sodium acetate and saponifying the acetate with sodium hydroxide to produce nerol/geranil. This is then hydrogenated to produce dimethyloctanol, which is treated with HCl in the presence of zinc chloride to produce the dimethyloctyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2cccc(C)c2)ccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2cccc(CBr)c2)ccc1Cl
Yield: 95.1 %

Procedure:
Methyl 4-chloro-3′-methylbiphenyl-3-carboxylate (1.77 g, 6.5 mmol) and NBS (1.27 g, 7.19 mmol) were dissolved in CCl4 (20 mL), a catalytic amount of AIBN was added and the mixture was heated at reflux overnight. The reaction mixture was filtered, the solvent was removed in vacuo and the residue was purified using automated medium pressure silica gel chromatography (ISCO) eluting with 20% ethyl acetate/hexane to obtain methyl 3′-(bromo-methyl)-4-chlorobiphenyl-3-carboxylate (2.10 g, 91%) as a pale brown solid. 1H NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.68-7.45 (m, 6H), 4.58 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([F:30])[F:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([F:29])[F:30])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CC1(C)OB(c2cc(C(F)F)ccc2OCC2CC2)OC1(C)C
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (example B.c16) the title compound is obtained as off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:28](O)=[O:29])=[O:25])=[CH:18]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28](=[O:29])[CH:27]([NH:26][C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:14])=[CH:23][CH:22]=3)=[O:25])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
1-Piperazinecarboxylic acid t-butyl ester (1.2 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.6 mmol) were coupled according to procedure A (0-25° C. reaction temperature, reaction time 4 days, extraction with acid first, then base), and the crude product purified by column chromatography on silica gel eluted with 30% ethyl acetate in hexanes to give a colorless foam: Yield 290 mg, 95%; HPLC (70/30) 6.23 min (99%); PBMS 512/514 (MH+, 100%);
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([O:15]CC)=[O:14])=[CH:4]2.[OH-].[Na+].Cl>C(O)C.O>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=[O:14])=[CH:4]2
Reactant: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 193.69 g of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate in 1 liter of ethanol was added a solution of 62.9 g (1.57 mol.) of sodium hydroxide in 50 mL of water. The mixture was stirred for 0.5 hour at room temperature. To the reaction mixture was added about 130 mL of conc. hydrochloric acid while stirring until the pH became about 4-5. The resulting precipitate was collected by filtration. which was washed with ethanol, acetone and diethyl ether successively to give 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: CC(C)CCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCC(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].O[CH:15](S([O-])(=O)=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+]>C(O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1NCCCO
Reactant: O=S(=O)([O-])C(O)Cc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: OCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21

Procedure:
A mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 44.8 parts of sodium α-hydroxybenzeneethanesulfonate and 120 parts of ethanol is stirred and refluxed for 30 minutes. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichlormethane. The extract is dried, filtered and evaporated, yielding 5-chloro-2-(phenylmethyl)-1H-benzimidazole-1-propanol as a residue.