Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[N+:25]([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+].C(OCC)(=O)C>C(OCC)C.Cl>[Cl:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(Cl)c3[N+](=O)[O-])cc2C)cn1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc(Cl)c3N)cc2C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
6-Chloro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5-nitropyrimidin-4-amine hydrochloride (2.04 g) was suspended in diethyl ether (9.45 mL) and a solution of tin(IV) chloride dihydrate (9.1 g) in conc. hydrochloric acid (20.17 mL) was added under ice-cooling. After stirring at room temperature for 3 hrs, the reaction mixture was poured into ice water (400 mL). A 50% aqueous sodium hydroxide solution (18 mL) was added dropwise to adjust pH to 8. Ethyl acetate (300 mL) was added and the mixture was filtered through celite. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.30 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[C:11]=1[CH3:19].N([O-])=O.[Na+].Cl>O.CN(C)C=O>[CH3:19][C:11]1[C:10]([Cl:9])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[C:17](=[O:18])[NH:7][N:6]=[N:5]1
Reactant: Cc1c(Cl)cccc1N=C=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1-n1nn[nH]c1=O
Temperature: 0 °C
Yield: 54.1 %

Procedure:
Under ice-cooling, to N,N-dimethylformamide 250 mL was added anhydrous aluminum chloride 21.9 g and the resulting mixtures were stirred for fifteen minutes. Thereto was added sodium azide 10.7 g and the resulting mixtures were stirred for fifteen minutes and thereto was then added 1-chloro-3-isocyanato-2-methylbenzene 25.0 g and the resulting mixtures were heated at 80° C. for five hours. After cooling the mixtures, to a mixture of sodium nitrite g, water 2 L and ice 500 g was added the reaction solutions with stirring. The mixtures were acidified with 10% hydrochloric acid and were extracted with ethyl acetate. The organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-chlorophenyl)-1,4-dihydrotetrazole-5-one 17.0 g.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[SH:32]>>[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32][CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[CH2:8][OH:10]
Reactant: Sc1ccc2ccccc2n1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)oc1CSc1ccc2ccccc2n1

Procedure:
The title compound was prepared using methyl 2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 44) and 2-quinolinethiol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[C:11]3[CH2:12][CH2:13][C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[Na].[CH2:22](Br)[CH3:23]>C(O)C>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[C:11]3[CH2:12][CH2:13][C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: Oc1cccc(-c2cc3n(n2)-c2ccccc2CC3)c1
Reactant: CCBr
Agent: [Na]
Solvent: CCO
Product: CCOc1cccc(-c2cc3n(n2)-c2ccccc2CC3)c1
Reaction time: 8 h

Procedure:
2.62 Grams (0.010 mole) of the compound of Example 10 is added to a solution of 0.23 g. (0.010 mole) of sodium in 40 ml. of absolute ethanol at room temperature, then 2.2 g. (0.020 mole) of ethyl bromide is added dropwise. The resulting solution is refluxed for seven hours and allowed to stand overnight at room temperature. After dilution with 30 ml. of water and subsequent evaporation of the ethanol, a residue is obtained which is crystallized from methanol. Yield 2.29 g. of the title compound, m.p. 99°-100° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:15])[C:10](=[O:14])[C:11]([CH3:13])([CH3:12])[C:6]2=[CH:5][CH:4]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](O)=[O:21]>>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([NH:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:15])[C:10](=[O:14])[C:11]([CH3:12])([CH3:13])[C:6]2=[CH:5][CH:4]=1)=[O:21]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)nc21
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc3c(n2)N(C)C(=O)C3(C)C)ccn1

Procedure:
Prepared in analogy to example 26 using 6-amino-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (example 76c) and 2-methylisonicotinic acid. The title compound was obtained as light brown viscous oil.
Reaction SMILES: IC1C(C(N)=O)=C(I)C=C(I)[C:3]=1[C:4](N)=[O:5].C([O:19][CH2:20][C:21]([NH:23][C:24]1[C:25]([I:54])=[C:26]([C:43]([NH:45][CH2:46][CH:47]([CH2:49][CH:50]([OH:53])[CH2:51][OH:52])[OH:48])=[O:44])[C:27]([I:42])=[C:28]([C:40]=1[I:41])[C:29]([NH:31][CH2:32][CH:33]([CH2:35][CH:36]([OH:39])[CH2:37][OH:38])[OH:34])=[O:30])=[O:22])(=O)C.C([O-])([O-])=O.[K+].[K+].C(OCCBr)(=O)C>CC(N(C)C)=O>[OH:39][CH:36]([CH2:37][OH:38])[CH2:35][CH:33]([OH:34])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[C:40]([I:41])=[C:24]([N:23]([CH2:3][CH2:4][OH:5])[C:21](=[O:22])[CH2:20][OH:19])[C:25]([I:54])=[C:26]([C:43]([NH:45][CH2:46][CH:47]([CH2:49][CH:50]([OH:53])[CH2:51][OH:52])[OH:48])=[O:44])[C:27]=1[I:42]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Reactant: NC(=O)c1c(I)cc(I)c(C(N)=O)c1I
Agent: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(NCC(O)CC(O)CO)c1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(N(CCO)C(=O)CO)c1I
Temperature: 25 °C

Procedure:
5[N-(2-Acetoxyethyl)acetoxyacetamido]-N,N'-bis(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide. 5-Acetoxyacetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide, prepared as in Example 3, Step B, (89 g, 0.1 g-mole) is mixed with K2CO3 (27.6 g, 0.2-g mole) and 2-bromoethyl acetate (33.4 g, 0.2 g-mole) in DMAc (200 ml). The mixture is stirred at 35°-40° C. until the reaction is complete (approximately 8-12 hours). The solution is then cooled to room temperature and the inorganic salts are filtered. The filtrate is then evaporated under vacuum at 70° C. to yield a thick oil. The oil is triturated with isopropyl alcohol to dissolve the residual DMAC and bromoethyl acetate. The supernatant is decanted and the residual solid is evaporated to dryness to provide the desired product.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][S:28]([CH3:30])=[O:29])/[C:9]1=[O:31])=O)(C)(C)C.[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:48])=[C:37]([CH:39]=[N:40][C:41]([O:43][Si](C)(C)C)=[CH2:42])[CH:38]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:31])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][S:28]([CH3:30])=[O:29])[CH2:42][C:41](=[O:43])[NH:40][CH:39]3[C:37]3[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=3[CH3:48])[C:11]2=[CH:12][CH:13]=1
Reactant: CS(=O)COc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCS(C)=O)C12C(=O)Nc1cc(Cl)ccc12
Yield: 9.7 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-(5-chloro-2-methanesulfinylmethoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (400 mg, 0.83 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (5 mmol) in toluene to give the title compound as a white solid (45 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[N:11]3[C:12](=[N:17][C:18]([CH3:19])=[C:10]3[C:9]1=[O:20])[CH:13]=[CH:14][CH:15]=2.C(N(CC)CC)C.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:19][C:18]1[N:17]=[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[N:11]2[C:10]=1[C:9](=[O:20])[N:8]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:31]([CH2:30][C:29]([F:36])([F:35])[F:28])(=[O:33])=[O:32]
Reactant: Cc1nc2cccc3n(CCCCCCN)c(=O)c1n23
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCCCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 77.3 %

Procedure:
To a solution of 676 mg (2.48 mmol) of 1-[6-(amino)hexyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.52 ml (3.73 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.55 g (3.01 mmol) of 2,2,2-trifluoroethanesulfonylchloride, and the mixture was stirred for 30 minutes at the same temperature range. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 802 mg of the desired compound (77.2%, pale brown solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18](F)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[C:28]([CH3:46])=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][N:33]=[C:32]2[NH:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC(O)=O>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([NH:26][C:27]3[C:28]([CH3:46])=[CH:29][CH:30]=[C:31]4[C:36]=3[N:35]=[CH:34][N:33]=[C:32]4[NH:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1N
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4F)ncnc32)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Cn2cnc3c(-c4cccnc4Nc4c(C)ccc5c(Nc6ccc(C#N)cc6)ncnc45)ncnc32)cc1
Temperature: 140 °C

Procedure:
A mixture of 9-(4-methoxybenzyl)-6-(2-fluoropyridin-3-yl)-9H-purine (146 mg, 436 μmol) and 4-(8-amino-7-methylquinazolin-4-ylamino)benzonitrile (120 mg, 436 μmol) in THF (4 mL) was sonicated until all solids became a fine powder. Lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 1.53 mL, 1.53 mmol) was added dropwise with stirring (all solids dissolved and then some solid appeared again). The mixture was stirred at rt for 10 min and then heated in a microwave at 140° C. for 30 min. The mixture was poured into AcOH (0.5 mL) in MeOH (20 mL) and the mixture was stirred for 10 min. Solvent was removed and the product was purified by flash chromatography eluting with MeOH/DCM (2-5%) to give 4-(8-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-ylamino)-7-methylquinazolin-4-ylamino)benzonitrile. MS (ESI, pos. ion) m/z: 591.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18].CCN=C=NCCCN(C)C.Cl.[C:36]([O:40][C:41](=[O:55])[CH2:42][CH2:43][S:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](O)=[O:50])([CH3:39])([CH3:38])[CH3:37]>ClCCl.CN(C)C1C=CN=CC=1>[C:36]([O:40][C:41](=[O:55])[CH2:42][CH2:43][S:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:50])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinate (800 mg, 2.57 mmol, 1.00 equiv) in dichloromethane (2 mL), EDC.HCl (608 mg, 3.09 mmol, 1.20 equiv), 4-dimethylaminopyridine (380 mg, 3.11 mmol, 1.20 equiv), and 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (837 mg, 2.83 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at room temperature. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1-5:1). This resulted in 600 mg (40%) of methyl 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinate as yellow oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([OH:16])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].[C:18]1([CH3:36])[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=[C:26]([C:32]([F:35])([F:34])[F:33])[N:25]=2)[CH:19]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:17])[C:14]([NH:31][CH2:30][C:29]2[C:24]([C:20]3[CH:19]=[C:18]([CH3:36])[CH:23]=[CH:22][CH:21]=3)=[N:25][C:26]([C:32]([F:35])([F:33])[F:34])=[CH:27][CH:28]=2)=[O:16])=[CH:11][CH:12]=1)(=[O:3])=[O:4]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(C)(=O)=O)cc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2-(4-(methylsulfonamidomethyl)phenyl)propanoic acid (60 mg, 0.233 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (62 mg, 0.233 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (67 mg, 0.349 mmol), 1-hydroxybenzotriazole (47 mg, 0.349 mmol) and triethylamine (0.08 mL, 0.582 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography to obtain 2-(4-(methylsulfonamidomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 4) (81 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(-c2ccc(C(=O)O)s2)cccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1c(N)cccc1-c1ccc(C(=O)O)s1
Yield: 90.1 %

Procedure:
5-(2-methoxy-3-nitro-phenyl)thiophene-2-carboxylic acid 12a (7.7 g, 27.6 mmol) was dissolved in 300 mL of ethyl acetate followed by addition of 500 mg of palladium on carbon and ammonium formate (6.96 g, 110 mmol). The reaction mixture was heated to reflux for 4 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-(3-amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 12b (6.2 g, yield 90.1%) as a grey solid.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1([CH3:22])[C:19](=[O:20])[N:10]2[CH2:11][CH:12]=[CH:13][CH:14]([C:15]([O:17]C)=[O:16])[N:9]2[C:8]1=[O:21])(=O)C.Cl>>[SH:4][CH2:5][CH2:6][C:7]1([CH3:22])[C:19](=[O:20])[N:10]2[CH2:11][CH:12]=[CH:13][CH:14]([C:15]([OH:17])=[O:16])[N:9]2[C:8]1=[O:21]
Reactant: COC(=O)C1C=CCN2C(=O)C(C)(CCSC(C)=O)C(=O)N12
Agent: Cl
Product: CC1(CCS)C(=O)N2CC=CC(C(=O)O)N2C1=O
Yield: 38.4 %

Procedure:
1.1 g of methyl 2-(2-acetylthioethyl)-2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) were heated under reflux for 3 hours with 25 ml of 2 M hydrochloric acid. After evaporation, the residue was taken up in dichloromethane, the solution was dried over magnesium sulfate and then evaporated. There was obtained 0.35 g (38%) of 2,3,5,8-tetrahydro-2-(2-mercaptoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (diastereomer A) in the form of a white solid having a melting point of 113°-114° C. (from diethyl ether/petroleum ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:18][C@H:17]([CH2:19][O:20]C(=O)C)[C@@H:15]([OH:16])[C@H:13]1[OH:14])[C:6]([Br:24])=[C:5]2[CH:25]=[O:26].C[O-].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14])[C:6]([Br:24])=[C:5]2[CH:25]=[O:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)c(C=O)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=Cc1c(Br)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
5,6-Dichloro-2-bromo-3-formyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.136, 101 mg, 0.22 mmol) was dissolved in dry MeOH (10 mL) to which was added sodium methoxide (25 mg, 0.46 mmol). The solution was stirred at room temperature for 15 min, until the starting material was consumed (TLC). Water (30 mL) was added and the solution evaporated until the MeOH was completely removed. The residual aqueous suspension was extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine (20 mL), dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from MeOH and H2O to yield 43 mg (47%) of 4.137 as a pale tan powder: mp 210-211° C.; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 6.06 (d, 1H), 5.49-5.43 (m, 2H, D2O exch.), 5.31 (d, 1H, D2O exch.), 4.44 (q, 1H), 4.18 (m, 1H), 4.04 (d, 1H), 3.77-3.71 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 185.53, 134.05, 128.85, 126.58, 126.47, 125.31, 120.56, 116.00, 114.68, 90.27, 86.55, 71.69, 69.62, 60.98. HRMS (EI) m/z calcd. for C14H12BrCl2NO5 422.9276, found 422.9271. Anal calcd for C14H12BrCl2NO5: C, 39.56; H, 2.85; N, 3.30. Found: C, 39.77; H, 3.03; N, 3.32.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(O)C>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Yield: 100.6 %

Procedure:
To a suspension of ethyl 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carboxylate (Preparation 62) (250 g, 0.530 moles) in absolute ethanol (1250 ml) under an atmosphere of nitrogen was added trifluoroacetic acid (73.5 g, 0.645 moles) and the resultant mixture was heated at 50° C. for 20 hours. The mixture was cooled and the solid was collected by filtration. The filter cake was washed with absolute ethanol (350 ml) and was then dried in vacuo at 50° C. to give the title compound (206.5 g) as a cream coloured fine powder, m.p. >200° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([NH2:16])[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([NH:16][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: CC(N)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ccc(C#N)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 610 mg (1.8 mmol) 1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethylamine, 1.18 g (2.8 mmol) 2-bromo-5-cyano-pyridine and 0.838 g (2.8 mmol) DIPEA in 3.5 mL DMF was heated to 60° C. for 3 days. The mixture was evaporated, Na2CO3aq. was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried with Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from DCM, methanol and NH3aq. to yield after evaporation of the product containing fractions 0.526 g (66%) of the title compound as off-white foam. MS (m/e): 431.4 [(M+H)+].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH:8]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](OC)=[O:20].[OH-].[K+]>O1CCCC1>[CH2:19]([OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([OH:7])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCC(O)CCCCCCCCCCCO
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A 5-liter flask equipped with a stirrer, dropping funnel and reflux tube was charged with 28.5 g (0.75 mol) of LiAlH4 and 2 liters of tetrahydrofuran, to which a solution of 237.0 g (0.75 mol) of methyl 12-hydroxyoctadecanate in 1 liter of tetrahydrofuran was added dropwise over 5 hours with stirring. After completion of the dropping, the stirring was continued further for 1 hour at 65° C. After the reaction mixture was then cooled, 90 ml of a 5% aqueous solution of KOH were added with stirring. A salt precipitated was separated by filtration, and the resultant solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel, thereby obtaining 185.7 g (yield: 86.6%) of 1,12-octadecanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH3:25].Cl>ClCCCl>[Cl:23][C:22]1[C:17]([Cl:16])=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][C:21]=1[C:5]([C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)=[O:6]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(Cl)c(Cl)c2)c(Cl)c1Cl
Temperature: 60 °C

Procedure:
To a solution of 57.6 g of 3,4-dichlorobenzoylchloride in 1,2-dichloroethane (150 ml) is added 36.7 g of AlCl3 in portions over a 30 minute period. To the resultant mixture is added dropwise 44.26 g of 2,3-dichloroanisole in 1,2-dichloroethane (150 ml). There is an evolution of gas and the reaction mixture is heated to 60° C. for one hour. The mixture is then poured over 150 ml of concentrated HCl and 150 ml of ice and then extracted with CHCl3 and then ethanol. The resultant organic layer is washed with 10% aqueous K2CO3, then water, dried over (Na2SO4) and evaporated to yield 2,3-dichloro-4-methoxy-3',4'-dichlorobenzophenone, mp 113°-140° C.