Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:51][C:50]=2[CH:59]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:47]=[CH:48][C:49]5[O:53][C:52]([CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:51][C:50]=5[CH:59]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOCc1cc2cc(OB([O-])[O-])ccc2o1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOCc1cc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.41 g) was added toluene/ethanol/water (10/1/1,19.2 ml) and then were added 2-(propoxymethyl)-1-benzofuran-5-yl borate (0.22 g) and potassium carbonate (0.24 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (45 mg), and the mixture was refluxed for 14 hours, cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[2-(propoxymethyl)-1-benzofuran-5-yl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 136) (184 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-])=O)=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Nc2ccc(F)cc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(Nc2ccc(F)cc2)c(N)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 27c (1.4 g, 4.8 mmol) and SnCl2.2H2O (4.9 g, 21.7 mmol) in EtOH (50 mL) was stirred at 80° C. After 4 h, the mixture was cooled to room temperature and was slowly added to saturated aqueous NaHCO3. The solid was filtered and washed with H2O. The solid was triturated with EtOAc and the filtrate was concentrated. The crude product 27d was used in the next reaction without purification. MS m/z (M+H+) 261.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Reaction time: 0.75 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl 1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate (3.27 g, 8.09 mmol) in CH2Cl2 (75 mL) was added TFA (50 mL). The reaction was complete after 45 minutes After evaporating the solvents in vacuo, the crude material was diluted with CH2Cl2 and neutralized by adding a 1 N aqueous NaOH solution. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol as a solid (2.09 g, 84%). LC/MS: m/z 321.3 (M+H)+ at 1.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[CH:3]([OH:17])[CH2:4][NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[CH2:8][CH2:7]1.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([F:25])[CH:22]=1)[CH2:18][C@H:2]([NH:1][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C@H:3]([OH:17])[CH2:4][NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCC(=O)O1
Reactant: CCc1cccc(C2(NCC(O)C(N)Cc3cc(F)cc(F)c3)CC2)c1
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCC(=O)O)CC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-Amino-4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-butan-2-ol (0.500 g, 1.387 mmol) in chloroform (7 ml) was added TEA (0.58 ml, 4.161 mmol) with stirring under nitrogen for 30 min. To this solution was added succinic anhydride (0.138 g, 1.387 mmol) and reaction was stirred overnight at 50° C. The next morning reaction mixture was concentrated in vacuo, yielding the product. (ES+: 461.2)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:19][CH:20]=1)[CH:7]=[CH:8][CH:9]=O)[CH3:2].[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1.C(O)(=O)C>O1CCCC1.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][CH2:9][CH:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:19][CH:20]=1)[CH3:2]
Reactant: CCOc1cc(C=CC=O)ccc1OCc1coc(-c2ccccc2)n1
Reactant: O=C1COC(=O)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CCOc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1coc(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
A mixture of 3-ethoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (3.0 g), 2,4-oxazolidinedione (1.7 g), piperidine (0.73 g) and acetic acid (50 ml) was stirred for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure, and resulting crystalline precipitate was collected by filtration. The filtrate was dissolved in ethyl acetate. The solution was successively washed with a saturated aqueous solution of sodium hydrogencarbonate, water, 1N HCl and water, followed by drying (MgSO4). The ethyl acetate layer was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (50:1), further crystals were collected, which were combined with the crystalline product obtained above and dissolved in tetrahydrofuran (THF) (100 ml). To the solution was added palladium-carbon (5%, 1.0 g), which was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (50:1), 5-[3-[3-ethoxy-4-(2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione was obtained, which was recrystallized from chloroform-ether to give colorless prisms, m.p.119-120° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[O:16][CH3:17].[CH3:19][C:20]([CH3:23])([O-:22])C.[Na+]>O1CCCC1.CCOCC.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]>[O:16]1[C:20]2([CH2:19][CH2:11][N:10]([C:2]3[CH:3]=[CH:4][C:5]([F:18])=[C:6]4[C:11]=3[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]4[O:16][CH3:17])[CH2:9][CH2:23]2)[O:22][CH2:6][CH2:7]1
Reactant: COc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Reactant: CC(C)(C)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)nc2c(N3CCC4(CC3)OCCO4)ccc(F)c12
Temperature: 70 °C
Reaction time: 18 h
Yield: 126.8 %

Procedure:
To a solution of 8-chloro-5-fluoro-4-methoxy-2-(trifluoromethyl)quinoline (Step 2, 1.24 g, 4.45 mmol, 1 eq.) in anhydrous tetrahydrofuran (44 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3, 0.125 g, 0.14 mmol, 0.03 eq.), sodium tert-butoxide (0.69 g, 7.18 mmol, 1.61 eq.), 2-dicyclohexyl-phosphino-2′-(N,N-dimethylamino)biphenyl (CYMAP, 0.054 g, 0.14 mmol, 0.03 eq.), and 1,4-dioxo-8-azaspiro-4,5-decane (0.8 mL, 6.24 mmol, 1.4 eq.). The resulting mixture was stirred at 70° C. overnight (approximately 18 hours) under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with ether, filtered through a plug of silica gel and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 1.09 g (64% yield) of the desired product as a beige solid; MP=101-103° C.; MS (ES) m/z (relative intensity): 387 (M+H)+ (100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:15][CH2:16][CH2:17][CH2:18]3)[N:11]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: BrC1CCCC1
Reactant: CCc1cc(C#N)ccc1N=C1NC2(CCCC2)CS1
Product: CCc1cc(C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.I[CH2:8][CH2:9][OH:10].C(N(CC)CC)C>C(O)C>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:8][CH2:9][OH:10])=[N:2]1
Reactant: Sc1nc[nH]n1
Reactant: OCCI
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCCSc1nc[nH]n1
Yield: 34.7 %

Procedure:
A solution of 1H-1,2,4-triazole-3-thiol (14.7 g, 145 mmol), 2-iodoethanol (25.0 g, 145 mmol) and triethylamine (14.7 g, 145 mmol) in ethanol (400 mL) was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was acidified with water and 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (10%-100% ethyl acetate/hexane) to give the title compound as a colorless oil (7.30 g, 35%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13]>C(O)(C)C.N1CCCCC1>[C:12]([C:11]([C:10]#[N:14])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)#[N:13]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: N#CC(C#N)=Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
3.7 g of p-hydroxybenzaldehyde and 2.3 g of malononitrile were dissolved in 10 ml of isopropanol followed by adding 1 drop of piperidine and reacted at 80° C. for 1 hour. Crystals were precipitated after cooling to the room temperature, collected by filtration and recrystallized from isopropanol to obtain 3.6 g of 4-(2,2'-dicyanovinyl)phenol as yellow crystals. Melting point=188-189.5° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:38][O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29])(C(C)(C)C)(C)C>C1COCC1>[OH:26][C@@H:27]([CH2:38][O:39][C@@H:40]([CH3:44])[CH2:41][O:42][CH3:43])[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:29]
Reactant: COC[C@H](C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)OC[C@H](O)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (2028 μl, 2.03 mmol) was added to (S)-2-(tert-butyldimethylsilyloxy)-3-((S)-1-methoxypropan-2-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate Y4) (388 mg, 1.01 mmol) in THF (5 mL) at 20° C. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate (50 mL), and washed sequentially with water (25 mL) and saturated brine (10 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 10% s MeOH in DCM to afford the product (200 mg, 74%). 1H NMR (400 MHz, DMSO) δ 1.04 (d, 3H), 2.24 (s, 3H), 3.17-3.23 (m, 4H), 3.25-3.31 (m, 1H), 3.55-3.73 (m, 3H), 4.16-4.23 (m, 1H), 5.94 (d, 1H), 7.59-7.65 (m, 1H), 7.98 (d, 1H), 8.12-8.16 (m, 1H), 9.48 (s, 1H); m/z (ESI+) (M+H)+=269.31; HPLC tR=1.11 min.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:39]([C:40]2[C:41]([CH2:54][O:55][Si:56]([CH:63]([CH3:65])[CH3:64])([CH:60]([CH3:62])[CH3:61])[CH:57]([CH3:59])[CH3:58])=[N:42][N:43]([CH2:45][CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:44]=2)[N:38]=[C:37]([C:66]([CH3:69])([CH3:68])[CH3:67])[CH:36]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:66]([C:37]1[CH:36]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:39]([C:40]2[C:41]([CH2:54][O:55][Si:56]([CH:57]([CH3:59])[CH3:58])([CH:63]([CH3:65])[CH3:64])[CH:60]([CH3:61])[CH3:62])=[N:42][N:43]([CH2:45][CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:44]=2)[N:38]=1)([CH3:68])([CH3:67])[CH3:69]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
Intermediate B (0.23 g, 0.61 mmol) was treated with a solution of Intermediate 74g (0.47 g, 0.68 mmol) in 1,4-dioxane (3.4 mL) then DIPEA (0.13 mL, 0.74 mmol) was added. The mixture was stirred at 70° C. overnight. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7% MeOH in DCM, to give the title compound (0.34 g, 60%). LCMS (Method 3): Rt 5.48 min, m/z 923.7 [MH+].
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH:8]=C(C)C.CC(=CCCC(CC=[O:25])C)C.O=[O+][O-].[BH4-].[Na+]>CO.CO.O>[CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH2:8][OH:25]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: COC(CC(C)CCC=C(C)C)OC
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(CC(C)CCCO)OC
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of citronellal dimethyl acetal [55.0 g, 275 mmole, prepared from racemic citronellal, according to the process described by V. R. Mamdapur et al. in Tetrahedron 20, 2601 (1964)] in methanol (550 ml) was treated at -75° with a stream of ozone for 3.5 h (4.5 g of O3 per hour, 328 mmole of O3). The excess of ozone was purged with argon, the solution was allowed to warm to 0° and then treated with a solution of NaBH4 (5.22 g, 137.5 mmole) in MeOH-H2O (1:1, 154 ml). After 2 h, the reaction mixture was concentrated at reduced pressure, then extracted with ether, and the organic phase was washed to neutrality, dried over MgSO4 and concentrated at reduced pressure. 60.2 g of the desired hexanol (ca. 85% pure) were thus obtained and this product was used as such in the next preparation step. An analytical sample, obtained by preparative GLC (gas-liquid chromatography) gave the following data:
Reaction SMILES: [ClH:1].FC(F)(F)O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][NH2:12].[F:15][C:16]([F:26])([F:25])[O:17]C1C=CC=CC=1N>>[ClH:1].[F:15][C:16]([F:26])([F:25])[O:17][N:11]([C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:12]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: NNc1ccccc1OC(F)(F)F
Agent: Cl
Product: NN(OC(F)(F)F)c1ccccc1
Yield: 54 %

Procedure:
The title compound (115.8 g, 54%) is prepared essentially according to the preparation of (2-trifluoromethoxy-phenyl)-hydrazine hydrochloride using 2-trifluoromethoxy-phenylamine.
Reaction SMILES: Cl[C:2]1[N:20]=[CH:19][C:5]2[N:6]=[C:7]([CH3:18])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C[O-].[Na+].[C:24](O)(=[O:26])C>CO>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([O:26][CH3:24])[N:20]=[CH:19][C:5]=3[N:6]=[C:7]2[CH3:18])=[CH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(=O)n(-c3ccc(O)cc3)c(C)nc2cn1
Yield: 88 %

Procedure:
6-chloro-3-(4-hydroxyphenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (300 mg, 1.04 mmol) was dissolved in dry methanol (15 mL) in a current of nitrogen, sodium methoxide (7 mmol) was added and the mixture was heated under reflux for 20 hours. After leaving to cool, acetic acid was added and the solvent was distilled off under reduced pressure. Distilled water was added to the residue, the solid precipitate was filtered off, and the title compound (259 mg, 88%) was thus obtained as a lavender color solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].[O:23]1C2C(=CC=CC=2)C(NC2C(CC)=NC=C(CC)N=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:23][CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCOc3ccccc32)n1
Product: CCc1nc(NC2CCOc3ccccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.28–7.21, 6.96–6.89, 5.26, 4.54, 4.29–4.22, 2.84, 2.57, 2.22, 1.32–1.24; HRMS (FAB) calcd for C17H20BrN3O+H 362.0868, found 362.0861.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.CO.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>C(OCC)(=O)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[N:13][CH:14]=1)([O-:20])=[O:19]
Reactant: NCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1ccc(NCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-aminoethyl)pyrrolidine (237 μl) was added to a methanol (1 ml) suspension containing 2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 3 hours and 30 minutes. 1-(2-aminoethyl)pyrrolidine (158 μl) was added, followed by stirring for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with 10% saline and then with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether was added to the obtained residue, solid matter was collected by filtration and washed with diisopropylether and hexane, and a yellow solid of 5-nitro-N-(2-(pyrrolidin-1-yl)ethyl)pyridin-2-amine (27 mg) was thus obtained.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O.[S:17]([NH2:27])(=[O:26])([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([S:17]([NH2:27])(=[O:18])=[O:26])=[CH:20][CH:21]=3)[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: O=C(CCC1OCCO1)c1ccc(F)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-n2cccc2-c2ccc(F)cc2)cc1
Yield: 40.7 %

Procedure:
A mixture of 3-(1,3-dioxolan-2-yl)-1-(4-fluorophenyl)propan-1-one (Example 8, Step 2) (1.6 g, 7.14 mmol), sulfanilamide (1.35 g, 7.86 mmol), p-toluenesulfonic acid (120 mg) and molecular sieves (4 Å, 3 g) in toluene (250 ml) was heated to reflux for 98 hours. The reaction was cooled, filtered and concentrated. The crude brownish solid (3.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 4-[2-(4-fluorophenyl)-1H-pyrrol-1-yl]benzenesulfonamide (920 mg, 40%) as a white solid: mp (DSC) 206° C. Anal Calc'd. for C16H13N2SFO2 ·0.2 H2O: C, 60.06; H, 4.22; N, 8.76; S, 10.02. Found: C, 60.13; H, 4.21; N, 8.61; S, 10.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C(N(CC)CC)C.C([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:37]2[CH:42]=[CH:41][C:40]([O:43]C(=O)C)=[CH:39][CH:38]=2)[C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](Cl)=[O:31])=[CH:23][CH:22]=1)(=O)C.O>C(Cl)Cl>[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:37]2[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=2)[C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:31])=[CH:23][CH:22]=1
Reactant: COc1cccc(N)c1
Reactant: CC(=O)Oc1ccc(C(c2ccc(OC(C)=O)cc2)c2ccccc2C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cccc(NC(=O)c2ccccc2C(c2ccc(O)cc2)c2ccc(O)cc2)c1
Reaction time: 0.5 h

Procedure:
In 20 ml of methylene chloride were dissolved 0.62 g of m-anisidine and 5 ml of triethylamine. To this solution was added dropwise under ice cooling 20 ml of methylene chloride containing 2.64 g of 2-[bis(4-acetoxyphenyl)methyl]benzoyl chloride as obtained in Reference Example 2. After stirring for 30 minutes, water was added thereto. The organic layer was separated off, and the water layer was extracted with chloroform. The chloroform layer was combined with the organic layer, and the combined organic layer was washed with 2N aqueous hydrochloric acid solution and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was suspended in a mixture of 50 ml of saturated aqueous sodium hydrogencarbonate solution and 50 ml of methanol, and the resulting suspension was heated under reflux for 2 hours. The suspension was concentrated under reduced pressure, and water was added to the residue. The resulting mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and was recrystallized to afford 1.54 g of the desired product.