Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[C:12]1([S:18][CH:19]=[CH:20][C:21](O)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O.C(O)(C)C>[ClH:1].[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]\[S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)C=CSc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=C(/C=C\Sc1ccccc1)N[C@H]1CN2CCC1CC2
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To a stirred solution of (R)-1-Aza-bicyclo[2.2.2]oct-3-ylamine dihydrochloride (25 g, 0.125 mol), 3-(phenylthio)acrylic acid (23.5 g, 0.13 mol), and diisopropylethylamine (90 ml) in dry DMF (600 ml) at ambient temperature was added in succession 1-hydroxybenzotriazole hydrate (17 g, 0.126 mol) and O-benzotriazol-1-yl-N.N,N′,N′-tetramethyluronium tetrafluoroborate (40 g, 0.124 mol). The resulting amber-colored solution was stirred overnight, diluted with water (1 vol), and extracted with ether (2×700 ml). The aqueous phase was made basic (pH 10) with 50% aqueous sodium hydroxide and extracted with chloroform (3×700 ml). The chloroform extracts were combined, washed with water, brine, dried over sodium sulfate and concentrated to dryness to give crude product as a syrup (40 g). The syrup was taken in isopropanol (IL), made acidic with gaseous HCL, and allowed to stand. The resulting solid was collected by filtration, recrystallized from isopropanol (2×), and dried in vacuo to give the title compound (8 g) as a white solid. MS (ES+) 289. (MH30).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH2:33][CH3:34])[C:30](O)=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[CH:29]([CH3:28])[CH2:33][CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CCC(C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (91 mg, 88%), MS (ISP) m/z=415.3 [(M+H)+], mp 196.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-2-methyl-butyric acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH:17]1[CH2:19][CH2:18]1)[C:7]2=[O:20].Br[C:23]1C(F)=CC=C2C=1N=C(Cl)N(C1CC1)C2=O.Cl.CC1(N)CCC1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:14][CH2:15][CH2:23]1)[N:8]([CH:17]1[CH2:18][CH2:19]1)[C:7]2=[O:20]
Reactant: O=c1c2ccc(F)c(Br)c2nc(Cl)n1C1CC1
Reactant: CC1(Nc2nc3c(Br)c(F)ccc3c(=O)n2C2CC2)CC1
Agent: CC1(N)CCC1
Agent: Cl
Product: CC1(Nc2nc3c(Br)c(F)ccc3c(=O)n2C2CC2)CCC1

Procedure:
8-Bromo-3-cyclopropyl-7-fluoro-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (498a) was prepared according to the procedures described for Intermediate 495a, using 8-bromo-2-chloro-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (721) and 1-methylcyclobutanamine hydrochloride (Oakwood Chemical) as the starting materials. MS (ESI, pos. ion) m/z: 366.0/368.0 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=O>>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1c(Cl)cccc1Cl
Product: O=c1cc(N2CCN(Cc3c(Cl)cccc3Cl)CC2)nc[nH]1

Procedure:
6-[4-(2,6-Dichloro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,6-dichlorobenzaldehyde (available from Fluka). Mass spectrum (ES) MH+=339.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:21]=1[NH2:22])=[O:16])[CH3:13].[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31].Cl>ClCCl>[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=2)[C:21]=1[NH:22][S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])=[O:16])[CH3:13]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1NS(=O)(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
Add DBU (5.14 mL, 33.69 mmol) to a solution of 5-amino-1-(4-bromo-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.612 g, 8.42 mmol) in dichloromethane (25 mL) at 0° C. Stir for 15 min. at 0° C. and then add isopropylsulfonyl chloride (1.94 mL, 16.84 mmol). Immerse the mixture into a pre-heated oil bath (50° C.). After stirring for 5 min., add additional isopropylsulfonyl chloride (0.97 mL, 8.42 mmol). Stir overnight at 50° C. Add 1.0M HCl (aq) until pH 5, wash with water (2×50 mL), dry over sodium sulfate, filter, and concentrate. Adsorb the compound onto silica gel, and subject to silica gel flash column chromatography (15-30% EtOAc/n-hexane) to yield 1-(4-Bromo-phenyl)5-(propane-2-sulfonylamino)-1H-pyrazole-4-carboxylic acid ethyl ester (2.55 g, 73%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[CH:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH3:4].[C:18](Cl)(=[O:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([N:5]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[CH:15]([CH3:16])[CH3:17])[C:18](=[O:20])[CH3:19])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCCNc1c(C(C)C)nc2ccccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(C(C)=O)c1c(C(C)C)nc2ccccn12

Procedure:
N-butyl-2-isopropylimidazo[1,2-a]pyridin-3-amine 5 (250 mg, 1.08 mmol) was reacted with acetyl chloride (2 eq., 2.16 mmol, 154 μl) in the presence of K2CO3 (2 eq., 2.16 mmol, 299 mg) in acetonitrile (10 ml) at room temperature. The reaction progress was monitored by TLC. Purification of the product was achieved by column chromatography, eluting with ethyl acetate:hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28](O)[C:27]=1[CH3:32].C[O:34][C:35]1C(C)=C2C(C(=O)OC2)=C(OS(C2C=CC(C)=CC=2)(=O)=O)[C:36]=1CC1CCC(OC=C)C=1C.Cl([O-])(=O)(=O)=O.[Li+]>C(OCC)=C.CCOCC.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:36][CH:35]=[O:34])[C:27]=1[CH3:32]
Reactant: C=COC1CCC(Cc2c(OC)c(C)c3c(c2OS(=O)(=O)c2ccc(C)cc2)C(=O)OC3)=C1C
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(O)CC1)C(=O)OC2
Agent: C=COCC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCOCC
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC=O)CC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ol (0.157 g) in ethyl vinyl ether (10 mL) was added mercuric acetate (0.052 g). After stirring for 30 hours at ambient temperature, the reaction was diluted with ether and passed quickly through a fritted funnel half filled with celite and capped with silica. To this ethereal solution [containing 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy -5-isobenzofuranylmethyl)-2-methyl-1-vinyloxycyclopent-2-ene, which was not isolated or characterized] was then added lithium perchlorate (10 mL, 0.5M solution in ether). After 0.5 hours, the reaction was diluted with aqueous sodium bicarbonate and washed with brine. Drying over magnesium sulfate was followed by filtration and solvent removal. The product 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetaldehyde (0.050 g) was finally obtained after chromatography (hexanes/ethyl acetate, 2/1).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@@H:15]3[O:27][C@H:26]([CH3:28])[C@@H:21]([O:22]C(=O)C)[C@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[C:4]([F:29])[C:3]=1[F:30].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[F:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@@H:15]3[O:27][C@H:26]([CH3:28])[C@@H:21]([OH:22])[C@H:16]3[OH:17])[C:6]=2[CH:5]=[C:4]([F:29])[C:3]=1[F:30]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2c(F)c(F)c(F)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC(C)Nc1nc2c(F)c(F)c(F)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 73.8 %

Procedure:
4,5,6-Trifluoro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine (0.42 g, 1.02 mmol), ethanol (10 mL), sodium carbonate (0.19 g, 1.79 mmol), water (2 mL) and methanol (5 mL) were used according to general procedure III. The title compound was purified by silica gel chromatography using 10:1 dichloromethane-methanol as eluant to provide a white solid (0.26 g, 75%); m.p. 148-151° C.; 1H NMR (DMSO-d6) δ: 7.10 (m, 1H, Ar—H), 6.68 (d, J=7.5 Hz, NH), 5.70 (d, J=6.7 Hz, 1H, CH), 5.27 (m, 2H, overlapping OH), 4.35 (dd, J=6.6 Hz, 1H, CH), 4.12 (m, 1H, CH), 3.91 (m, 1H, CH), 3.85 (m, 1H, CH), 1.40 (d, J=6.5 Hz, 3H, CH3), 1.24 (d, J=6.4 Hz, 6H, overlapping CH3).
Reaction SMILES: Cl[C:2]1[C:3](=[O:25])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].[Cl:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]([CH:35]([CH3:37])[CH3:36])[C:32]([SH:34])=[N:33][C:29]=2[CH:28]=1.CCN(CC)CC>>[Cl:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]([CH:35]([CH3:37])[CH3:36])[C:32]([S:34][C:2]3[C:3](=[O:25])[O:4][C:5]([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=4)([CH:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:6][C:7]=3[OH:8])=[N:33][C:29]=2[CH:28]=1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4n3C(C)C)C(=O)O2)cc1Cl
Yield: 11.1 %

Procedure:
A solution of 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one (300 mg, 0.78 mmol), 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol (181 mg, 0.80 mmol) and Et3N (0.1 mL, 0.80 mmol) was stirred at 55° C. for 5 hrs. The mixture was concentrated and purified by prep HPLC to obtain 50 mg product (11% yield).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][C@H:11]([C:13](OC)=[O:14])[C@H:10]([C:17](OC)=[O:18])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.[OH-].[Na+]>C1COCC1.O>[C:1]1([CH2:7][N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[C@H:10]([CH2:17][OH:18])[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 128.4 %

Procedure:
Dimethyl (cis)-1-(phenylmethyl)-3,4-pyrrolidinedicarboxylate (Chem. Pharm. Bull. 1985 33; 896-898) (2.44 g, 8.8 mmol) was dissolved in THF (100 mL) and cooled to 0° C. LiAlH4 (1 g, 26 mmol) was added in portions and the reaction was heated overnight at 60° C. Upon cooling to 0° C., wet ether was added followed by water (1 mL), 15 w/w NaOH (aq) (1 mL) and water (3 mL). The resulting mixture was stirred for 15 min and filtered through Celite yielding crude [(cis)-1-(phenylmethyl)-3,4-pyrrolidinediyl]dimethanol (2.5 g) which was used directly in the next reaction. LCMS: (M+H)+: 222.3.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.C([Mg]Cl)(C)C.[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCCl>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])([C:9]3[C:8]([OH:11])=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[CH:10]=3)[C:31]2=[O:40])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Cc1nc2cc(O)ccc2o1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc2cc(O)c(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
To a cooled (0° C.) suspension of 2-methyl-1,3-benzoxazol-5-ol (Fujita, et al., Synthesis (1982):62-9) (10.3 g, 68.9 mmol) in anhydrous tetrahydrofuran (150 mL) was added isopropylmagnesium chloride (34.4 mL, 2.0 M solution in tetrahydrofuran, 68.9 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, and 1-benzhydrylindoline-2,3-dione (18.8 g, 59.9 mmol) and anhydrous dichloromethane (150 mL) were added. The reaction mixture was heated at reflux for 6 days and was allowed to cool to ambient temperature. The reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (200 mL) and ethyl acetate (200 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL) and the combined organic solution was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/ethyl acetate (3/1), followed by recrystallization from hexanes/ethyl acetate to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one (3.10 g, 10%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ8.41 (br s, 1H), 7.63-7.60 (m, 2H), 7.47-7.32 (m, 10H), 7.15 (s, 1H), 7.04-6.96 (m, 1H), 6.96-6.88 (m, 1H), 6.87 (d, J=9.0 Hz, 1H), 6.41 (d, 7.8 Hz, 1H), 4.58 (br s, 1H), 2.44 (s, 3H); MS (ES+) m/z 445.2 (M−17).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].B>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-Chloroisonicotinic acid (2.0 g; 12.7 mmol) is dissolved in 25 mL THF under anhydrous conditions and borane (1.0 M in THF; 25.4 ml; 25.4 mmol) is added drop wise via a syringe. The solution is stirred overnight at 50° C. The mixture is cooled to RT and quenched with 5 mL MeOH, concentrated under reduced pressure and purified by column chromatography on silica gel using a solvent gradient of hexanes to EtOAc. The final product is isolated as a white powder (1.1 g, 60% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25]C)=[O:24])[N:18]=2)[CH2:13][CH2:12]1.[OH-].[Na+]>O1CCCC1>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=[O:24])[N:18]=2)[CH2:15][CH2:16]1
Reactant: COC(=O)c1nccc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nccc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Reaction time: 1 h

Procedure:
0.50 g (1.4 mmol) methyl 4-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-2-carboxylate, 1.1 mL d-water and 1.1 mL 4 M sodium hydroxide solution in 9.0 mL tetrahydrofuran was stirred overnight at RT. The organic solvent was removed and the residue was diluted with 250 mL water. After the addition of 25 mL 4M hydrochloric acid solution the mixture was stirred for 1 h. The precipitated solid was suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH:5]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][C:16]2([CH3:21])OCC[O:17]2)[C:10]1=[O:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH:5]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][C:16](=[O:17])[CH3:21])[C:10]1=[O:22]
Reactant: COC(=O)CC(CCCN1CC[C@@H](CCC2(C)OCCO2)C1=O)c1ccc(OC)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COC(=O)CC(CCCN1CC[C@@H](CCC(C)=O)C1=O)c1ccc(OC)nc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-12 (440 mg) in acetone (30 mL) was added p-toluenesulfonic acid (270 mg) and the mixture was heated at reflux for 2 h, then cooled to ambient temperature for 3 h. The reaction mixture was concentrated at reduced pressure. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give 1-13 as an oil, which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.C(=O)([O-])[O-].[Na+].[Na+].O>CO>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[N:2][OH:3]
Reactant: NO
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=Cc1ccccc1Cl
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Hydroxylamine hydrochloride (35.6 g) was added to a 0° C. mixture of 2-chlorobenzaldehyde (60.0 g) and sodium carbonate (22.6 g) in methanol (1.0 L)-water (1.0 L). The reaction was stirred overnight and then concentrated to half volume. The mixture was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (65.4 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(N(CC)CC)C.Cl.C(N(CC)CC)C>C(#N)C.O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
156.5 g (0.5 mol) of (p-chlorophenyl)-(diphenyl)-methyl chloride and 34 g (0.5 mol) imidazole are dissolved in 500 ml acetonitrile, with stirring, and 51 g (0.5 mol) triethylamine are added, whereupon separation of triethylamine hydrochloride occurs even at room temperature. In order to complete the reaction, heating at 50°C is carried out for three hours. After cooling, 1 liter of benzene is added and the reaction mixture is stirred, then washed salt-free with water. The benzene solution is dried over anhydrous sodium sulfate, filtered and concentrated by evaporation; giving 167 g of crude 1-[(p-chlorophenyl)-(bisphenyl)-methyl]-imidazole, m.p. 125°C. By recrystallization from 200 ml benzene and 100 ml ligroin, 115 g (= 71% of the thoery) of pure 1-[(p-chlorophenyl) (bis-phenyl)-methyl]-imidazole of m.p. 140°C are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[S:9][C:8]2[C:10]([CH3:17])=[C:11]([OH:16])[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]=2[O:6]1.[I-:18].[Na+].O>CC(C)=O>[OH:16][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:7]2[O:6][CH:5]([CH2:4][CH2:3][CH2:2][I:18])[S:9][C:8]=2[C:10]=1[CH3:17]
Reactant: [I-]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCCl)O2
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2

Procedure:
120 mg of 2-(3-chloropropyl)-5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 77) were dissolved in 2 ml of acetone, after which 660 mg of sodium iodide were added, and the reaction mixture was heated under reflux for 10 hours. The reaction mixture was cooled and then poured into water, and the resulting precipitate was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure and the resulting crude product was purified in the same manner as described in (a), to give the title compound having the same Rf value and mass spectrum as the product of (a) above.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].I[CH3:27]>C1COCC1.[Ag]=O>[CH3:27][O:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25]
Reactant: CI
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Agent: O=[Ag]
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
(+/−)-Tert-butyl (1R,5S,6R)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) was suspended in iodomethane (100.0 equiv.). Silver oxide (6.0 equiv.) was added to the mixture and the reaction vessel was wrapped in foil (kept dark) and allowed to stir 45° C. for 10 hrs. The reaction was diluted with THF and filtered through a pad of celite. The celite cake was further washed with MeOH. The organics were concentrated and the crude was taken up in DCM, washed with NaHCO3(aq.), dried over Na2SO4, filtered and concentrated. The crude was loaded onto silica gel and purified via ISCO to yield (+/−)-tert-butyl ((1R,5S,6R)-6-methoxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate in 35% yield. LC/MS (m/z)=364.1 (MH+), Rt=0.89 min.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1)(=O)C.[OH-].[Na+].C(O)C.C(OCC)(=O)C>O>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][NH:4][CH2:9][CH2:8][N:7]3[N:10]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: CC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCNC3)c1=O
Yield: 91 %

Procedure:
A 50 mL round bottom flask with a magnetic stirrer and reflux condenser was charged with 125g (250 mg, 0.7 mmol), aqueous NaOH (5N, 6 mL), ethanol (6 mL). The mixture stirred at reflux for 30 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a 91% yield (200 mg) of crude 125h.