Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.CC(C)([O-])C.[K+].[C:18](#[N:21])[CH:19]=[CH2:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:20][CH2:19][C:18]#[N:21])[N:10]=2)[N:7]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: C=CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCn1nc2ccc(Cl)nn2c1=O
Yield: 11.2 %

Procedure:
To a solution of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on [P. Francabilla and F. Lauria, J. Het. Chem. 8, 415 (1971)] (17 g., 0.1 .mole) in dry DMF (300 ml.) was added potassium tert.-butoxide (0.5 g., 4.5 m.moles) with stirring. Acrylonitrile (6.6 g., 0.12 .mole) in dry DMF (10 ml.) was added to the mixture. The mixture was stirred at 100°-110° C. for 24 hours, then poured into water (700 ml.) and extracted with ethyl acetate (5 × 400 ml.). The organic extracts were combined, dried over Na2SO4 and evaporated. The residue was crystallized from ethyl acetate to give light yellow needles of 6-chloro-2-(2-cyanoethyl)-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-on (2.5 g., 11%). M.p. 166°-168° C.
Reaction SMILES: [OH-].[Li+].[CH:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=1)([CH3:5])[CH3:4]>O1CCOCC1.C(OCC)(=O)C>[CH:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(OC(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)O)nc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To methyl 5-hydroxypyridine-2-carboxylate (0.6 g, 3.92 mmol) in DMF (3.6 mL) was added potassium carbonate (2.2 g, 15.7 mmol) followed by 2-bromopropane (736 μL, 7.8 mmol) The reaction mixture was heated at 60° C. for 1.5 hours. The reaction mixture was cooled and filtered using EtOAc and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water (3×10 mL) and brine solution (10 mL). The organics were separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-50% EtOAc: hexanes as eluent to give methyl 5-isopropoxypyridine-2-carboxylate (555 mg, 73%) as a colorless oil. ESI-MS m/z calc. 195.1. Found 196.3 (M+1)+; Retention time: 1.09 minutes (3 min run). Lithium hydroxide (5.7 mL of 2 M, 11.37 mmol) was added to a solution of methyl 5-isopropoxypyridine-2-carboxylate (555 mg, 2.84 mmol) in dioxane (4 mL) and stirred at 55° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and layers were separated. The aqueous layer was acidified with 1N HCl solution and extracted with ethyl acetate. The organics were separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 5-isopropoxypyridine-2-carboxylic acid (150 mg, 29%). ESI-MS m/z calc. 182.1. Found 182.3 (M+1)+; Retention time: 0.33 minutes (3 min run).
Reaction SMILES: C([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])C1C=CC=CC=1.[BrH:22]>>[BrH:22].[OH:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1N=C1NCCN1OCc1ccccc1
Agent: Br
Product: Cc1ccccc1N=C1NCCN1O

Procedure:
22.5 g of 1-(benzyloxy)-2-[(o-tolyl)-imino]imidazolidine are heated at 150° for 30 minutes with 150 ml of 48 percent hydrobromic acid. The mixture is evaporated in vacuo. From the residue there is obtained 1-hydroxy-2-(o-tolylimino)imidazolidine hydrobromide of melting point 176°-187° (acetone).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br.Br[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[N:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:17]=1
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Br
Product: CCOC(=O)C(Cc1ccncc1)C(=O)OCC
Yield: 38.5 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (6.41 g) and 4-(bromomethyl)pyridine hydrobromide (10.1 g). This was purified by silica gel column chromatography to give the title compound (3.86 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][SH:21])=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Br)n1
Reactant: COc1ccc(CS)cc1
Product: CCOC(=O)Cc1cccc(SCc2ccc(OC)cc2)n1

Procedure:
Prepared according to the procedure described in Example 16, Step 2, using the following starting materials: (6-bromo-pyridin-2-yl)-acetic acid ethyl ester and 4-methoxybenzyl mercaptan.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][C:16]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[CH3:15][C:16]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: Cc1ccc(C)c(C=CC(=O)O)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(C)ccc3C)nc2n(CC)c1=O
Yield: 50.1 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.20 g (18.2 mmol) of 2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/toluene to give 2.56 g (yield 50%) of Compound 109 as white needles.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([B:13]([OH:15])[OH:14])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([B:13]([OH:15])[OH:14])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1
Reactant: O=C(O)c1cc(B(O)O)cc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(B(O)O)cc(C(=O)O)c1

Procedure:
A solution of 3-nitro-5-carboxyphenylboronic acid (3.3 g, 0.016 mol) in absolute ethanol (25 ml) was hydrogenated in the presence of Raney Nickel (1 g) at 50 lbs per square inch for 4 hours in a Parr shaker. The catalyst was removed by filtration and the solvent was removed on a rotary evaporator. The solid obtained was recrystallized from water. M.P. 210°-12° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:14]O>>[CH:5]1([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CO
Reactant: O=C(O)CC1CCCC1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1CCCC1
Reaction time: 20 h

Procedure:
Thionyl chloride (7.0 ml) was slowly added to a solution of cyclopentylacetic acid (8.0 ml) in dry methanol (60 ml) and the mixture was stirred at 23° for 20 h. The mixture was concentrated in vacuo; then, the residue was taken up in DCM (100 ml), washed with a 5% sodium bicarbonate solution (50 ml), water (50 ml) and brine (50 ml), dried and concentrated in vacuo to give the title compound (6.47 g) as a yellow oil, which was not purified further. T.l.c. CH-EA (1:1), Rf =0.79. 1H-NMR: 3.70(s); 2.35(s); 2.4-2.15(m); 1.8(m); 1.7-1.5(m); 1.2(m).
Reaction SMILES: [N+:1](C1C2C(=CC=CC=2)CCN1)([O-:3])=[O:2].[H][H].[F:16][C:17]([F:34])([F:33])[C:18]([N:20]1[CH2:29][CH2:28][CH:27]2[C:22](=[CH:23][C:24]([N+]([O-])=O)=[CH:25][CH2:26]2)C1)=[O:19]>>[N+:1]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[CH2:28][CH2:29][NH:20][C:18](=[O:19])[C:17]([F:16])([F:33])[F:34])([O-:3])=[O:2].[CH2:18]=[O:19]
Reactant: O=C(N1CCC2CC=C([N+](=O)[O-])C=C2C1)C(F)(F)F
Reactant: O=[N+]([O-])C1NCCc2ccccc21
Reactant: [H][H]
Product: C=O
Product: O=C(NCCc1ccccc1[N+](=O)[O-])C(F)(F)F

Procedure:
The nitro-tetrahydroisoquinoline of formula (IV) in which XA is hydrogen may be prepared by hydrolysis of 2-trifluoroacetyl-7-nitro-tetrahydroisoquinoline obtained by reaction of an N-(nitrophenyl)ethyl-trifluoroacetamide and paraformaldehyde in acidic conditions using the procedure of Stokker, Tet. Lett., 1996, 37, 5453. N-(nitrophenyl)ethyl-trifluoroacetamides can be prepared from readily available materials by reaction of trifluoracetic anhydride with lutidine and nitrophenethylamine hydrochloride, as illustrated in the Descriptions below.
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>>[C:7]([O:6][C:4](=[O:5])[NH:11][C@@H:12]([C:20](=[O:22])[NH:3][CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: CN
Agent: Cl
Product: CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Methylamine hydrochloride (3.1 mmol) and Boc-D-phenyl-alanine (2.8 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 144 hour reaction time, washed with acid first, then base) giving the product which was used without further purification. Yield 760 mg, 96%.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([CH:18]=[CH:19][CH:20]=2)[N:12]([CH3:17])[C:13](=[O:16])[CH2:14][N:15]=1.[Cl:21]N1C(=O)CCC1=O>O1CCCC1>[ClH:21].[Cl:1][C:18]1[N:11]2[N:12]([CH3:17])[C:13](=[O:16])[CH2:14][N:15]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[C:10]2=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cccn21
Agent: Cl
Solvent: C1CCOC1
Product: CN1C(=O)CN=C(c2ccccc2F)c2ccc(Cl)n21
Yield: 55.7 %

Procedure:
A solution containing 5-(2-fluorophenyl)-1-methyl-1H-pyrrolo[1,2-b][1,2,5]triazepin-2(3H)-one hydrochloride (3.3 g, 12.9 mmol) and N-chlorosuccinimide (1.87 g, 14 mmol) in 100 ml of dry tetrahydrofuran was refluxed under N2 for 3 hours. The resultant solution was evaporated and the residual oil was taken up in 200 ml of EtOAc, washed with H2O, dried (MgSO4), filtered, and evaporated to an oil. This oil was purified by flash chromatography (silica, 4:7 hexane-ether) to given an oil (2.1 g). This oil was treated with ethereal HCl and the resultant solid was recrystallized from isopropanol-ether to give 2.36 g (55%) of powder, m.p. 218° dec.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[I:5][C:6]1[C:7](=[O:23])[C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:9]=2[O:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:3][CH:2]([F:4])[O:14][C:10]1[N:11]=[CH:12][CH:13]=[C:8]2[C:7](=[O:23])[C:6]([I:5])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:15][C:9]=12
Reactant: FC(F)Cl
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(I)c(-c2ccccc2)oc2c(OC(F)F)nccc12
Temperature: 40 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
Chlorodifluoromethane was bubbled into a solution of 3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione (100 mg, 0.27 mmol) and potassium carbonate (55 mg, 0.40 mmol) in DMF (3.0 mL) over 2 min. The reaction mixture was stirred at 40° C., for 2 days under a chlorodifluoromethane balloon. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases were separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a white solid (33 mg, 29%). LCMS (Method B): RT=4.46 min, [M+H]+=416.
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=2[CH:10]=[C:9]([C:22](=[O:24])[CH3:23])[C:8]=1[O:25]C.Cl>CCCCCC.CN(C)C=O>[Br:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=2[CH:10]=[C:9]([C:22](=[O:24])[CH3:23])[C:8]=1[OH:25]
Reactant: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCS
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CC=C2C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.07 g, 26.64 mmol) was rinsed with hexane and suspended in dry N,N-dimethylformamide (80 mL). To the suspension was added ethanethiol (1.9 mL, 26.6 mmol) and stirred at room temperature for 30 min, which resulted in the formation of a clear solution. A solution of 1-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-ethanone (Compound A-103,2.6 g, 7.4 mmol) in N,N-dimethylformamide (10 mL) was added to the solution and the mixture was heated at 130° C. for 5 h. The mixture was cooled to room temperature, acidified with 10% HCl and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexane) to yield the title compound as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:29])[C:20]1[CH:28]=[CH:27][CH:26]=[C:22]([C:23](Cl)=[O:24])[CH:21]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:29])[C:20]2[CH:28]=[CH:27][CH:26]=[C:22]([C:23]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:17][CH:18]=3)=[O:24])[CH:21]=2)=[CH:18][CH:17]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: CCCCCCCCOC(=O)c1ccc(O)cc1
Product: CCCCCCCCOC(=O)c1ccc(OC(=O)c2cccc(C(=O)Oc3ccc(C(=O)OCCCCCCCC)cc3)c2)cc1

Procedure:
Octyl p-hydroxybenzoate and isophthalic dichloride are made to react and treated in a similar procedure to Example 4 to yield di(p-octyloxycarbonylphenyl)isophthalate in a pale yellow oily state.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2=[C:11]3[C:20](=[C:21](Br)[CH:22]=[C:9]2[NH:8][C:7]=1[CH3:30])[CH2:19][CH:18]1N(CCC2C=C(OC)C=CC=21)C3)=[O:5])[CH3:2].C1C[O:34][CH2:33][CH2:32]1.C([OH:38])C>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:9](=[CH:22][CH:21]=[C:20]([CH2:19][C:18]([O:34][CH2:33][CH3:32])=[O:38])[CH:11]=2)[NH:8][C:7]=1[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2cc(Br)c3c(c12)CN1CCc2cc(OC)ccc2C1C3
Reactant: CCO
Reactant: C1CCOC1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc2[nH]c(C)c(C(=O)OCC)c2c1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 5-bromo-9-methoxy-2-methyl-6,11,12,13-tetrahydro-3H,6aH-3,12a-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylic acid ethyl ester (Example 1, Step 9) (0.2 g, 0.42 mmol) in THF/ethanol 1:1 (30 mL) is added palladium on carbon (20%). The suspension is hydrogenated for 8 hours. The catalyst is filtered and the solution is concentrated in vacuo. Ethanol (1 mL) is added and white crystals precipitated. The solid material is filtered and recrystallized from ethanol to afford the desired product (Compound 3) (0.09 g, 54%). MS: 391.1 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH3:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc(Br)ccc1O
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2-methoxyphenol (1.0 g, 0.0049 mol), (2-methylphenyl)boronic acid (1.7 g, 0.012 mol), TEA (4.1 mL, 0.030 mol), cupric acetate (1.4 g, 0.0079 mol) and DCM (50 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=2.28 (s, 3H), 3.88 (s, 3H), 6.61 (d, J=8.59 Hz, 1H), 6.78 (d, J=8.08 Hz, 1H), 6.99 (dd, J=8.59, 2.02 Hz, 1H), 7.04 (t, J=7.33 Hz, 1H), 7.09-7.17 (m, 2H), 7.24 (d, J=7.33 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34]>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: OCCNCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(CCO)CCO)O2
Reaction time: 1.5 h
Yield: 9.3 %

Procedure:
To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.00 mmol) in 10 mL THF was added 356 mg CDI (2.20 mmol). After stiffing for 1.5 h., a solution of diethanolamine (231 mg, 2.2 mmol) in 10 mL THF was added over 1 h and the reaction was stirred overnight. The reaction was concentrated, dissolved into 70 mL CH2Cl2 and washed sequentially with 50 mL 0.62 M HCl, 50 mL 1.0 M NaHCO3, 50 mL saturated NaCl and dried over Na2SO4. The combined aqueous phases were extracted 3×50 mL 3:1 isopropyl alcohol/isopropyl acetate which was dried and concentrated to a brown oil. Flash chromatography yielded 63 mg of 6-hydroxy-N,N-bis(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC#N)=O)=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29].C(O)(=O)C.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([NH:29][C@H:28]([C:27]([O:26][CH3:25])=[O:31])[CH3:30])=[O:17])=[CH:10][C:9]=2[CH3:21])=[O:7])=[CH:22][CH:23]=1
Reactant: COC(=O)[C@H](C)N
Reactant: Cc1cc(CC(=O)OCC#N)n(C)c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Yield: 169.8 %

Procedure:
A solution of 10.0 g (0.03 mole) of cyanomethyl [5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]acetate, 1.6 g (0.015 mole) of alanine methyl ester hydrochloride, 0.3 ml of glacial acetic acid, and 2.1 ml (0.015 mole) triethylamine in 40 ml of THF was heated under reflux for 31/2 hours. A second addition of 1.6 g of alanine methyl ester hydrochloride and 2.1 ml of triethylamine was made. The mixture was heated under reflux for 2 hours. A fourth addition of 2.0 g (0.018 mole) of triethylamine was made. The mixture was heated under reflux for 16 hours. The reaction was partitioned between chloroform and dilute hydrochloric acid. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was recrystallized from acetonitrile to give 9.6 g of methyl N-{[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]acetyl}alaninate, m.p. 163°-165° C. (85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19]C(=O)OCC3C=CC=CC=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.I[Si](C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1)OCc1ccccc1
Agent: C[Si](C)(C)I
Product: NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1
Yield: 65.9 %

Procedure:
Treatment of (+)-benzyl {[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (2.06 g, 4.81 mmol) with iodotrimethylsilane (3.85 g, 19.24 mmol) generally according to the procedure described for Example 129 gave 0.933 g (85%) of (−)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=−3.34 (c 10.0 in dimethylsulfoxide); mp 203-206° C.; Anal. calcd. for C15H13Cl2NOHCl: C, 54.59; H, 4.27; N, 4.24. Found: C, 53.69; H, 3.96; N, 3.99.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([NH2:32])[CH2:27][CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([NH:32][C:20]1[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=1)[CH2:27][CH2:26]2
Reactant: NC1CCc2cc(F)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Product: O=[N+]([O-])c1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Yield: 75.6 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (1.22 g, 3.76 mmol; HPLC: 4.446 min) and rac-5-fluoro-indan-1-ylamine (CAS 148960-33-2) (568 mg, 3.76 mmol; HPLC 0.4 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (0.93 g, 90%), MS (ISP) m/e=328.2 [(M+H)+].
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([Cl:16])=[N:8][CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>ClCCl>[Cl:16][C:7]1[C:6]([N:5]=[C:1]=[S:2])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1cnc(Cl)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cnc(Cl)c(N=C=S)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.1 %

Procedure:
Thiophosgene (6.367 g, 55.37 mmol) in dichloromethane (10 mL) was added to a mixture of methyl 5-amino-6-chloronicotinate (8.61 g, 46.14 mmol) and sodium carbonate (9.781 g, 92.29 mmol) in dichloromethane (200 mL). The reaction mixture was stirred for four days at ambient temperature. The reaction mixture was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 12:1 hexane:ethyl acetate to afford methyl 6-chloro-5-isothiocyanatonicotinate (8.03 g, 76.1% yield) as a white solid: 1H NMR (CDCl3) δ 3.97 (s, 3H), 8.09 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:22]12[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:27]C(=O)O[C:23]2=[O:24].C(Cl)(Cl)Cl>ClCCl>[NH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[C:23]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:24]
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
A solution of 4-aminomethyl-1-diphenylmethylpiperidine (2.5 g, 9.15 mmol) in dichloromethane (10 ml) was added to a suspension of isatoic anhydride (1.0 g, 6.1 mmol) in dichloromethane (25 ml) at room temperature. The reaction mixture was stirred for 1 hour and then poured into chloroform and washed with 5% NaHCO3 solution. The organic layer was concentrated. The residue was dissolved in dichloromethane (25 ml) and poured into hexane (400 ml) to give 2-amino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as precipitate (100%): mp 153°-154° C.