Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][C:5]=1[CH2:6][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: COc1cc(O)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1cc(O)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of 4-hydroxy-2-methoxybenzaldehyde (1.0 g, 6.57 mmol) and morpholine (2.0 g, 23.0 mmol) in 50 ml dichloroethane was stirred at rt for 1 h. Sodium triacetoxyborohydride (2.0 g, 9.44 mmol) was added in portions over 20 minutes. The reaction mixture was stirred at rt over night. Aqueous NaHCO3 (sat.) was added, the phases were separated and the aqueous phase was extracted with DCM once. The solvent was removed by evaporation and the residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 1.19 g (81%) of 7A iii as a solid. 1H NMR (500 MHz, CDCl3): δ 2.41-2.71 (m, 4H), 3.52 (s, 2H), 3.72 (s, 3H), 3.69-3.79 (m, 4H), 6.27 (d, 1H), 6.32 (s, 1H), 7.10 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][OH:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH:28]=[O:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3cc(CO)ncn3)ccc21
Solvent: ClCCl
Product: O=Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Temperature: 25 °C

Procedure:
To a suspension of 5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (310 mg, 0.724 mmol) in DCM (10 mL), DMP (337 mg, 0.795 mmol) is added. The reaction mixture is stirred at rt until complete as seen by LCMS (about 1 H). The reaction is quenched with saturated aqueous NaHCO3 and extracted with EtOAc (3×10 mL). The combined organic layers are then washed by brine, dried (Na2SO4), filtered and concentrated. The crude residue is purified by FCC (0-40% EtOAc/Heptane) to provide the title compound. MS (ESI) m/z 443.1 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.84 (d, J=1.01 Hz, 1 H), 8.36 (d, J=9.09 Hz, 1 H), 8.06 (s, 1 H), 7.96 (d, J=3.79 Hz, 1 H), 7.89 (s, 1 H), 7.55-7.60 (m, 1 H), 7.45 (s, 1 H), 7.40 (d, J=1.01 Hz, 2 H), 7.44 (d, J=2.53 Hz, 1 H), 7.13 (dd, J=8.97, 2.40 Hz, 1 H), 6.76 (d, J=3.79 Hz, 1 H), 2.66 (s, 3 H).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH2:12][CH2:13][CH2:14][NH2:15])=[N:9][N:8]=1.I.CS[C:25]1[C:33]2[CH:34]=[CH:35][CH:36]=[C:31]3[C:32]=2[C:27](=[CH:28][CH:29]=[CH:30]3)[N:26]=1>C(O)C>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH2:12][CH2:13][CH2:14][NH:15][C:25]2[C:33]3[CH:34]=[CH:35][CH:36]=[C:31]4[C:32]=3[C:27](=[CH:28][CH:29]=[CH:30]4)[N:26]=2)=[N:9][N:8]=1
Reactant: NCCCc1nnc(-c2ccccc2-c2ccccc2)s1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: I
Solvent: CCO
Product: c1ccc(-c2ccccc2-c2nnc(CCCNC3=Nc4cccc5cccc3c45)s2)cc1

Procedure:
A solution of 3-(5-(2-biphenylyl)-1,3,4-thiadiazol-2-yl)propanamine in ethanol is treated with 2-methylthiobenz(cd)indole hydriodide by the conditions of Example 52. Neutralization yields the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)/[C:12](OC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)/[CH2:12][OH:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2ccc(C)o2)C(=O)OC)n1Cc1ccccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCc1ncc(/C=C(/CO)Cc2ccc(C)o2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-propenoate (Example 6, Method A) (1.5 mmol) in dry tetrahydrofuran (10 mL) held at -78° C. under argon is treated dropwise with a solution of diisobutyl aluminum hydride in toluene (3.30 mmol, 2.2 mL of 1.5M). The mixture is allowed to warm to ambient temperature and stirred an additional 17 hours. Excess reducing agent is quenched with methanol and water, dilute acetic acid and methylene dichloride are added, and the organic layer is washed with sodium bicarbonate solution, dried and concentrated to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([O:15][CH3:16])=[CH:12]2)=[CH:7][CH:6]=1)#[C:2][CH2:3][CH3:4].CCCCCC>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([O:15][CH3:16])=[CH:12]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC#Cc1ccc2ccc(OC)cc2c1
Agent: [Pd]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCc1ccc2ccc(OC)cc2c1
Yield: 97 %

Procedure:
Using 7-methoxy-2-naphthyltrifluoromethanesulfonate (30.63 g, 0.10 mol) and butyne gas (a product manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD., 100 g, large excess), 7-butyn-1-yl-2-methoxynaphthalene was synthesized by the same operation as that in the method for synthesizing 7-decyl-2-methoxynaphthalene according to Example 3, and subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain a light yellow oil product of 7-butyn-1-yl-2-methoxynaphthalene (18.1 g, yield of 56%). The obtained 7-butyn-1-yl-2-methoxynaphthalene (total amount) was subjected to catalytic reduction in toluene (275 ml) under a hydrogen atmosphere by adding 10% Pd/C (1.83 g). The obtained product was subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain 7-butyl-2-methoxynaphthalene (compound (3)-04, 17.80 g, yield of 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@:9]([OH:29])([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=3[N:16]=2)[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[N:30]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH3:34])=[C:31]=[O:32].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@:9]2([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[N:16]=3)[O:29][C:31](=[O:32])[N:30]([C@@H:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH3:34])[C:10]2=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@](O)(Cc1ccc(F)cc1)c1nc2cc(NS(C)(=O)=O)ccc2[nH]1
Reactant: CCCCC[C@@H](C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC[C@@H](C)N1C(=O)O[C@](Cc2ccc(F)cc2)(c2nc3cc(NS(C)(=O)=O)ccc3[nH]2)C1=O
Temperature: 70 °C

Procedure:
To a solution of (R)-ethyl 3-(4-fluorophenyl)-2-hydroxy-2-(5-(methylsulfonamido)-1H-benzo[d]imidazol-2-yl)propanoate (50 mg, 0.12 mmol) in THF (0.5 ml) at rt were added (R)-2-isocyanatoheptane (25 mg, 0.18 mmol) and NaOH (6 mg, 0.15 mmol). The mixture was heated at 70° C. for 25 min. The resulting mixture was filtered through a short plug of silica and concentrated. The resulting residue was purified by Combiflash (silica gel column, 5-35% ethyl acetate in hexane) to give the title product. LC/MS (m/z): 517.0 [M+1]; 1H NMR (400 MHz, CDCl3) δ 10.8-10.9 (d, 1H), 7.6 (t, 1H), 7.5 (s, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 6.9 (m, 2H), 3.7-3.8 (m, 2H), 3.5 (d, 1H), 2.9 (s, 3H), 1.3 (q, 2H), 0.9-1.1 (m, 5H), 0.6-0.9 (m, 7H);
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:21])[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:22])[CH3:7].[N+:23]([O-])([OH:25])=[O:24].[OH-].[NH4+]>>[CH2:6]([N:8]1[C:12]2[C:13]([N+:23]([O-:25])=[O:24])=[C:14]([Cl:21])[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:22])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CCn1c(C)nc2cc(S(C)(=O)=O)c(Cl)cc21
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1c(C)nc2cc(S(C)(=O)=O)c(Cl)c([N+](=O)[O-])c21
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To a stirred, cooled solution of 40 ml. of concentrated sulfuric acid (at 0°-5° C.) was added, dropwise, 4.0 g. (0.015 mole) of 1-ethyl-2-methyl-5-methylsulfonyl-6-chlorobenzimidazole. Stirring was continued until all solid was in solution. To this stirred and cooled solution was added 6.0 g. (0.086 mole) of 90% fuming nitric acid, dropwise, over a 30 minute period. Stirring was continued while cooling for 9 hours and then the reaction mixture allowed to warm to room temperature over a 14 hour period. An additional 13.5 g. of 30% fuming sulfuric acid was then added, dropwise. The reaction mixture was stirred for about 24 hours and then stirred at about 40° C. for an additional 64 hours. The resultant reaction mixture was poured into a stirred mixture of 300 ml. of ice +200 ml. of concentrated ammonium hydroxide. The resultant aqueous mixture was extracted thrice with 100 ml. portions of chloroform and the combined chloroform extracts dried over anhydrous sodium sulfate. The resultant chloroform solution was evaporated to dryness under reduced pressure to give 3.04 g. (73.4%) of the desired product, melting at 75°-79° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:25][C@@H:26]1[O:31][C@H:30]([CH3:32])[CH2:29][N:28]([C:33]([C:35]2[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=2)=[O:34])[CH2:27]1>O1CCCC1.CCOCC>[CH3:25][C@H:26]1[O:31][C@@H:30]([CH3:32])[CH2:29][N:28]([C:33]([C:35]2[CH:36]=[C:37]([S:41]([N:9]3[CH2:10][CH2:11][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:8]3=[O:12])(=[O:42])=[O:43])[CH:38]=[CH:39][CH:40]=2)=[O:34])[CH2:27]1
Reactant: C[C@@H]1CN(C(=O)c2cccc(S(=O)(=O)Cl)c2)C[C@H](C)O1
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)c2cccc(S(=O)(=O)N3CCC(c4ccccc4)(c4ccccc4)C3=O)c2)C[C@H](C)O1
Reaction time: 0.5 h

Procedure:
To 3,3-diphenylpyrrolidin-2-one (166 mg, 0.7 mmol; Example 1A) in anhydrous tetrahydrofuran (6 mL) was added potassium tert-butoxide (1 mL, 1.0 M in tetrahydrofuran) at room temperature followed by stirring for 30 minutes. Then the crude 3-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)benzene-1-sulfonyl chloride (0.7 mmol; Example 147A) in tetrahydrofuran (8 mL) was added slowly. The mixture was stirred at room temperature for 3 hours. Then the mixture was concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=1:1) to give crude material. The crude material was dissolved in ether (60 mL), the insoluble solid was removed, and the ether solution was concentrated to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (m, 3H), 1.10 (m, 3H), 2.83 (m, 3H), 3.30-3.60 (m, 4H), 3.80 (m, 2H), 4.37 (m, 1H), 7.00 (m, 4H), 7.20 (m, 6H), 7.71 (t, 1H, J=7 Hz), 7.88 (m, 1H), 8.00 (m, 2H); MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[N:35]=[CH:36][O:37][C:38]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:38]6[O:37][CH:36]=[N:35][C:34]=6[CH3:33])[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ncoc1C1(N)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ocnc5C)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Preparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml).
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (406 mg) was dissolved in dimethylformamide (DMF: 2 mL), ethyl bromoacetate (167 mg) was added, and potassium carbonate (138 mg) was further added. The reaction solution was stirred at room temperature overnight. After water was added carefully, ethyl acetate (100 mL) was added, followed by extraction. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Recrystallization from methanol afforded 338 mg of white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.FC(F)(F)S(O[CH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)(=O)=O>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:32][C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: O=S(=O)(OC[C@@H]1CCCCO1)C(F)(F)F
Product: CC(C)(C)OC(=O)C(C[C@@H]1CCCCO1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
570 mg (1.46 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 1.75 ml (1.75 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were reacted with 707 mg (purity 87%, 2.48 mmol, 1.7 eq.) of (2S)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate according to General Method 7B. Yield: 396 mg (57% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:13]/[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])/[CH:3]=1.[Cl:22]C1SC(S(N)(=O)=O)=CC=1>>[Cl:22][C:19]1[S:18][C:17]([S:14]([N:13]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:12])[C:2]([Cl:1])=[CH:3]2)(=[O:15])=[O:16])=[CH:21][CH:20]=1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Product: O=C1C(Cl)=CC(=NS(=O)(=O)c2ccc(Cl)s2)c2ccccc21

Procedure:
5.2.33 5-chloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (12d) was prepared according to the procedure for 12a except using 5-chlorothiophene-2-sulfonamide, which afforded the title compound 320.1 mg (43.0%) as a yellow solid, m.p.: 149-151° C.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]1[CH:14]2[CH2:15][C:16](=O)[CH:12]([CH2:13]2)[CH2:11]1>>[CH2:15]1[CH:14]2[C:10]3[C:11]([CH:12]([CH2:13]2)[CH2:16]1)=[N:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]=3[NH2:9]
Reactant: N#Cc1ccccc1N
Reactant: O=C1CC2CCC1C2
Product: Nc1c2c(nc3ccccc13)C1CCC2C1

Procedure:
Anthranilonitrile (ortho-isomer) is allowed to react with norcamphor to obtain 9-amino- 1,4-methano- 1,2,3,4-tetrahydroacridine (Formula VIa). ##STR8##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:25])[CH2:23][CH3:24])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CCC(=O)Cl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added propionyl chloride (0.07 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.07 g (63%) of product as an off-white solid: mp 222–224° C.; 1H NMR (DMSO-d6) 11.03 (s, 1H), 9.63 (s, 1H), 8.51 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 2.76–2.45 (m, 5H), 2.10–2.03 (m, 1H), 1.90 (s, 3H), 1.12 (t, J=7.5 Hz, 3H); 13C NMR (DMSO-d6) 172.70, 172.14, 172.03, 168.80, 167.37, 136.48, 135.94, 131.20, 125.59, 117.67, 116.21, 58.81, 29.71, 29.07, 28.53, 20.97, 14.74, 9.18; Anal. Calcd. For C17H17N3O5: C, 59.47; H, 4.99; N, 12.24 Found: C, 59.24; H, 5.06; N, 11.97.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)N)=[CH:5][CH:4]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:11][CH2:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:31]3[CH2:32][CH2:33][N:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=4)[CH2:29][C:30]=3[C:5]=2[CH:4]=1
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: Cc1ccc(CCN(N)c2ccc(Cl)cc2)cn1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(c2cccc(C(F)(F)F)c2)CC3)cn1
Yield: 8.5 %

Procedure:
To a stirred solution of N-(4-Chloro-phenyl)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-hydrazine hydrochloride (0.13 g, 0.5 mmol) in absolute ethanol (5 mL) was added 1-(3-Trifluoromethyl-phenyl)-piperidin-4-one (0.122 g, 0.5 mmol) at RT and then refluxed for 1 h. After completion (TLC), ethanol was evaporated. The crude was purified by preparative HPLC to provide desired compound as brown colored solid (0.02 g, 10% yield) 8-Chloro-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2-(3-trifluoromethyl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.020 g, 0.0425 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0053 g, 0.0425 mmol) in 1.5 mL THF was added and stirred for 30 min at RT. Precipitate was filtered and dried to give oxalate salt as brown solid (0.01 g, 43% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([CH:20]3[CH2:28][CH2:27][C:23]4[N:24]=[CH:25][NH:26][C:22]=4[CH2:21]3)=[O:19])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.ClCCl.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]([CH:20]3[CH2:28][CH2:27][C:23]4[N:24]=[CH:25][NH:26][C:22]=4[CH2:21]3)=[O:19])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CN(C(=O)C3CCc4nc[nH]c4C3)c3ccccc32)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(C1CCc2nc[nH]c2C1)N1CC(c2cccc(O)c2)c2ccccc21
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
In 9 ml of chloroform, 300 mg of the optically active 5-[3-(3-methoxyphenyl]indolin-1-ylcarbonyl!-4,5,6,7-tetrahydrobenzimidazole obtained in Example 24 was solved. This solution and 3.1 ml of a 1.0M dichloromethane solution of boron tribromide added thereto in a stream of argon at -78° C. were together stirred at -78° C. for three hours and further at normal room temperature for three hours. The resultant reaction solution was poured into ice water, neutralized with an aqueous sodium hydrogen carbonate solution, and then extracted with a mixed solution of chloroform and ethanol. The organic layer was dried over magnesium sulfate and then distilled. The residue of the distillation was refined by silica gel column chromatography to obtain 220 mg of optically active 5-[3-(3-hydroxyphenyl)indolin-1-ylcarbonyl]-4,5,6,7-tetrahydrobenzimidazole (76.1%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)[CH3:3].CC(C)([O-])C.[K+].N#C[Br:25]>C1COCC1>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[Br:25])[CH3:1]
Reactant: N#CBr
Reactant: CN(C)C[C@@H]1C[C@H]1c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC1CC1c1ccc2[nH]cc(Br)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
A solution of trans N,N-dimethyl-2-(indol-5-yl)cycloprop-1-yl methylamine (75 mg, 0.35 mmol), and potassium t-butoxide (29 mg, 0.35 mmol) in anhydrous THF at 0° C. was stirred at 0° C. for 30 min before cyanogen bromide (37 mg, 0.35 mmol) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo, and the residue was dissolved in water, and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N,N-dimethyl-2-(3-bromoindol-5-yl)cycloprop-1-yl methylamine (100 mg, 98%) as a colorless oil. 1H NMR (MeOH-d4): δ7.26 (d, J=8.4 Hz, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 6.94 (dd, J=8.7, 1.5 Hz, 1H), 2.58 (dd, J=6.0, 1H), 2.35 (s, 6H), 2.31 (m, 1H), 1.80 (m, 1H), 1.22 (m, 1H), 1.03 (m, 1H), and 0.88 (m, 1H). FIMS: 293.1 (M−H), reverse-phase HPLC purity: 85%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([CH2:25][C:26](=[O:28])[CH3:27])[CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)ccc23)C1
Yield: 77.8 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.009 moles), triethylamine (1.4 ml, 0.010 moles), and 1-chloro-2-propanone (0.8 g, 0.009 moles) in ethanol (50 ml) is stirred and heated to reflux. After 20 hours the mixture is cooled and the precipitate filtered off, rinsed with ethanol, and dried to give the product (1.9 g), mp 128°-129° C.