Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.[CH2:3]([C:6]1[CH:7]=[C:8]([N:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH2:13])[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5].[O-:19][C:20]#[N:21].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:21][C:20]([NH:13][N:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:3][CH2:4][CH3:5])[CH:7]=1)=[O:19]
Reactant: N#C[O-]
Reactant: CCCc1cccc(N(N)CC(=O)OC)c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cccc(N(CC(=O)OC)NC(N)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
The hydrazine (Intermediate 33; 910 mg, 4.1 mmol) was dissolved in dry toluene (30 ml) under nitrogen at room temperature. Sodium cyanate (880 mg, 13.5 mmol) was added to the reaction mixture, followed by trifluoroacetic acid (0.95 ml, 12.3 mmol). The reaction was stirred at room temperature for 3 h, then poured into sodium bicarbonate solution (30 ml, 8%) and extracted with ethyl acetate (3×75 ml). The combined dried (Na2SO4), organic phases were concentrated in vacuo to give a yellow oil. The crude material was triturated with ether and hexane to give the title compound (Intermediate 34; 500 mg, 46%) as a white powdery solid m.p. 111°-116°.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]3[NH:33][CH:34]=[CH:35][N:36]=3)[CH2:24][C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:39]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:1]1([N:7]([CH3:39])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:31][C:32]3[NH:33][CH:34]=[CH:35][N:36]=3)[CH2:24][C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC2CCCCC2)cc1)Cc1ncc[nH]1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCCNS(=O)(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The compound (69.5 mg) obtained in Example 102-5 was treated with an anion-exchange resin (Amberlite IRA-410), and the treated product was dissolved in anhydrous methanol (2.7 ml). The solution was added with a 36% formaldehyde aqueous solution (0.025 ml). Subsequently, the solution was added with sodium cyanoborohydride (20.7 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 20 hours. After the reaction, the solution was added with a 1 mol/l sodium hydroxide aqueous solution (1.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate. The solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (34.8 mg) of the subject compound as a white solid.
Reaction SMILES: Cl.N[C:3]1[C:4]2[C:5](=[N:15][N:16]([CH3:18])[CH:17]=2)[NH:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[N:9]=1.C(=O)([O-])[O-:20].[K+].[K+]>C(O)C.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[NH:6][C:5]3=[N:15][N:16]([CH3:18])[CH:17]=[C:4]3[C:3](=[O:20])[NH:9][C:8]=2[CH:10]=1
Reactant: Cn1cc2c(n1)Nc1ccc(Cl)cc1N=C2N
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1cc2c(n1)Nc1ccc(Cl)cc1NC2=O

Procedure:
4-Amino-7-chloro-2,10-dihydro-2-methylpyrazolo[3,4-b][1,5]benzodiazepine hydrochloride (11.3 g) and potassium carbonate (16.8 g) were heated under reflux in a mixture of ethanol (200 ml) and water (20 ml) for 48 hours. Water (300 ml) was added and the solution cooled. The precipitate was crystallised from acetic acid to give the title compound m.p.>260° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].O.[Se](=O)=[O:15]>O1CCOCC1>[CH3:1][S:2]([NH:5][C:6]1[C:7]([CH:12]=[O:15])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: Cc1ncccc1NS(C)(=O)=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)Nc1cccnc1C=O
Yield: 83.6 %

Procedure:
To a solution of 3-methylsulfonamido-2-methylpyridine (310 mg, 1.66 mmol) in dioxane (8 mL) was added water (0.8 mL) and selenium(IV) oxide (241 mg, 2.17 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ethyl acetate, 1:1) to afford the title compound (278 mg, 83%). 1H NMR (CDCl3) □ 3.14 (s, 3H), 7.53 (dd, 1H, J=9, 6 Hz), 8.16 (dd, 1H, J=9, 3 Hz), 8.53 (dd, 1H, J=6, 3 Hz), 10.09 (s, 1H), 10.41 (br s, 1H, NH).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(O)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-Hydroxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[C-:11]#[N:12].[Na+]>O>[C:11]([C:4]1([OH:10])[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH2:3]1)#[N:12]
Reactant: [C-]#N
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC1(O)CN2CCC1CC2
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a cooled (ice bath), stirred solution of 3-quinuclidinone hydrochloride (300 g) in water (400 ml) was added dropwise a solution of sodium cyanide (90.97 g) in water (400 ml). After stirring at ice bath temperature for three hours the precipitate was collected by filtration, washed with water and dried under vacuum to afford the title compound (282 g); m.p. 153°-157° C. (lit m.p. 152°-155° C.; Helv. Chim. Acta., 1954, 37, 1689).
Reaction SMILES: [F:1][C:2]([F:29])([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:49]C(Br)(Br)Br>ClCCl>[F:1][C:2]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11][Br:49])([F:29])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(F)ccc1OC(F)(F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(OC(F)(F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(CBr)c1
Yield: 81 %

Procedure:
220 mg (0.53 mmol) of (2-{difluoro-[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-5-fluorophenyl)-methanol from Example 40A, 154 mg (0.59 mmol) of triphenylphosphine and 194.6 mg (0.59 mmol) tetrabromomethane are stirred in 5 ml dichloromethane at RT for 12 hours. 2 g of silica gel are added to the reaction mixture, and the mixture is then dried in vacuo and purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 217 mg (0.46 mmol, 95% purity, 81% yield) of a solid are isolated.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:21]/[CH:22]=[O:23])=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccnc2ccccc12
Product: O=C/C=C/c1ccnc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-quinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[C:24]#[N:25].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)(C)C>O1CCCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH:1]([CH3:6])[CH3:2])[C:24]#[N:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc(O)c(Cl)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(C#N)cc1Cl
Yield: 95.9 %

Procedure:
Into a round bottom flask containing triphenylphosphine (27.3 g, 104 mmol) and 3-chloro-4-hydroxy-benzonitrile (10 g, 65 mmol) was added anhydrous tetrahydrofuran (600 mL). The mixture was stirred briefly under nitrogen, di-tert-butyl azodicarboxylate (24 g, 104 mmol) was then added. The mixture was stirred for a few minutes, followed by addition of anhydrous isopropanol (6.23 mL, 81.4 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen. The crude product was purified by flash chromatography using 1:4 (v/v) ethyl acetate/heptane as eluent. Fractions were dried to give 3-chloro-4-isopropoxy-benzonitrile (12.2 g, 91%) as a red-orange semi-solid.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH:36]1[CH:37]=[CH:38][C:39]2[N:44](O)N=[N:42][C:40]=2[CH:41]=1.O>CN(C=O)C>[NH2:42][C:40]1[CH:41]=[CH:36][CH:37]=[CH:38][C:39]=1[NH:44][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:5][NH:4][CH:1]2[CH2:2][CH2:3]2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(C=C(CNC2CC2)c2ccc(F)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)c1ccc(C=C(CNC2CC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
To a solution of 4-(3-(cyclopropylamino)-2-(4-fluorophenyl)prop-1-en-1-yl)benzoic acid (0.4 g, 1.3 mmol) in DMF (5 mL), EDCl (0.49 g, 2.6 mmol), HOBt (0.175 g. 1.3 mmol) and TEA (0.54 mL, 3.9 mmol), were added, followed by n-phenylenediamine (0.280 g, 2.6 mmol). The reaction mixture was stirred at room temperature for 2 hours, subsequently the residue was poured into water and extracted with ethyl acetate (300 mL) and washed with water (3×50 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the crude compound. The obtained compound was purified with flash chromatography using 15% ethyl acetate/hexane as the eluent, pure fraction evaporated to afford title compound (0.040 g, 9% yield). 1H NMR (DMSO-d6) δ (ppm): 0.24-0.25 (2H, m, —CH2), 0.37-0.39 (2H, m, —CH2), 2.13-2.14 (1H, m, —CH), 3.57 (2H, s, —CH2), 4.86 (2H, s, —NH2), 6.55-6.59 (1H, t, Ar—H), 6.70 (1H, s, ═CH), 6.74-6.76 (1H, d, Ar—H), 6.93-6.95 (1H, t, Ar—H), 7.02-7.04 (2H, m, Ar—H), 7.10-7.12 (1H, d, Ar—H), 7.16-7.26 (4H, m, Ar—H), 7.74-7.76 (2H, d, Ar—H), 9.52 (1H, s, —NH), MS m/z: 402.2 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C([SiH](CC)CC)C>C(Cl)Cl.FC(C(O)=O)(F)F>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH2:13][NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH2:22])=[CH:16][CH:17]=2)=[CH:11][N:12]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(NCc2cnc(Nc3ccccn3)s2)cc1

Procedure:
A solution of 2-(pyridine-2-ylamino)-thiazole-5-carbaldehyde (0.10 g, 0.49 mmol, WO2004/001059), benzene-1,4-diamine (0.105 g, 0.97 mmol) and triethylsilane (0.19 mL, 1.2 mmol) in CH2Cl2-TFA (3:1, 4 mL) was stirred at ambient temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The organic phase was washed with saturated aqueous NaHCO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The crude product which contained the title compound along with the starting aldehyde and benzene-1,4-diamine was carried on directly into the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(OCc2ccccc2)c1

Procedure:
A mixture of methyl 3-benzyloxybenzoate (23.9 g; 0.099 mol), potassium hydroxide (8.42 g; 0.15 mol) and methanol (100 cm3) was stirred at room temperature until a small sample in water gave a clear solution (−18 hrs). The solution was then evaporated to dryness and the colourless solid residue dissolved in water (100 cm3) and the resulting stirred solution was acidified slowly with 50% sulphuric acid (30 cm3). After stirring for ˜30 minutes, the crystalline precipitate was filtered, washed with water and dried in vacuo at 40° to give the title compound as a colourless powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:29][CH:30]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCOC1CCCCO1
Reactant: O=C(O)Cc1ccc(O)cc1
Product: COc1cc2c(Oc3ccc(CC(=O)O)cc3)ncnc2cc1OCCOC1CCCCO1
Yield: 74 %

Procedure:
Using an analogous procedure to that described in the portion of Note [1] above that is concerned with the preparation of starting materials, 4-chloro-6-methoxy-7-(2-tetrahydropyran-2-yloxyethoxy) quinazoline was reacted with 2-(4-hydroxyphenyl)acetic acid to give 2-{4-[6-methoxy-7-(2-tetrahydropyran-2-yloxyethoxy)quinazolin-4-yloxy]phenyl}acetic acid in 74% yield; 1H NMR: (DMSOd6) 1.5 (m, 4H), 1.7 (m, 2H), 3.45 (m, 1H), 3.6 (s, 2H), 3.8 (m, 2H), 3.95 (s, 3H), 4.0 (m, 1H), 4.35 (m, 2H), 4.7 (s, 1H), 7.25 (d, 2H), 7.35 (d, 2H), 7.4 (s, 1H), 7.55 (s, 1H), 8.55 (s, 1H); Mass Spectrum: M+H+ 455.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>CN(C=O)C.CCOCC>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[C:17]=1[C:18]#[N:19])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: N#Cc1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(CCOc1cccc(Cl)c1C#N)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N-benzyl-N-methylethanolamine (145 g) in dry DMF (500 ml) was added dropwise to a stirred suspension of sodium hydride (35.15 g of a 60% dispersion in mineral oil) in dry DMF (1000 ml) over 20 minutes under nitrogen. The mixture was heated on a steam bath for 30 minutes to give a solution. The solution was cooled to ambient temperature and a solution of 2-chloro-6-fluorobenzonitrile (136.7 g) in dry DMF (300 ml) was added over 30 minutes with stirring. The mixture was heated on a steam bath for 3 hours with stirring and distilled at approximately 13 mbar to remove 1 liter of DMF. The residue was cooled to ambient temperature and poured into ice (2 l), basified with 5M sodium hydroxide solution to pH 14 and extracted with dichloromethane to give an oil. This oil was dissolved in ether (2 l) and washed with water (4×200 ml). The ether solution was extracted with 2M hydrochloric acid (500 ml) which gave three layers in the separating funnel. The bottom two layers were run off and the top ether layer was extracted with 2M hydrochloric acid (2×250 ml). The combined acidic layers were basified with concentrated sodium hydroxide solution with cooling and then extracted with dichloromethane to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-6-chlorobenzonitrile as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:35]=[N:36][S:37][CH:38]=2)=[CH:30][CH:29]=1>CC(N(C)C)=O>[S:37]1[CH:38]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][CH:30]=2)[N:35]=[N:36]1
Reactant: BrCc1ccc(-c2csnn2)cc1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4csnn4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
In a 4 mL vial were placed ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (64.8 mg, 0.250 mmol), cesium carbonate (81 mg, 0.250 mmol), and 4-(4-(bromomethyl)phenyl)-1,2,3-thiadiazole (63.8 mg, 0.250 mmol). DMA (1 mL) was added and the reaction was stirred at room temperature overnight. The solid was removed by filtration and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (42.7 mg). LCMS m/z=434.2 [M+H]+.
Reaction SMILES: [CH:1]1([O:4][C:5]2[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.O[C@H:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18]>>[CH2:2]1[CH2:3][CH:1]1[O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C@@H:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])=[CH:7][CH:6]=1
Reactant: Oc1ccc(OC2CC2)nc1
Reactant: O=C1NCC[C@@H]1O
Product: O=C1NCC[C@H]1Oc1ccc(OC2CC2)nc1

Procedure:
Typical Procedure 3 was followed. Reaction of 6-cyclopropoxy-pyridin-3-ol and (S)-3-hydroxy-pyrrolidin-2-one provided the title compound. MS ESI+: m/z=235 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[C:11]1(=O)[O:16][CH2:15][CH2:14][CH2:13][CH2:12]1>Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C1CCCCO1
Agent: Cl
Product: OCCCCc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 135 °C
Yield: 86.7 %

Procedure:
4,5-Dichlorobenzene-1,2-diamine (5.018 g, 28.4 mmol) was dissolved in HCl solution (4 M solution) (25 ml) at r.t. and delta-valerolactone (5.3 ml, 56.7 mmol) was added slowly. The reaction was heated to 135° C. for 2 hrs then slowly cooled to r.t. The reaction was quenched by the addition of sat. NaHCO3 solution (200 ml) until the pH was 8. The mixture was extracted with EtOAc (3×100 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product as a brown solid which was triturated with ether (100 ml) to give the pure product as a purple solid (6.383 g, 87%): MS (ESI+) for C11H12Cl2N2O m/z 259.1 [M+H]+; LC purity 89% (ret. time, 1.23 min); 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 2H), 3.55 (t, J=6.38 Hz, 2H), 2.86 (t, J=7.57 Hz, 2H), 1.84 (quin, J=7.68 Hz, 2H), 1.43-1.69 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)[C:24]1=[S:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: CCCCc1ccc(N=C=S)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(N2C(=O)CN(Cc3ccccc3)C2=S)cc1
Yield: 75.4 %

Procedure:
A mixture of N-benzyl glycine (8.7 g), 4-n-butylphenyl-isothiocyanate (8.55 g), triethyl amine (5.5 g) and chloroform (150 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (300 mL) and water (2×200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethyl acetate afforded the title compound (11.4 g) as an off-white solid, m.p. 149°-151° C. Anal. Calcd. for. C20H22N2O S: C, 70.97; H, 6.55; N, 8.28. Found: C, 70.81; H, 6.76; N, 8.32. Mass spectrum (EI, M.+) m/z 338.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:12]([O:20][C:1]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)c1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Next, a solution of the above terephthalaldehydic acid chloride (20 g) dissolved in toluene (100 ml) was dropwise added to a solution of 1-octanol (20 g) dissolved in pyridine (150 ml), followed by heating the mixture on a water bath at 60° C. with stirring, allowing to stand overnight, thereafter adding toluene (500 ml), adding 6N hydrochloric acid, separating the liquid layer, washing with an aqueous solution of 2N NaOH, washing with water, drying, distilling off toluene, and further distilling under reduced pressure to obtain p-octyloxycarbonylbenzaldehyde (166°~167° C./4 mmHg) (22 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.CC(=O)CC.[I-:21].[Na+]>C(OC(=O)C)C>[I:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCCCCCI)cc1
Reaction time: 6 h
Yield: 98.9 %

Procedure:
While 50 g of 4-(5-chloro-pentoxy)-benzonitrile (8) prepared in Example 5 were added to 500 ml of 2-butanone and stirred, 167 g of sodium iodide were added. Subsequently, the reaction temperature was gradually increased and stirring was continued at 70-80° C. for 6 hr. After the reaction was completed, the reaction temperature was decreased to room temperature, and the resultant reaction mixture was added with 1 L of ethylacetate, and then washed with water and brine. The ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residual solution was crystallized with methylalcohol, thus obtaining 69.7 g (yield: 99%) of a title compound as a white solid.