Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOC(C)=O>[CH3:28][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Yield: 97.3 %

Procedure:
In a 100 mL round bottomed flask equipped with magnetic stirring was added tert-butyl 4-{2-[(methylsulfonyl)-amino]phenyl}-piperazinecarboxylate (Preparation III) (692 mg, 1.947 mmol) and DMF (5 mL). After stirring 5 min, NaH (60% oil dispersion) (100 mg, 2.5 mmol) (Aldrich) in DMF (10 mL) was added. The reaction was stirred 20 min, then iodomethane (190 μl, 3.05 mmol) (Aldrich) was added via syringe. After stirring 2.5 h, the reaction was diluted with 150 mL EtOAc and washed 75 mL each, satd NH4Cl, H2O, 10% NaHCO3 and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-{2-[methyl(methylsulfonyl)amino]phenyl}piperazine-carboxylate (700 mg). MS (ESI, pos. ion) m/z: 370(M+H), (ESI, neg. ion) m/z: 368 (M−H). Calc'd for C17H27N3O4S: 369.48.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][CH2:4][NH:3]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[O:1]=[C:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][NH:3]1
Reactant: COC(=O)C1CCNC1=O
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C1CCNC1=O
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A flask was charged with methyl 2-oxopyrrolidine-3-carboxylate (500 mg, 3.49 mmol), potassium trimethylsilanolate (1344 mg, 10.48 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then HCl (20 mL, 2.0M in Et2O) was added and the mixture was stirred for 30 minutes. Then the mixture was filtered to remove the solid and the solvent was removed under reduced pressure to give the crude product (188.7 mg, 41.84%), which was used for next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH:2]1[CH:3]([OH:5])[CH3:4].Cl.[SH:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]>C(Cl)Cl.C[O-].[Na+]>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][S:8][CH2:6][CH:2]([OH:1])[CH:3]([OH:5])[CH3:4]
Reactant: COC(=O)CCS
Reactant: CC(O)C1CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCSCC(O)C(C)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To a solution of 3,4-epoxy-2-butanol as obtained in Reference Example 43 (1.13 g) in methylene chloride (4 ml), methyl 3-mercaptopropionate (2.00 ml) and sodium methylate (260 μl) were added under ice cooling conditions, followed by stirring at room temperature for 1 day. To the reaction mixture, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate; the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1) to yield the title compound (1.47 g, yield 55%) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])#[N:13]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C(=O)O)ccc1C#N
Temperature: 90 °C

Procedure:
4-Bromo-3-methylbenzoic acid (3.0 g) was dissolved in N,N-dimethylformamide (20 ml). The resulting solution was subjected to deaeration three times under argon atmosphere (i.e., the reaction solution was de-pressurized to 20 mmHg, and then brought back to atmospheric pressure under argon atmosphere). To the solution, zinc cyanide (1.6 g) and tetrakis(triphenylphosphine) palladium (0) (1.6 g) were added and the mixture was stirred under heating at 90° C. for 6 hours under argon atmosphere. After adjusting to room temperature, precipitates were filtered off. The filtrate was diluted with water, added with lithium hydroxide monohydrate (2.9 g) and washed twice with tert-butyl methyl ether. The aqueous phase was acidified with 2N hydrochloric acid and extracted twice with ethyl acetate. The organic phases were combined, washed with brine and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 4-cyano-3methylbenzoic acid as a crude product (1.9 g). Without further purification, the crude product was used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].Cl.Cl[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]1.[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH:4]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]1)[C:5]#[N:6]
Reactant: CN1CCCC(CCl)C1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1CCCC(CC(C#N)c2ccc(Cl)cc2Cl)C1

Procedure:
This intermediate (7.6 g.) was prepared using the procedure described in Example 14a except using 10 g. (0.054 mole) of 2,4-dichlorobenzyl cyanide, 10 g. (0.054 mole) of 3-chloromethyl-1-methylpiperidine hydrochloride, 11 g. (0.135 mole) of aqueous 50% sodium hydroxide, and 100 ml. of DMSO to yield an oil boiling 160°-165° C. at 5 mm of Hg.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:24][C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([O:22][CH2:24][C:25](=[O:26])[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: CC#N
Product: O=C(Cc1ccc(OCc2ccc3ccccc3n2)cc1)OCC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.6 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (2.0 g, 0.006 mol) in acetonitrile (200 mL) were added TEA (1.74 mL, 0.01 mol), and 2-bromo-1-(pyridin-3-yl)ethanone (3.42 g, 0.017 mol) under an inert atmosphere. The reaction mixture was then stirred at RT for 16 h, concentrated in vacuo and the residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2-oxo-2-(pyridin-3-yl)ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (1.5 g, 54%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][O:11][CH2:12][CH2:13][CH2:14][C:15](OC)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]([CH2:14][CH2:13][CH2:12][O:11][CH3:10])=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(Br)cn1
Reactant: COCCCC(=O)OC
Product: COCCCc1nnc2ccc(Br)cn12

Procedure:
A mixture of 18.80 g of (5-bromopyridin-2-yl)hydrazine [77992-44-0] and 14.54 g of methyl 4-methoxybutyrate [29006-01-7] is heated to reflux over 16 hours. The reaction solution is subsequently cooled and purified by means of flash chromatography (SiO2 60F). The title compound is identified on the basis of the Rf value.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH2:9]([N:11]=[C:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:20])=[CH:13]1)[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([N:11]([CH2:9][CH3:10])[C:12]1[CH:13]=[C:14]([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH:17]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCN=C1C=C(C)CC(C)(C)C1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(C(=O)COC(C)=O)C1=CC(C)(C)CC(C)=C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 1076.8 %

Procedure:
2-Acetoxyacetyl chloride (6.42 g, 4.7 mmol) is added slowly to a mixture of 1A (7.62 g, 4.2 mmol) and toluene (50 ml), which is cooled to −5° C. After the addition is complete, the mixture is stirred for a further 1 hour at −5° C., then allowed to warm to room temperature and stirred for a further 1.5 hours. The reaction mixture is then cooled down to −3° C. and a mixture of triethylamine (6.5 ml, 4.7 mmol) and toluene (25 ml) is added slowly to the mixture. The mixture is stirred for a further 16 hours, during which time the temperature is gradually allowed to rise to room temperature. The mixture is filtered, and the filtrate is washed three times with water, dried over sodium sulfate and evaporated in vacuo to give the crude product (12.0 g, 89%) as an oil. A portion of this crude material (4 g) is purified by flash column chromatography, eluting with a mixture of ethyl acetate and petroleum ether (1:4) to give pure product (2.3 g, equivalent to 51% overall), with m.p. 38-40° C. NMR analysis of this indicates that the product has a purity of about 88 mol %, the impurity consisting mainly of two isomeric products.
Reaction SMILES: [CH2:1]([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:38]1([C:46](=O)[CH2:47]Cl)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:46][CH2:47][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCCCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 127.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 1-azocan-1-yl-2-chloroethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (20 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:32]3[CH:31]=[N:30][C:29]([N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)=[CH:34][CH:33]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CCN4)cn2)CC1
Yield: 16 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg) was coupled to 1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a light brown solid (16% yield). M.p.=219° C., LCMS: m/z=471.12 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (3H, s), 2.54 (4H, t, J=5.1 Hz), 3.27 (2H, t, J=4.8 Hz), 3.51 (2H, t, J=4.7 Hz), 3.59 (4H, t, J=5.1 Hz), 4.50 (2H, d, J=1.0 Hz), 5.01 (1H, bs), 6.70 (1H, d, J=8.8 Hz), 7.03 (2H, m), 7.11 (1H, m), 7.61 (1H, dd, J=8.8, 2.5 Hz), 7.64 (1H, d, J=1.8 Hz), 8.35 (1H, d, J=2.3 Hz).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:39])([F:40])[C:35]([F:37])([F:38])[F:36])=[CH:32][CH:33]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-bromo-4-(perfluoroethyl)benzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:23]=O)[CH:6]=[CH:5]2.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[NH2:26]>CCO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:23]=[N:26][NH:25][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH:6]=[CH:5]2
Reactant: NNc1ccccn1
Reactant: CC(C)[Si](Oc1cc(F)cc2ccc(C=O)nc12)(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)[Si](Oc1cc(F)cc2ccc(C=NNc3ccccn3)nc12)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 73.8 %

Procedure:
6-Fluoro-8-(triisopropylsilyloxy)quinoline-2-carbaldehyde (15.0 g, 43.2 mmol) and 2-hydrazinylpyridine (4.71 g, 43.2 mmol) were combined in 100 mL of anhydrous EtOH, and stirred at ambient temperature over night. Following over night stirring, the desired product was collected by filtration (washing with cold EtOH), affording 6-fluoro-2-((2-(pyridin-2-yl)hydrazono)methyl)-8-(triisopropylsilyloxy)quinoline (14.0 g, 31.9 mmol, 74% yield) as a yellow-white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: O=[N+]([O-])O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
9H-β-carboline-3-carboxylic acid ethyl ester (20 g, 833 mmol) was slowly added to concentrated nitric acid (400 mL). The reaction mixture was stirred at 70°-75° C. for 2 h. After cooling to room temperature the resulting mixture was poured onto ice (1 kg). The precipitated compound was collected, and recrystallized from pyridine (650 mL). This afforded the title compound (14.9 g, 63%). M.p. 339°-341° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[CH3:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1
Reactant: C#CCCO
Product: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(-n3cc(CCO)nn3)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 445 (0.03 mmol) and but-3-yn-1-ol (0.06 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 100:0 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.7, 149.5, 146.2, 141.1, 138.2, 136.4, 135.7, 134.7, 134.1, 132.6, 131.2, 130.8, 127.4, 127.2, 125.6, 122.1, 120.7, 120.1, 115.8, 112.4, 61.5, 28.6, 19.9, 17.9
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30](=[O:33])(=[O:32])[NH2:31])=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:8]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:31][C:1](=[O:3])[CH3:2])(=[O:33])=[O:32])=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.11 ml (1.10 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 438 mg (1.00 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 456 mg (yield: 96.0%) of the title compound.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]([CH3:26])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[CH3:26][N:16]1[C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:27])=[O:5])=[CH:8][N:9]=2)=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:18]=[N:17]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A solution of lithium hydroxide monohydrate (51 mg, 1.22 mmol) in water (1.5 mL) was added dropwise to a suspension of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid methyl ester (199 mg, 0.61 mmol) in THF (1.5 mL) and MeOH (0.3 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (162 mg, 70%) as a white solid. MS: m/e=310.3 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([C@@H:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH3:21])[C:18](=O)[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1.O=P(Cl)(Cl)Cl.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN1C(=O)CCC1.CS(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([C@@H:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH3:21])[C:18]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n([C@H](C)c3ccccc3)c12
Solvent: CN1CCCC1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CS(C)=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N3CCOCC3)n([C@H](C)c3ccccc3)c12
Temperature: 100 °C
Yield: 0.75 %

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (for a preparation see Intermediate 11) (0.16 g, 0.386 mmol) was dissolved in POCl3 (1 ml, 10.73 mmol) and heated at 100° C. for 3 days. The reaction mixture was evaporated in vacuo to give a black gum. The residue was dissolved in NMP (2 ml) and morpholine (2 ml, 22.96 mmol) was added, then the solution was heated in the microwave at 150° C. for 1 h. The reaction mixture was loaded onto a 20 g SCX-2 cartridge and washed through with methanol (40 ml), then eluted with 2M methanolic ammonia and the eluant evaporated in vacuo to give an amber oil. This was dissolved in DMSO (1 ml) and purified by MDAP (HpH) to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-2-(4-morpholinyl)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (1.4 mg, 2.90 μmol, 0.750% yield). LCMS (formate) Rt 0.86 min, MH+ 484
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][C:17]1[CH:18]=[C:19]([CH3:35])[C:20]2[NH:21][C:22](=O)[C:23]3[CH:33]=[CH:32][CH:31]=[N:30][C:24]=3[N:25]([CH2:28][CH3:29])[C:26]=2[N:27]=1.C(Cl)Cl.[CH:39]([N:42](C(C)C)CC)(C)C>[C-]#N.C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[C:39]([C:22]1[C:23]2[CH:33]=[CH:32][CH:31]=[N:30][C:24]=2[N:25]([CH2:28][CH3:29])[C:26]2[N:27]=[C:17]([CH3:16])[CH:18]=[C:19]([CH3:35])[C:20]=2[N:21]=1)#[N:42]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(C)nc21
Reactant: CCN(C(C)C)C(C)C
Agent: CC[N+](CC)(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [C-]#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(C#N)=Nc2c(C)cc(C)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluorornethanesulfonic anhydride (0.24 mL, 14 mmol) was added to a solution of 0.314 g (1.2 mmol) 5,11-dihydro-2,4-dimethyl-11-ethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine-6-one in 15 mL of methylene chloride containing 0.25 mL (14 mmol) of diisopropylethylamine. The resulting mixture was refluxed under Ar for 3 hr. Ethyl acetate (~200 mL) was then added and the solution was washed three times with water and four times with brine. After drying (magnesium sulfate), the solution was concentrated in vacuo and the residue dried under high vacuum for 2 hr. The residue was dissolved in 20 mL of methylene chloride, and 0.23 g (14 mol) of tetraethylammonium cyanide was added. After stirring the resulting solution overnight at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate, and the solution washed with water and brine, and then dried (magnesium sulfate). The solution was concentrated in vacuo and the residue was chromatographed over silica (eluted with 5% ethyl acetate/hexane). The resulting solid was crystallized from heptane to provide 33 mg of the title compound as red crystals, m.p. 154°-155° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH:35]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([N:13]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:32]([Cl:31])[CH:33]=2)[CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(Cl)c(Cl)c1)C1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 4.4 %

Procedure:
To a mixture of 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (0.1 mmol) and 3,4-dichloro-benzaldehyde (0.15 mmol) in 2 mL of CH2Cl2 stirring at rt, was added NaBH(OAc)3 (0.15 mmol) and NEt3 (0.3 mmol), and then the resulting mixture was stirred overnight. After purification through preparative HPLC, 2.5 mg of 2-(4-{1-benzyl-4-[(3,4-dichloro-benzyl)-methyl-amino]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile was obtained as colorless oil in 4.8% yield.