Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH: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.[NH2:32][CH2:33][C@H:34]([OH:36])[CH3:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:36][C@H:34]([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: C[C@@H](O)CN
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Reaction time: 15 h
Yield: 83.9 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (51.4 g, 115 mmol) synthesized in Example (106c) was dissolved in methanol (600 mL), and (R)-(−)-1-amino-2-propanol (19.9 mL, 253 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (63.7 g, 230 mmol) were added, followed by stirring for 15 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and water (500 mL) was added, followed by extraction twice with ethyl acetate (500 mL). Subsequently, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=25%-67%) to afford the desired compound (48.7 g, yield 84%) as a white solid.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([OH:6])[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]12.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:16][CH2:15][CH2:14][O:6][CH:4]1[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]2[O:1][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1COC2C(O)COC12
Reactant: BrCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1COC2C(OCCOCc3ccccc3)COC12
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
To a suspension of hexahydrofuro[3,2-b]furan-3,6-diol (7.50 g, 51.37 mmol) in anhydrous DMF (100 mL) was added sodium hydride (60% mineral oil suspension, 2.90 g, 72.39 mmol) at 0° C. in portions under the nitrogen atmosphere. Then the mixture was moved to room temperature and stirred for 15 min. To the mixture was added 2-bromoethoxymethylbenzene (12.26 g, 56.97 mmol), and then the mixture was stirred at 115° C. overnight. The mixture was quenched with water (100 mL), and extracted with DCM (300 mL×3). The combined organic phases were washed with brine (200 mLx3), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as brown liquid (3.90 g, 27%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21](Cl)=[C:20](Cl)[N:19]=[C:18](Cl)[C:17]=2Cl)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+]>CO.C1COCC1.[Pd]>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)CC1
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNc2ccncc2)CC1
Reaction time: 30 h
Yield: 58.9 %

Procedure:
To a stirred solution of 1-Boc-4-[(2,3,5,6-tetrachloropyrid-4-ylamino)methyl]piperidine (2.5 g, 5.83 mmol) in a mixture of methanol (23 mL) and THF (23 mL) was added sodium methoxide (1.89 g, 35 mmol) and 5% palladium on carbon (1.24 g). The mixture was hydrogenated for 30 h and the cataylst was filtered off and the solution concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water and satd sodium bicarbonate. The aqueous washes were back extracted with ethyl acetate, and the combined organics dried (MgSO4) and concentrated in vacuo to give the product (1.0 g, 59%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1.[C:22]([NH2:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:15]([NH:31][C:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23])=[O:16])[CH2:2]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CN2CCC1CC2
Reactant: CC(C)(N)c1ccccc1
Product: CC(C)(NC(=O)NC1CN2CCC1CC2)c1ccccc1
Yield: 12.2 %

Procedure:
Using general procedure C, quinuclidin-3-amine (102 mg, 0.6 mmol), CDI (131 mg, 0.789 mmol) and cumylamine (95 mg, 0.70 mmol) gave the title compound as a white solid (21 mg, 10%). 1H NMR (400 MHz, CDCl3) δ 7.61-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.34-7.28 (m, 1H), 4.86 (s, 1H), 4.20 (d, J=7.3 Hz, 1H), 3.71-3.60 (m, 1H), 3.14 (ddd, J=2.3, 9.4, 14.2 Hz, 1H), 2.79-1.89 (m, 6H), 1.64 (d, J=3.3 Hz, 6H), 1.58-1.10 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.4, 146.2, 129.3, 127.8, 125.8, 57.1, 54.9, 47.7, 47.1, 46.7, 30.6, 30.5, 26.0, 20.3 ppm. Purity: 79% UPLCMS (210 nm); retention time 0.61 min; (M+1) 288.2.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@@:19]3([CH3:26])[C:23](O)=[O:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][CH:33]=1)=[O:31].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([C:30](=[O:31])[CH2:29][NH:28][C:23]([C@:19]2([CH3:26])[CH2:20][CH2:21][CH2:22][N:18]2[C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])=[O:24])=[CH:33][CH:34]=1
Reactant: C[C@@]1(C(=O)O)CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@]1(C(=O)NCC(=O)c2ccc(Br)cc2)CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 102 %

Procedure:
To (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (intermediate LS30; 1.5 g; 4.3 mmol) in 50 mL DMF was added sequentially 2-amino-1-(4-bromophenyl)ethanone hydrochloride (1.2 g; 4.7 mmol), HOAT (290 mg; 2.1 mmol), Hunig's base (0.7 mL; 4.3 mmol) and EDCI (1.2 g; 6.4 mmol). After 1 h, the reaction mixture was poured into 150 mL water and allowed to stir for 15 min before filtering the resultant precipitate which was dissolved in dichloromethane and dried over magnesium sulfate. The dichloromethane mixture was filtered and applied to a Biotage 40 samplet. Chromatography on a 40M column (25 to 60% ethyl acetate/hexane over 1200 mL) provided (S)-(9H-fluoren-9-yl)methyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate (intermediate LS31; 2.4 g; quant) as a yellow foam. LC (Cond'n 11): RT=3.75 min; MS: Anal. Calcd. for [M+H]+ C29H27BrN2O4: 547.1; found 547.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:6](=[O:23])[NH:7][C:8](=[O:22])[NH:9][C:10]=1[CH:11](C#N)[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[CH3:4].C1(C)C=CC(S(O[CH2:34][CH:35]2[CH2:39][CH:38]=[CH:37][CH2:36]2)(=O)=O)=CC=1.[O:41]=O>CN(C)C=O.O>[CH:35]1([CH2:34][N:9]2[C:10]([C:11](=[O:41])[C:12]3[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:5]([CH2:3][CH3:4])[C:6](=[O:23])[NH:7][C:8]2=[O:22])[CH2:39][CH:38]=[CH:37][CH2:36]1
Reactant: O=O
Reactant: CCc1c(C(C#N)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CC=CC2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
480 mg of 60% sodium hydride (12.0 mmol) was slowly added to 2.83 g of 5-ethyl-6-(α-cyano-3,5-dimethylbenzyl)-2,4-pyrimidinedione (10.0 mmol) dissolved in 50 ml of dimethyl formamide, and the mixture was stirred at room temperature for one hour. Then, to the resulting solution, 5.07 g of (cyclopent-3-en-1-yl)methyl para-toluenesulfonate (20.0 mmol) was added and stirred with injecting oxygen at 50˜60° C. for 48 hours. After cooling, 200 ml of distilled water was added to the resulting product, and extracted with 200 ml of ethyl acetate (2 ×). The obtained extract was dried with anhydrous magnesium sulfate and concentrated under the reduced pressure. Then, the concentrated residue was separated and purified with column chromatography (hexane:ethyl acetate=2:1) to obtain 2.52 g of the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O.C(OCC)(=O)C>CO.CCCCCC.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccncc1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: Cc1ccncc1Nc1ccccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
10% Pd/C (100 mg) was charged portion wise to a solution of (4-methyl-pyridin-3-yl)-(2-nitro-phenyl)-amine (I-171a: 600 mg, 2.62 mmol) in methanol (15 mL) under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The reaction was monitored by TLC (80% ethyl acetate in hexane). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 525 mg of the product (98.91% yield).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:14][OH:15])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13].C(N(CC)CC)C.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[OH:1][CH2:2][CH:3]([CH2:14][O:15][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn(CCC(CO)CO)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(CCC(CO)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a solution of compound 35 (45 g, 0.213 mol) in dry DMF (225 mL) was added triethylamine (60 mL, 0.425 mol) and stirred at RT for 15 min. The above reaction mixture was cooled to 0° C., added tritylchloride (59 g, 0.213 mol) followed by addition of catalytic amount of 4-DMAP (app. 20 mg) and allowed to stir at RT for 24 h. The reaction was diluted with water (100 mL), extracted with ethyl acetate (5×200 mL), dried and concentrated under vacuum. The crude was purified by column chromatography over silica gel (6% methanol in chloroform) to give the title compound (33 g, 34%). TLC: Chloroform/Methanol, 9:1, Rf=0.5
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][S:14][C:15](SC)=[N:16][C:17]#[N:18].[OH-].[Na+].Cl>C(O)C.O>[C:17]([N:16]=[C:15]([S:14][CH3:13])[NH:12][S:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:11])#[N:18]
Reactant: NS(=O)(=O)c1cc(Cl)ccc1Cl
Reactant: CSC(=NC#N)SC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSC(=NC#N)NS(=O)(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 60.7 %

Procedure:
A solution of 10.6 g (43.2 mmol) of 2,5-dichlorobenzenesulfonamide, 7.15 g (44.0 mmol) of 90 percent dimethyl N-cyanodithioiminocarbonate and 1.8 g (44 mmol) of NaOH in 60 ml of ethanol and 10 ml of H2O was heated at reflux for 6 hours. After cooling to room temperature the reaction mixture was poured into 600 ml of ice water. The resulting solution was acidified with 6N HCl to separate 2.2 g of the desired product as a white solid. Concentration of the filtrate gave an additional 8.5 g of the desired product. The total yield of material was 10.7 g (76 percent) of white solid, mp 145° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][C:5]([F:9])=[CH:6][C:7]=1[CH3:8].[Li]C(C)(C)C.[C:16](=[O:18])=[O:17]>CCOCC>[F:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:16]([OH:18])=[O:17])=[C:3]([CH3:10])[N:4]=1
Reactant: Cc1cc(F)nc(C)c1Br
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: Cc1cc(F)nc(C)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of 3-bromo-2,4-dimethyl-6-fluoropyridine (1.45 g, 7.10 mmol) in anhydrous Et2O (25 mL) at −78° C. was added t-BuLi (1.7M in pentane, 8.8 mL, 15 mmol) dropwise. After addition the mixture was stirred at −78° C. for 10 min, and CO2 was introduced. After 10 min the cooling bath was removed, and the bubbling of CO2 was continued until the mixture was warmed to 0° C. Water (30 mL) was then added and Et2O was removed. The aqueous layer was washed CH2Cl2 (2×30 mL) and acidified with 6N HCl, resulting in precipitation of a pale brown solid (0.87 g, 73%) which was collected by filtration and dried under vacuum. 1H NMR (CD3OD): δ 2.38 (s, 3H), 2.46 (s, 3H), 6.69 (s, 1H). 19F NMR (CD3OD): δ 0.63.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:19][CH:20]([CH3:24])[C:21](Br)=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:21](=[O:22])[CH:20]([Br:19])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)C(=O)Br
Reactant: OCCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)OCCOCc1ccccc1
Temperature: -5 °C

Procedure:
15.2 g of 2-benzyloxyethanol and 10.6 g of triethylamine were dissolved in 150 ml of toluene, and the solution was cooled to -5° C. A solution of 21.6 g of 2-bromopropionylbromide in 30 ml of toluene was added dropwise thereto at -5° to 0° C. with stirring. The reaction mixture was further maintained at room temperature for two hours. The mixtue was then washed successively with 1% strength by weight sodium hydroxide solution and water, and the toluene solution was then dried and filtered. The toluene was distilled off under reduced pressure, and the end product of 2-benzyloxyethyl-2-bromopropionate was obtained in a yield of 26.7 g (nD20.5 1.5182)
Reaction SMILES: CN(C)C1C=CC=CC=1.Cl[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12].[Br:26][C:27]1[CH:36]=[C:35]([CH3:37])[C:34]([CH3:38])=[CH:33][C:28]=1[NH:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[Br:26][C:27]1[CH:36]=[C:35]([CH3:37])[C:34]([CH3:38])=[CH:33][C:28]=1[N:29]([CH:30]([CH3:32])[CH3:31])[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Cc1cc(Br)c(NC(C)C)cc1C
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1cc(Br)c(N(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C(C)C)cc1C
Temperature: 25 °C

Procedure:
N,N-dimethylaniline (7.12 mL, 56.2 mmol) followed by tert-butyl 4-(chlorocarbonyl)piperidine-1-carboxylate 1-11 (42.1 mL of a 1 M solution in methylene chloride, 42.1 mmol) were added to a neat stirred mixture of 2-bromo-N-isopropyl-4,5-dimethylaniline 1-9 (6.80 g, 28.1 mmol) and N,N-dimethylamino-pyridine (172 mg, 1.40 mmol) at approximately 0° C. The resulting mixture was heated to reflux for 30 min, cooled to ambient temperature and partitioned between diethyl ether and aqueous 1 N hydrochloric acid. The organic phase was separated and washed successively with aqueous 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-40% ethyl acetate/hexanes as eluent) afforded 1-12 as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[N:10]3[C:11]4[C:16]([NH:17][C:18](=[O:19])[C:9]3=[CH:8][N:7]=2)=[CH:15][C:14]([C:20]([OH:22])=O)=[C:13]([CH3:23])[CH:12]=4)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH3:29])(C)C.ClCCl.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1C[CH2:48][CH2:47][CH2:46]1>O>[CH:1]1([C:6]2[N:10]3[C:11]4[C:16]([NH:17][C:18](=[O:19])[C:9]3=[CH:8][N:7]=2)=[CH:15][C:14]([C:20]([N:27]2[C:30]3[C:31](=[CH:46][CH:47]=[CH:48][CH:32]=3)[CH2:29][CH2:28]2)=[O:22])=[C:13]([CH3:23])[CH:12]=4)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc2c(cc1C(=O)O)[nH]c(=O)c1cnc(C3CCCC3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(cc1C(=O)N1CCc3ccccc31)[nH]c(=O)c1cnc(C3CCCC3)n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 90 mg of 1-cyclopentyl-8-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid, 0.18 mL of diisopropylethylamine, and 5.4 mL of dichloromethane was added 162 mg of bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3). The obtained solid was heated and washed with 3 mL of ethyl acetate and 15 mL of normal hexane to obtain 183 mg of 1-cyclopentyl-7-(2,3-dihydro-1H-indol-1-ylcarbonyl)-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([OH:25])=O)=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][N:28]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[CH2:22][CH2:21][CH2:20][C:19]([C:23]([NH:40][C:39]5[CH:41]=[CH:42][C:36]([CH2:35][N:28]([CH:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)[CH3:27])=[CH:37][CH:38]=5)=[O:25])=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCCCC4)cc3)ccc2CCC1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCCCC5)cc4)ccc3CCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To a solution of 2-(4-piperidinophenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (0.45 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.31 g) and 1-hydroxybenzotriazole (0.18 g) in dimethylformamide (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-chloride (0.37 g) under ice-cooling. Under nitrogen atmosphere, the mixture was warmed to room temperature. To the mixture were added 4-dimethyl-aminopyridine (catalytic amount) and triethylamine (0.54 ml), and the mixture was stirred over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 2-(4-piperidinophenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-6,7-dihydro-5H-benzocyclo-hepten-8-carboxamide (Compound 224) (0.44 g) as pale orange crystals.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([S-:19])#[N:18].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][NH2:29])[CH:25]=[CH:26][CH:27]=1.Cl>C(O)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][N:29]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:18][C:17]2=[S:19])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: NNc1cccc(Cl)c1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: S=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1Nc1cccc(Cl)c1
Yield: 56 %

Procedure:
A mixture of benzoine (1.0 g, 0.0071 mol), KSCN (0.68 g, 0.0071 mol) and 3-chlorophenylhydrazine×HCl (1.26 g, 0.0071 mol) was stirred in acetic acid (10 mL) for two days. The white precipitate formed was filtered off (0.4 g). Water (50 mL) was added and the precipitate formed was filtered off. Recrystallization from MeOH/water (1:1) yielded 1.5 g (56%) of 9.26.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][C:5]=1[CH:6]=[CH:7][C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(Cl)([Cl:23])=O.[CH2:25](O)[CH3:26]>>[ClH:23].[CH2:25]([O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:26]
Reactant: CCO
Reactant: O=C(O)C=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Product: Cl

Procedure:
2-Nitro-5-piperazinylcinnamic acid (10 g) was suspended in 100 ml of ethyl alcohol and to the suspension was added dropwise 3 ml of thionyl chloride with ice cooling externally while stirring. After completion of addition, the mixture was heated under reflux for 3 hours and ethyl alcohol and thionyl chloride were removed by distillation. The residue was added to isopropyl alcohol and heated to dissolve. After cooling, yellow crystals which precipitated were collected by filtration to give 4.3 g of 2-nitro-5-piperazinylcinnamic acid ethyl ester hydrochloride, m.p. 210°-220° C.
Reaction SMILES: CC1C=CC([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:10]=3[CH:9]=2)=CC=1.O[N:22]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:45][N:46]([CH2:53][C@H:54]1[CH2:59][CH2:58][C@H:57](N)[CH2:56][CH2:55]1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:45][N:46]([CH2:53][CH:54]1[CH2:59][CH2:58][CH:57]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][C:16]([C:18]([NH2:22])=[O:20])=[CH:17][C:10]=3[CH:9]=2)[CH2:56][CH2:55]1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(-c2cc3c(s2)CCCC(C(=O)O)=C3)cc1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: CN(CC1CCC(c2cc3c(s2)CCCC(C(N)=O)=C3)CC1)C1CCOCC1
Reaction time: 2 h
Yield: 64.5 %

Procedure:
Into a suspension of 2-(4-methylphenyl)-7,8-dihydro-6H-cyclohepta[b]thiophene-5-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (107 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (152 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (236 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (240 mg) and triethylamine (0.15 ml) in acetonitrile (20 ml), and the resulting mixture was stirred for 20 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:2→2:3) and to recrystallization (ethyl acetate/hexane) to obtain trans-2-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl-7,8-dihydro-6H-cyclohepta[b]thiophene-5-carboxamide (compound 69) (137 mg) as light yellow crystals.