Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17]C3C=NC=CC=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Reactant: Fc1cc(F)cc(Br)c1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(F)c2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=355.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6]C(=O)N[C:3]1=[O:8].[OH-:17].[Na+].Cl>O>[CH3:1][C@@:2]([C:3]([OH:17])=[O:8])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:6]
Reactant: [OH-]
Reactant: CC1(CCc2ccccc2)NC(=O)NC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C[C@](N)(CCc1ccccc1)C(=O)O

Procedure:
54.6 g 5-methyl-5-phenethyl-hydantoin (0.25 Mol) are reacted with 30 g sodium hydroxide (0.75 Mol) and 150 ml water for 3.5 hours in an autoclave at an oil bath temperature of 180° C. After cooling, 350 ml H2O are added and the clear, light brown solution adjusted with hydrochloric acid to pH 7.0. The white precipitate is suctioned off, washed with 20 mg H2O and dried in a vacuum drying cabinet at 65° C. The produce is recrystallized twice from water.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].O[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Reactant: OCc1ccccn1
Product: CCOC(=O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1a, using 5-bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (CAS Registry No. 862111-61-3) and 2-(hydroxymethyl)-pyridine as starting materials, MS (ISP) 407.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])=[S:11].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:16])[CH2:14][CH3:15])[S:11][CH3:17]
Reactant: CCC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCC(=O)N=C(Nc1c(Cl)cccc1Cl)SC

Procedure:
33.2 g (0.12 M) of N-(2,6-dichlorophenyl)-N'-propionyl-thiourea, 10.5 g (0.08 M) of ground potassium carbonate, 9.6 ml (0.15 M) of methyliodide and 300 ml of acetone are boiled in a reflux for 4 hours under energetic shaking. The acetone is distilled off, 300 ml of water are added to the residue. The sediment is filtered and dried. 34.4 g (98.5% of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-propionyl-S-methyl-isothiourea with a melting point of 165°-170° are obtained. After recrystallization from ethyl alcohol 23.5 g of the product (68.2 % from the raw one) are obtained with a melting range of 173°-176°.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23]Cl)[C:18]([CH2:25][O:26][CH2:27][CH3:28])=[N:17][C:12]=3[CH:13]=[N:14][C:15]=2[CH:16]=1>CN(C=O)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][S:3][C:1](=[O:4])[CH3:2])[C:18]([CH2:25][O:26][CH2:27][CH3:28])=[N:17][C:12]=3[CH:13]=[N:14][C:15]=2[CH:16]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCCl
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCSC(C)=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 103.4 %

Procedure:
Potassium thioacetate (1.70 g, 14.9 mmol) was added in one portion to a stirred solution of 7-bromo-1-(4-chlorobutyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (5.37 g, 13.5 mmol) in DMF (65 mL), and the reaction was stirred at ambient temperature for 21 hours. The DMF was removed under reduced pressure, and the residue was partitioned between dichloromethane (300 mL) and water (150 mL). The organic layer was separated, washed with brine (120 mL), dried over magnesium sulfate, filtered, and concentrated to provide 6.09 g of thioacetic acid S-[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ester as a brown solid.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14](=O)[CH3:15]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]([CH3:15])=[CH2:2]
Reactant: [Li]CCCC
Reactant: CC(=O)c1cc(F)ccc1Br
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C(C)c1cc(F)ccc1Br
Reaction time: 89 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (5.69 g, 15.91 mmol) in diethyl ether (80 mL) at room temperature was added n-BuLi (2.5 M in hexanes, 6.37 mL, 15.91 mmol) dropwise. The reaction immediately turned bright orange and the resulting solution was stirred for 35 min at room temperature after which time a solution of l-(2-bromo-5-fluorophenyl)ethanone (3.14 g, 14.47 mmol) in diethyl ether (20 mL) was added dropwise. The reaction lost the bright yellow color and became almost completely white with a significant amount of white precipitate, the reaction was stirred for 89 h after it was quenched by addition of water and extracted with diethyl ether (3×), the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-5% Diethyl Ether/Hexanes) to afford 1-bromo-4-fluoro-2-(prop-1-en-2-yl)benzene. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (dd, J=8.8, 5.3 Hz, 1H), 6.92 (dd, J=9.0, 3.1 Hz, 1H), 6.85 (td, J=8.3, 3.1 Hz, 1H), 5.24 (t, J=1.7 Hz, 1H), 4.96 (s, 1H), 2.08 (d, J=1.4 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:18]Br.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:18][C:7]1[CH:6]=[C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(O)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1ccc(O)c(Br)c1

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)-4-methylpentanoate E-9 (15 g, 63.55 mmol) in 100 ml of glacial acetic acid at 0° C., slowly added bromine (20.26 g, 64.14 mol) and stirred at same temperature for 2.5 h. After completion the reaction, the reaction mixture was poured into water and neutralized with saturated sodium carbonate solution and extracted with ethyl acetate (300 ml×3). The organic layer was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was then distilled off to yield product ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate. Yield: (16 g, 80%). 1H NMR (CDCl3): δ 7.20 (m 2H), 6.80 (d, J=7.9 Hz, 1H), 4.90 (bs, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H). Mass: (315, M+1,100%).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[Na].[O:6]([CH2:11][CH:12]1[CH2:14][O:13]1)[CH2:7][CH:8]1[CH2:10][O:9]1>O>[CH2:1]([O:4][CH2:14][CH:12]1[O:13][CH:8]([CH2:10][OH:9])[CH2:7][O:6][CH2:11]1)[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: C(OCC1CO1)C1CO1
Agent: [Na]
Solvent: O
Product: C=CCOCC1COCC(CO)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17 %

Procedure:
136 ml of allyl alcohol (2.0 mole, Aldrich) is stirred under nitrogen at room temperature and 0.25 g of sodium is added to the mixture and stirring continued for 2.5 hours. Then 13.1 g of 2,2'-(oxybismethylene)bisoxirane (0.1 mole) is added and the mixture then heated at reflux for 18 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with 2×200 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the resulting yellow oil then vacuum distilled through a 10 cm vigreux column. The fraction distilling at 120°-123° @ 0.4 mm is collected yielding 3.2 g (18%) of the above compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:12]#[N:13])[C:10]=1N)=[O:5])[CH3:2].[I:18]C1CC(C(C)C)CCC1(I)C.N(OCCC(C)C)=O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:14]([F:17])([F:16])[F:15])=[C:9]([C:12]#[N:13])[C:10]=1[I:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1N
Reactant: CC(C)C1CCC(C)(I)C(I)C1
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1sc(C(F)(F)F)c(C#N)c1I
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
Combine 3-amino-4-cyano-5-trifluoromethyl-thiophene-2-carboxylic acid ethyl ester, prepared in preparation 45, (1.12 mmol), diiodomenthane (3.92 mmol), and isoamyl nitrite (2.8 mmol) in CH3CN and heat to 80° C. After 45 minutes, cool to room temperature and concentrate in vacuo. Purify the dark residue by flash chromatography eluting with methylene chloride. Concentration of desired fractions and recrystallization from hexanes provides the title compound: 1H NMR (400 MHz, CDCl3) δ 4.45 (q, 2H, J=7.2 Hz) and 1.44 (t, 3H, J=7.3 Hz), 19F NMR (CDCl3) δ—57.6 ppm (s).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][OH:55]>CN(C)C=O>[OH:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: OCCOCCOCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCN(CCOCCOCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl ester (129 mg, 0.25 mmol) (Example 22(a)) was dissolved in dimethylformamide (1 ml). Sodium iodide (7.5 mg, 0.5 mmol) , triethylamine (76 mg, 0.75 mmol) and 2-[2-(2-chloroethoxy)-ethoxy]ethanol (85 mg, 0.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred at ambient temperature for 90 minutes, the temperature was then raised to 100° C. and kept there for 1 hour. The solvent was evaporated, and the residue was dissolved in dichloromethane (2 ml) and washed with water (1 ml). Trifluoroacetic acid (2 ml) was added to the organic phase and the mixture was stirred at ambient temperature for 1 hour. The solvents were evaporated and the residue dissolved in water (4 ml). The aqueous solution was acidified, the water was evaporated and the title compound was isolated as a hygroscopic white powder. Yield 77 mg (64%). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:30][CH:29]=2)[C@H:10]([O:47][CH2:48][C@H:49]([OH:56])[CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])[CH2:9]1)=O)(C)(C)C.Cl>CO>[OH:56][C@H:49]([CH2:50][O:51][CH2:52][CH2:53][O:54][CH3:55])[CH2:48][O:47][C@H:10]1[C@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:32][CH:33]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13][NH:8][CH2:9]1
Reactant: COCCOC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOc2ccccc2C#N)cc1
Agent: Cl
Solvent: CO
Product: COCCOC[C@@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOc2ccccc2C#N)cc1

Procedure:
In analogy to the procedure described in example 1 (l) the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the 2-[3-[4-[(3S,4R,5R)-3-[(2R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile as colorless foam; MS: 671 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:20][CH2:19]1)[C:10]([S:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])([F:12])[F:11].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:19][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[C:10]([S:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])([F:12])[F:11]
Reactant: c1nc[nH]n1
Reactant: CCOCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 26.4 %

Procedure:
Using 2-(2,4-difluorophenyl)-1-(2-ethyoxyethyl)thio-1,1-difluoro-2,3-epoxypropane (3.1 g, 0.01 mol), DMSO (30 ml), 1,2,4-triazole (1.7 g, 0.025 mol) and potassium carbonate (3.4 g, 0.025 mol), 2-(2,4-difluorophenyl)-1-(2-ethoxyethyl)thio-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g, yield: 25.0%) was obtained as colorless crystals by similar procedures to Example 14.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:41][CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CC2CCOCC2)C3)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.100 g, 0.252 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) at 0° C. was added tetrahydro-2H-pyran-4-carbaldehyde (0.02752 mL, 0.2522 mmol). The reaction mixture was stirred at 50° C. for 15 minutes then cooled at 0° C. and added Sodium triacetoxyborohydride (0.1069 g, 0.5044 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for 2 hours. LC-MS shows mostly product. The reaction mixture was concentrated, chromatographed through silica gel (40 g, 0-5% MeOH in dichloromethane), and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.15 (d, J=8.7, 2H), 7.46 (d, J=8.7, 2H), 6.16 (t, J=5.5, 1H), 4.13 (d, J=6.7, 1H), 3.85 (t, J=9.0, 3H), 3.70 (d, J=9.0, 1H), 3.61 (dd, J=12.3, 4.0, 4H), 3.52-3.31 (m, 4H), 3.17-3.07 (m, 2H), 2.67 (s, 3H), 2.51 (m, 1H), 2.34 (d, J=7.3, 2H), 1.90 (d, J=7.3, 1H), 1.66 (d, J=12.6, 2H), 1.28-1.10 (m, 5H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.3 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CNC(=O)Cc1cc(OC)c(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNCCc1cc(OC)c(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 5, react N-methyl-3,4,5-trimethoxybenzeneacetamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[NH:15][N:14]=[CH:13][C:12]=2[N:11]2[CH:19]([CH3:25])[CH2:20][N:21]([CH3:24])[C:22](=[O:23])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[N:14]=[CH:13][C:12]=2[N:11]2[CH:19]([CH3:25])[CH2:20][N:21]([CH3:24])[C:22](=[O:23])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1CN(C)C(=O)c2c(OCc3ccccc3)c3c(=O)[nH]ncc3n21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1CN(C)C(=O)c2c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)ncc3n21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10-(benzyloxy)-6,8-dimethyl-7,8-dihydropyrazino[1′,2′:1,5]-pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.12 g, 0.34 mmol), 4-fluorobenzyl bromide (63 μL, 0.34 mmol), and cesium carbonate (0.22 g, 0.68 mmol) in anhydrous DMF (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and the residue partitioned between ethyl acetate and aqueous citric acid. The organic extract was washed with brine, dried over MgSO4, filtered, and concentrated to provide the titled dione. The residue was subjected to column chromatography on silica gel eluted with a methanol-chloroform gradient to provide the titled product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:1]#[CH:2])[CH:4]=1)=[O:20]
Reactant: C#Cc1cccc(N)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#Cc1cccc(NC(=O)C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethynylaniline (2.61 g, 22.3 mmol) was dissolved in anhydrous dichloromethane (20 mL) with triethylamine (3.1 mL, 22.3 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (2.21 mL, 23 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a beige solid (m.p. 99–100° C.). NMR (300 MHz, CDCl3): 8.05 (broad s, 1H, NH), 7.69 (s, 1H), 7.62 (m, 1H), 7.33 (m, 2H), 6.04 (s, 1H), 3.10 ppm (s, 1H, acetylenic).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:19]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C>[CH3:26][O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:24]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: COC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a mixture of (2-amino-5-chlorophenyl)(3-chlorophenyl) methanone (81 mg, 0.31 mmol, 1 eq) and methyl 3-cyclopropyl-3-oxopropanoate (56.2 mg, 0.40 mmol, 1.3 eq) in ethanol (3 ml) was added ytterbium triflate (19 mg, 0.03 mmol, 0.1 eq) and the yellow solution was stirred overnight at room temperature. The resultant precipitate was filtered and washed with a small amount of ethanol to give the desired product (49 mg, 43%) as a white solid which did not require any further purification. MS (ESI): 372.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].[OH-].[Na+].Cl>CO>[CH:7]1[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1ccc2[nH]c3ccccc3c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2[nH]c3ccccc3c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Carbazole-3-carboxylic acid methyl ester (450 mg) was dissolved in 7 mL of methanol, and the solution was added with 2.5 mL of 2 N aqueous sodium hydroxide, and stirred at 60° C. for 3 hours. Subsequently, the reaction mixture was cooled and then neutralized with hydrochloric acid, and the deposited precipitates were collected to obtain 410 mg of carbazole-3-carboxylic acid. The resulting carbazole-3-carboxylic acid (205 mg), 6-(1-naphthalenesulfonyl)aminopentylamine (292 mg) obtained in the example and WSC (192 mg) were dissolved in 5 mL of DMF and stirred at room temperature for 3 hours. The reaction mixture was added with water and extracted with ethyl acetate. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: chloroform/methanol=95/5) to obtain 123 mg of the compound, 3-(1-naphthylsulfonylaminopentylaminocarbonyl)carbazole.
Reaction SMILES: C([O:8]C1C=C(O)C=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([OH:34])(=[O:8])=[O:33]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(O)c1ccccc1Cl
Yield: 185.2 %

Procedure:
3-Benzyloxyphenol (2.97 g, 15 mmol), as prepared in the preceding step, in methylene chloride (50 mL) was treated with diisopropylethylamine (2 mL) and 2-chlorobenzenesulfonyl chloride (3.27 g, 15.5 mmol) at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with 200 mL of methylene chloride, washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (5.35 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 4.97 (s, 2H), 6.71 (dd, 1H, J=1.1, 4.1 Hz), 6.78 (t, 1H, J=2.3 Hz), 6.85 (dd, 1H, J=1.1,4.1 Hz), 7.17 (t, 1H, J=8.3 Hz), 7.37 (m, 5H), 7.58 (m, 2H), and 7.91 (dd, 1H, J=1.1, 4.1 Hz).
Reaction SMILES: [CH3:1][C:2]([NH2:12])([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)[CH3:3].C=O.[C:15](=O)([O-])O.[Na+]>>[CH2:15]=[N:12][C:2]([CH3:1])([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1)[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(N)c1cc(Cl)cc(Cl)c1
Agent: C=O
Agent: [Na+]
Product: C=NC(C)(C)c1cc(Cl)cc(Cl)c1
Reaction time: 7 h

Procedure:
1-Methyl-1-(3,5-dichlorophenyl)ethylamine (7.5 g) was added slowly to formalin (aqueous 37% HCHO solution) (4.6 g) at room temperature. This was allowed to react as it was for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, which was then extracted with ether. After it was washed with saturated saline, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the captioned compound (8.6 g) as white crystals.