Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH3:24].C(N(CC)CC)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([NH:7][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:4][C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH3:24]
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(Oc2cc(C)c(-c3nc(N)sc3Br)c(C)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2cc(C)c(-c3nc(NC(=O)c4ccncc4)sc3Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of 5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (2-4, 325 mg, 0.70 mmol) in CH2Cl2 (10 ml) was added triethylamine (0.50 mL, 1.7 mmol) followed by isonicotinoyl chloride hydrochloride (302.5 mg, 3.4 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give N-{5-bromo-4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (2, 345 mg) as white solids in 99% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.3 (s, 1 H), 8.82 (m, 2 H), 7.98 (m, 2 H), 7.05 (d, J=9.0 Hz, 2 H), 6.99 (d, J=9.0 Hz, 2 H), 6.70 (s, 2 H), 3.76 (s, 3 H), 1.99 (s, 6 H); ESI-MS: m/z 509.6, 511.1 (M+H)+.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH:6]([CH:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CN(C=O)C.CCOC(C)=O>[CH2:10]([O:9][C:7](=[O:8])[CH:6]([NH2:1])[CH:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH3:11]
Reactant: CCOC(=O)C(Br)C(C)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)C(C)C(F)(F)F
Reaction time: 48 h
Yield: 49.7 %

Procedure:
Sodium azide (1.9 g, 28.7 mmol) and ethyl 2-bromo-3-methyl-4,4,4-trifluorobutyrate (5 g, 19.2 mmol) were placed in DMF (20 mL) and stirred for 48 h. The mixture was diluted with EtOAc (200 mL) and washed with brine (4×100 mL). The organic layer was dried over Na2SO4 and solvent removed. The crude oil was placed in EtOH (20 mL) with 5% Pd/C (1.6 g) and shaken for 6 hours under H2 (50 psi). The reaction was filtered through the Celite® reagent and the solvent was removed providing a clear oil (1.9 g) in 50% yield.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)=O)cs3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-Methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc(Cl)c1Cl
Yield: 60.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.7 mmol), 2,3-dichlorobenzenesulfonyl chloride (190 mg, 0.8 mmol) and DMAP (cat.) gave the title compound (150 mg, 63%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:22]([N:24]1[C:28]([C:29](O)=[O:30])=[CH:27][C:26]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[N:25]1)[CH3:23]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:29]([C:28]4[N:24]([CH2:22][CH3:23])[N:25]=[C:26]([C:32]5[S:33][CH:34]=[CH:35][CH:36]=5)[CH:27]=4)=[O:30])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CCn1nc(-c2cccs2)cc1C(=O)O
Product: CCn1nc(-c2cccs2)cc1C(=O)Nc1ccc(C)c(-c2ccc(C(=O)NCC3CC3)cc2)c1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-1-ethyl-3-(thiophen-2-yl)pyrazole-5- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 1-ethyl-3-(thiophen-2-yl)pyrazole-5- carboxylic acid using method D. NMR; δH CDCl3 8.02,(1H, b), 7.86-7.83,(3H, m), 7.57,(1H, dd), 7.47,(1H, d), 7.40,(2H, d), 7.34,(1H, m), 7.30-7.26,(3H, m), 7.07,(1H, m), 4.63,(2H, q), 3.35,(2H, m), 2.24,(3H, s), 1.08,(1H, m), 0.58,(2H, m), 0.30,(2H, m). LCMS: retention time 3.81 min, MH+485.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(O[C:16](=[O:21])[C:17]([F:20])([F:19])[CH3:18])C.[Br:22][CH2:23][Br:24]>C1COCC1>[Br:22][CH:23]([Br:24])[C:16](=[O:21])[C:17]([F:19])([F:20])[CH3:18]
Reactant: BrCBr
Reactant: CCOC(=O)C(C)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(F)(F)C(=O)C(Br)Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To N,N-diisopropylamine (4.06 ml, 2.93 g, 29.0 mmol) in THF (20 ml) was added n-butyllithium (11.6 ml of a 2.5 M solution in hexanes; 29.0 mmol) dropwise, maintaining the temperature of the mixture below 5° C. throughout the addition. The resulting solution was stirred at 0° C. for 15 min, and was then added dropwise to a solution of 2,2-difluoropropionic acid ethyl ester (prepared according to the procedure described in U.S. Pat. No. 5,859,051) (2.00 g, 14.5 mmol) and dibromomethane (2.02 ml, 5.04 g, 29.0 mmol) in THF (20 ml) over 30 min with stirring, maintaining the temperature of the mixture below −60° C. throughout the addition. The solution was stirred for 15 min at −78° C. under nitrogen, and was then quenched by the addition of 5 N hydrochloric acid (10 ml). The mixture was allowed to warm to room temperature, and was diluted with water (10 ml). The aqueous phase was separated and washed with diethyl ether (2×30 ml). The combined organic layers were dried over magnesium sulfate, and concentrated in vacuo. The residual oil was purified by flash chromatography on silica gel, eluting with 10% to 20% diethyl ether in 40-60 petroleum ether (UV detection), yielding 1,1-dibromo-3,3-difluorobutan-2-one as a yellow oil (1.65 g, 43%): 1H NMR (360 MHz, CDCl3) δ 1.90 (3H, t, J 19.2 Hz), 6.39 (1H, s).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH2:38][O:39][CH2:40][CH2:41]O>C(Cl)Cl.[Al]>[Br:1][CH2:41][CH2:40][O:39][CH2:38][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=1
Reactant: OCCOCc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution 2-[(2-naphthalenylmethyl)oxy]ethanol (101 mg, 0.499 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (57 mg, 43%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[NH2:7].C[O-].[Na+].[Na].[C:19]([CH2:21][C:22](OC)=[O:23])#[N:20]>CO>[C:19]([CH2:21][C:22]([NH:7][C@@H:6]([CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)[C:5]([O:4][CH3:3])=[O:14])=[O:23])#[N:20]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CC#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.0 g (20.4 mmol) of L-histidine methyl ester dihydro-chloride were added at room temperature to a sodium methoxide solution obtained by dissolving 0.94 g (40.7 mmol; 1.95 equivalents) of sodium in 100 ml of methanol. After 30 min, 3.03 g (30.6 mmol) of methyl cyanoacetate were added and the mixture was refluxed for 16 h. After cooling to room temperature, the mixture was filtered. The yellowish filtrate was concentrated under reduces pressure and the residue was purified by means of flash chromatography on silica gel (eluent: ethyl acetate→ethyl acetate/methanol 3:1 gradient).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:21]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:13](=[O:21])[CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Reactant: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a vigorously stirred solution of RuCl3.H2O (2.39 g, 11.5 mmol) and NaIO4 (24.6 g, 115.0 mmol) in water (250 mL) was added (S)-piperidine-1,2-dicarboxylic acid di-tert-butyl ester (8.22 g, 28.8 mmol) in ethyl acetate (250 mL) at room temperature. After stirring for 4 h, the reaction mixture was partitioned and the aqueous layer washed with ethyl acetate. To the combined organic layers was added iPrOH (2.5 mL) and stirring was continued for 2 hours in order to destroy excess RuO4. The precipitate was removed by filtration through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to afford the title compound as a pale yellow oil, which crystallized upon standing (6.69 g, 78%): 1H NMR (400 MHz, CDCl3) δ 1.49 (9H, s), 1.52 (9H, s), 1.75-1.82 (2H, m), 1.97-2.06 (1H, m), 2.15-2.21 (1H, m), 2.41-2.61 (2H, m), 4.59 (1H, dd, J 3.5 Hz)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Br)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 109.1 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (10 g, 0.0543 mol) and N,N-diisopropylethylamine (14.2 mL, 0.0814 mol) in dry dichloromethane (200 mL) at 0° C. under nitrogen was added dropwise a solution of 4-bromobenzenesulfonyl chloride (10.4 g, 0.0407 mol) in dry dichloromethane (80 mL) over 10 minutes. The ice bath was removed and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was then washed with 1 M hydrochloric acid (2×250 mL), 0.5 M sodium hydroxide (250 mL) and water (250 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a purple syrup (17.91 g). Purification by flash chromatography using a solvent gradient of 5 to 10% ethyl acetate in hexane afforded a tan solid (3.21 g) that was recrystallized from ethyl acetate/hexane to afford the title compound (2.55 g, 16%) as a tan crystalline solid, m.p. 128-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([CH:17]=[O:18])=[C:9]2[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][C:10]=12)=[O:4].[O-:19]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:9]=2[C:8]([C:17]([OH:19])=[O:18])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1ncc(C(=O)O)c2c1OC(C)(C)OC2

Procedure:
8-(methoxycarbonyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carboxylic acid (23a) was synthesized from 5-Formyl-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylic acid methyl ester [J. Org. Chem. 1999, 64, 4537] 1 mmol and 1.5 mmol NaClO2 in t-butanol/water
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][C:11](=O)[CH2:12]2.[OH-].[K+].O.NN.Cl>C(O)COCCO>[CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][CH2:11][CH2:12]2
Reactant: CCC(CCCCC1CCC2CC(=O)CC12)OC
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: CCC(CCCCC1CCC2CCCC12)OC
Temperature: 95 °C

Procedure:
2-(5-Methoxyhept-1-y)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} (5 g, 19.8 mmoles) is mixed with diethylene glycol (27 ml) and potassium hydroxide (3.8 g, 6.7 mmoles). The reaction is stirred and mixed with 80% hydrazine hydrate (2.8 ml, 7.0 mmoles). The reaction is heated to 95° C. for 2 hours. After which time the temperature is increased to 200° C. and maintained with stirring for 5 hours. Then the reaction is cooled and added to 6N hydrochloric acid (200 ml). The solution is partitioned between ether and the phases separated. The aqueous phase is extracted with ether (2×100 ml) and the extracts combined. The ether solution is dried over anhydrous magnesium sulfate and the solvent removed under vacuum leaving a clear, purple oil. The crude product is kugelrohred under reduced pressure leaving a clear, colorless oil (4.0 g, 16.8 mmoles).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][CH:30]([NH:29][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:27][CH:26]=1)[CH2:33][OH:34]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: NC(CO)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(CO)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-aminopropane-1,3-diol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=449.2 [M+H]+.
Reaction SMILES: O[C:2]12[CH2:21][CH:20]([O:22][CH3:23])[CH2:19][CH:3]1[NH:4][C:5]([C:7]1[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])=[N:6]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:23][O:22][CH:20]1[CH2:21][C:2]2[NH:6][C:5]([C:7]3[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=3)[C:12]([O:14][CH3:15])=[O:13])=[N:4][C:3]=2[CH2:19]1
Reactant: COC(=O)c1cc(C2=NC3(O)CC(OC)CC3N2)c(C)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nc3c([nH]2)CC(OC)C3)c(C)cc1C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate (compound 461.5, 200 mg, 0.38 mmol, 1.00 equiv, 60%) in N,N-dimethylformamide (mL). p-Toluenesulfonic acid (20 mg, 0.12 mmol, 0.18 equiv) was added and the resulting solution was stiffed overnight at 80° C., then concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (10:1) as the eluent to obtain the title compound as a brown oil (100 mg, 66%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13]C)[C:6]([O:8]C)=[O:7])#[N:2].Cl.N1C=CC=CC=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1cc(C(=O)O)ccc1O
Temperature: 180 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A mixture of methyl 3-cyano-4-methoxybenzoate (70 g) and pyridine hydrochloride (128.3 g) was stirred for 1 hour at 180° C. in an oil bath. Ice-water (1 L) was added to the reaction mixture, and the thus-precipitated crystals were filtered and recrystallized from ethyl acetate, thereby giving 48.1 g of the desired compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10](=[O:12])[NH:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:7]=1[C:20]([OH:22])=O.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:33]1([CH:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30][CH2:31][NH:32][C:20]([C:7]2[CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:9][C:10](=[O:12])[NH:11][C:6]=2[CH2:5][O:4][CH2:3][CH2:2][Cl:1])=[O:22])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: O=C1NC(COCCCl)=C(C(=O)O)C(c2cccc(Cl)c2)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1NC(COCCCl)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
139 mg (0.417 mmol) of 6-(2-chloroethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 106 mg (0.500 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of dichloromethane. 120 mg (0.626 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1) to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:19][NH:1][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])[C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)(O)CN
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CNCC(C)(C)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
1-Amino-2-methyl-propan-2-ol (0.408 g, 4.58 mmol) was added to a solution of methyl 2-(4-chlorophenyl)acrylate (0.300 g, 1.52 mmol) in tetrahydrofuran (3.84 mL). The reaction was allowed to stir at room temperature overnight and produced crude methyl 2-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropylamino)propanoate (436 mg, 100%). LCMS: M+1 286.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH3:31])[C:18](=[O:32])[N:17]([CH3:33])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:22]1[C:21]2[C:20](=[O:30])[N:19]([CH3:31])[C:18](=[O:32])[N:17]([CH3:33])[C:16]=2[N:15]=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2Cl)n(C)c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(nc(N3CCNCC3)n2-c2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 135.4 %

Procedure:
4-[7-(2-Chlorophenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (102 mg) was dissolved in trifluoroacetic acid (5 ml), and the solution was stirred at room temperature for 30 minutes. After the solvent was removed, the residue was purified by column chromatography using NH-silica gel to obtain 109 mg of the title compound from a fraction eluted with ethyl acetate-methanol (9:1).
Reaction SMILES: [CH2:1]([C:3]([CH3:14])([O:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])[CH2:4][CH3:5])[CH3:2].[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl.CN(C)C=O>[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:31][CH2:32][N:33]([C:11](=[O:13])[CH2:10][NH:9][C:7](=[O:8])[O:6][C:3]([CH2:1][CH3:2])([CH3:14])[CH2:4][CH3:5])[CH2:34][CH2:35]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(C)(CC)OC(=O)NCC(=O)O
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(C)(CC)OC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
284 mg (1.40 mmol) of {[(1-ethyl-1-methylpropoxy)carbonyl]-amino}-acetic acid, 320 mg (1.17 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-piperidine and 322 mg (1.68 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in a mixed solvent of 15 ml of dichloromethane and 5 ml of dimethylformamide. 0.23 ml (1.68 mmol) of triethylamine and 14.7 mg (0.12 mmol) of dimethylaminopyridine were added to the obtained solution, and they were stirred at room temperature overnight. After the concentration under reduced pressure, ethyl acetate was added to the reaction mixture. The resultant mixture was washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by the silica gel chromatography (hexane:dichloromethane=95:5 to 2:3) to obtain the title compound.