Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:51](C(OC(C)(C)C)=O)[C@H:52]([C:57]([O:59]C(C)(C)C)=[O:58])[CH2:53][CH2:54][CH2:55][NH2:56]>C(Cl)Cl>[NH2:51][C@H:52]([C:57]([OH:59])=[O:58])[CH2:53][CH2:54][CH2:55][NH2:56]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCCC[C@H](N)C(=O)O
Reaction time: 1 h

Procedure:
DOTA (1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid) 0.5 mmol and 1.5 mmol of triethylamine were dissolved in 10 ml DCM. 0.6 mmol of DCC was dissolved in 5 ml DCM and added to the mixture. The reaction was carried out for 1 hour at room temperature. The white crystals that appeared in the mixture were filtered out. 0.5 mmol of solid BOC-Orn-OtBu was added to the reaction. The reaction was carried out for 20 hours at room temperature. The mixture was filtered and the DCM was evaporated. The product was washed several times with ethanol and air-dried. Cleavage of the protecting groups (BOC, OtBu) was carried out in 1 ml TFA+5% water for 3 hours. The acid was evaporated in a vacuum over a KOH pellet. The final product, L-Orn(DOTA), was washed several times with diethyl ether and dried. The product was dissolved in water and lyophilized.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:22]([F:23])=[CH:21][C:20](/[C:24](=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2F)/[C:25]#[N:26])=[C:19]([F:36])[CH:18]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]([C:20]2[CH:21]=[C:22]([F:23])[C:17]([Cl:16])=[CH:18][C:19]=2[F:36])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1cc(F)c(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1cc(F)c(Cl)cc1F
Yield: 95.5 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (5 mmol) was reacted with give (Z)-2-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile (1.3 g, 3 mmol) prepared in Example 109a, AgF (0.77 g, 6 mmol), and triethylamine (1.4 mL, 10 mmol) in dichloromethane (120 mL) at room temperature for 18 h, followed by the reaction with DBU (4.8 ml) in tert-butanol (20 mL) at 100° C. for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,5-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a light yellow gum (1.5 g, 69%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])[N:3]=1.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH:33]=[CH2:34])=[N:3][C:4]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:14])=[CH:5]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1nc([C@H](C)NC(=O)OCC2c3ccccc3-c3ccccc32)cc2cccc(Cl)c12
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl-1-(1,8-dichloroisoquinoline-3-yl)ethylcarbamate (346) (36 g, 77.7 mmol, 1.0 eq) in THF (300 mL) under argon, tributyl(vinyl)stannane (27 g, 85.5 mmol, 1.1 eq), Pd(OAc)2 (5.23 g, 23.3 mmol, 0.3 eq) and PPh3 (12.2 g, 46.6 mmol, 0.6 eq) were added, and the resulting mixture was stirred at reflux for 16 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-30% ethyl acetate-petroleum ether) to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-vinylisoquinolin-3-yl)ethylcarbamate (347).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4]Cl.[OH-:6].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C)C=O>[CH2:4]([O:6][CH2:4][CH:2]1[O:3][CH2:1]1)[CH:2]1[O:3][CH2:1]1
Reactant: [OH-]
Reactant: ClC[C@H]1CO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(OCC1CO1)C1CO1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The starting formula derivative (2.50 g) of the following formula: ##STR17## and the same R-(-)-epichlorohydrin (4.25 g) and benzyltriethylammonium chloride (20 mg) as used in Preparation 2 are dissolved in dimethylformamide (3 ml) and thereto is added dropwise 24 wt. % aqueous sodium hydroxide (1.2 equivalent) at 60° C. After reacting at the same temperature for 40 minutes, the reaction mixture is cooled to room temperature and extracted with ether. The extract is distilled under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography to give S isomer of glycidyl ether (1.62 g) of the following formula: ##STR18##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])([CH3:8])[CH3:7])=[O:5])[CH3:2].S([O-])([O-])(=O)=O.[Ca+2].[CH2:24](Br)[CH:25]=[CH2:26].[OH-].[Na+]>[Cu].O>[CH2:26]([C:9]1([C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])([CH3:8])[CH3:7])[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]1=[O:17])[CH:25]=[CH2:24]
Reactant: CCOC(=O)C(C)(C)C1C(=O)NC(=O)NC1=O
Reactant: C=CCBr
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: C=CCC1(C(C)(C)C(=O)OCC)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a one liter three-neck flask equipped with mechanical stirrer, reflux condenser and a dropping funnel, were placed 100 g. of 5-(1-ethoxycarbonylisopropyl)barbituric acid, 100 mg. of calcium sulfate, 50 mg. of copper dust and 500 ml. of water. The mixture was stirred at room temperature for 15 minutes and 53.6 g of allyl bromide were added in one portion followed by the dropwise addition of 125 ml. of 20% sodium hydroxide over 45 minutes at 50°-55°. After stirring at 50°-55° for 3 hours, the reaction mixture was cooled to about 30° and an additional 26.8 g. of allyl bromide were added in one portion. The reaction mixture was heated with stirring, for 90 minutes, and a solution (65-70 ml.) of 20% sodium hydroxide was then added at a rate such that the reaction mixture was always slightly alkaline. The mixture was cooled to room temperature. The pH of the mixture was adjusted to about 9 by the addition of 20% sodium hydroxide and the mixture was extracted with 4 × 250 ml. of ethyl acetate. The combined ethyl acetate extracts were re-extracted with 4 × 300 ml. of 1% sodium hydroxide and the aqueous extracts were added to a mixture of 500 g. of ice and 300 ml. of 6N hydrochloric acid. The precipitate which formed upon standing at room temperature overnight was collected to give 91.0 g. (78%) of the alkylbarbituric acid, m.p. 112°-114°.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[C:5](=[O:27])[N:6](C2CCCCO2)[N:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:16][C@@H:15]2[CH2:17][C@@H:13]([C:14]2([CH3:19])[CH3:18])[C@H:12]1[CH3:20]>C(O)(=O)C.O1CCCC1.O.Cl>[F:28][CH:2]([F:1])[O:3][C:4]1[C:5](=[O:27])[NH:6][N:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:16][C@@H:15]2[CH2:17][C@@H:13]([C:14]2([CH3:19])[CH3:18])[C@H:12]1[CH3:20]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3CCCCO3)c(=O)c1OC(F)F)C2(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cn[nH]c(=O)c1OC(F)F)C2(C)C
Yield: 76.6 %

Procedure:
4-Difluoromethoxy-2-(tetrahydro-2H-pyran-2-yl)-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (80 mg, 0.20 mmol) in acetic acid-tetrahydrofuran-water (5/1/1) was stirred at 90° C. for 3 hours and then stirred with two drops of concentrated hydrochloric acid for another 3 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/1) to give the desired product (48 mg, 79% yield).
Reaction SMILES: C(OC([NH:6][C:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:14]([O:16][CH3:17])=[O:15])=O)C.C[O-].[Na+]>>[NH2:6][C:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)NC1=C(C(=O)OC)CCCCC1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1=C(N)CCCCC1
Yield: 73.9 %

Procedure:
Using the method of Example 1 Part B, methyl 2-[(ethoxycarbonyl)amino]-1-cycloheptene-1-carboxylate (59 g, 0.24 mole) was reacted with sodium methoxide to provide 30 g of methyl 2-amino-1-cycloheptene-1-carboxylate as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22](=[O:29])[N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:43][C:44]#[N:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:43][C:44]#[N:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22](=[O:29])[N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17]1=[O:31])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: N#CCBr
Reactant: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](N(CC#N)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide (0.015 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.042 ml), followed by bromoacetonitrile (0.019 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was then cooled to −78° C. and further lithium bis(trimethylsilyl) amide (0.042 ml) added. After reaching room temperature, the reaction mixture was stirred for a further 18 h and then quenched by the addition of methanol (1 ml). The resultant solution was concentrated under reduced pressure and the residue partitioned between water and DCM. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified by mass directed preparative h.p.l.c to give the title compound (0.007 g) as a colourless gum.
Reaction SMILES: ClC1C=CC(C(CCC(O)=O)=O)=CC=1C(F)(F)F.N1CCC[C@H]1C(O)=O.[Cl:27][C:28]1[CH:47]=[CH:46][C:31]([C:32]([CH2:34][CH2:35][C:36]([N:38]2[CH2:45][CH2:44][CH2:43][C@H:39]2[C:40]([OH:42])=[O:41])=[O:37])=[O:33])=[CH:30][C:29]=1[C:48]([F:51])([F:50])[F:49].[C:52]([O-:55])(=[S:54])[CH3:53].[K+]>C(O)C.O>[C:52]([S:54][CH:34]([C:32](=[O:33])[C:31]1[CH:46]=[CH:47][C:28]([Cl:27])=[C:29]([C:48]([F:51])([F:49])[F:50])[CH:30]=1)[CH2:35][C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([OH:42])=[O:41])=[O:37])(=[O:55])[CH3:53]
Reactant: CC([O-])=S
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(O)CCC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The preceding compound is converted to 3-(4-chloro-3-trifluoromethylbenzoyl)propionic acid, hydroxysuccinimide ester and coupled to L-proline as in Example 16. The 1-([3-(4-chloro-3-trifluoromethylbenzoyl)propionyl]-L-proline is brominated as in Example 20 and the product reacted with potassium thioacetate in ethanol-water (1:1) as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.BrC1SC(S(Cl)(=O)=O)=CC=1.[CH2:21]1[CH2:26][CH2:25][CH:24]([C@H:27]([NH2:31])[C:28](O)=[O:29])[CH2:23][CH2:22]1.CC(C1C=CC=CC=1)C(C(O)=O)N.N[C@H](C(O)=O)[C@@H](CC)C>>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:31][C@@H:27]([CH:24]2[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]2)[CH2:28][OH:29])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: N[C@H](C(=O)O)C1CCCCC1
Agent: CC(c1ccccc1)C(N)C(=O)O
Agent: CC[C@@H](C)[C@H](N)C(=O)O
Agent: O=S(=O)(Cl)c1ccc(Br)s1
Product: O=S(=O)(N[C@H](CO)C1CCCCC1)c1ccc(Cl)s1

Procedure:
The following compounds (Examples 12-17, Table 4) were prepared using 5-chlorothiophene-2-sulfonyl chloride, and 5-bromothiophene-2-sulfonyl chloride with L-cyclohexylglycine, β-methyl-DL-phenylalanine, and L-allo-isoleucine and following the procedure outlined in Example 12.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20]C)=[O:19])[NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[K+].Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([OH:20])=[O:19])[NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Reaction time: 72 h

Procedure:
Methyl 6-benzyloxyindole-2-carboxylate (EXAMPLE 247, 3.77 g) is dissolved in 33.5 ml of dioxane and 3.35 ml of water is added. Then solid potassium hydroxide (0.9 g) is added and the reaction is heated to 50° for 6 hr. Then a further 0.9 g of potassium hydroxide is added and the reaction is stirred at 20°-25° for 72 hr and heated at 50° a further 4 hr. Then it is cooled to 20°-25° and acidified to pH 4-5 with 2N hydrochloric acid. The reaction is extracted with methanol/chloroform (10/90, 3 times) and the extracts are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Cl[C@@H:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27]>O>[CH2:29]([C@@H:25]1[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1)[CH3:30]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CC[C@H](Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (5.90 g) in a mixed solvent of ethyl acetate (60 ml) and water (60 ml) were added sodium hydrogen carbonate (5.40 g) and (S)-2-chlorobutyryl chloride (7.00 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (70 ml), to the solution was added potassium carbonate (4.90 g) and the mixture was stirred at room temperature overnight. Water was added to the reaction solution and the resulting crystals were taken by filtration to give (R)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (6.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[NH:4][C:5]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:14]([OH:25])(=O)[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1>>[CH3:1][N:2]([CH3:13])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([C:14]([NH:12][C:10]4[CH:9]=[CH:8][C:6]5[NH:7][C:3]([N:2]([CH3:1])[CH3:13])=[N:4][C:5]=5[CH:11]=4)=[O:25])=[CH:23][CH:22]=3)=[CH:11][C:5]=2[N:4]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CN(C)c1nc2ccc(N)cc2[nH]1
Product: CN(C)c1nc2cc(NC(=O)c3ccc(C(=O)Nc4ccc5[nH]c(N(C)C)nc5c4)cc3)ccc2[nH]1

Procedure:
Compound 435 was prepared according to the procedure similar to that described in Scheme V from 2-dimethylamino-5-aminobenzimidazole and terephthalic acid. [M+H]+ calcd for C26H26N8O2: 483.22; found: 483.02.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.Cl>CO>[CH3:8][O:7][C:6]1[C:5](=[O:9])[C:4](=[O:10])[C:3]=1[NH:12][C:13]1[CH:14]=[C:15]([CH:19]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(NC(=O)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
3,4-dimethoxy-3-cyclobutene-1,2-dione (428 mg) was added to a solution of N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]benzamide hydrochloride (555 mg) [prepared as described in step (d) above] in methanol (15 ml) at ambient temperature. After stirring for 10 minutes, a solution of triethylamine (153 mg) in methanol (10 ml) was added dropwise to the mixture. This mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then slightly acidified with hydrochloric acid (0.5N) and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford the title compound (505 mg) as a white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br.Br[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCBr
Reactant: Nc1ccc(Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chloro-aniline (0.5 g, 3.9 mmol) was added to a solution of 2-bromo-N,N-diethylethylamine hydrobromide (1.12 g, 4.3 mmol) and N,N-diisopropylethylamine (2 mL, 11.7 mmol) in toluene (7.8 mL). The mixture was stirred at room temperature for 5 hours. The mixture was then diluted with EtOAc (30 mL) and saturated NaHCO3 (20 mL). The organic layer was washed with H2O (1×20 mL), dried (Na2SO4), filtered and concentrated to give 4-chloro-N-(2-(diethylamino)ethyl)benzenamine as an oil which was used without purification. MS (APCI+) [M+H]+227.3.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:11]1([O:21][CH2:22][CH:23]([OH:33])[CH2:24][NH:25]C(C)CCC(O)=O)[C:20]2[C:15](=C[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[CH2:19]([C:20]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:21][CH2:22][CH:23]([OH:33])[CH2:24][NH:25][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:18]=[CH2:17]
Reactant: CC(CCC(=O)O)NCC(O)COc1cccc2ccccc12
Reactant: CC(=O)CCCCC(=O)O
Product: C=CCc1ccccc1OCC(O)CNC(C)CCCCC(=O)O

Procedure:
The title compound was synthesized from Compound V (R=2-allylphenyl) and 6-oxoheptanoic acid p-toluide on a 1.5 mmol scale using the general procedure described above for Compound 7.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:30])[NH:18][C@H:19](C=O)[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]2[CH2:31][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])OCC.C(=O)(O)[O-].[Na+]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:30])[NH:18][C@@H:19]([CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH:32]([O:36][CH2:37][CH3:38])[O:39][CH2:40][CH3:41])[C@@H:15]2[CH2:31][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)C[C@@H](C=O)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Yield: 77.6 %

Procedure:
To a solution of (1R,3S,4S)-3-((S)-2-tert-Butoxycarbonyl-1-formyl-ethylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (698 mg) in dichloromethane (10 ml) was added triethyl orthoformate (720 mg) and p-toluenesulfonic acid monohydrate (6 mg). The resulting mixture was stirred at ambient temperature until no aldehyde remained by TLC. Saturated aqueous sodium bicarbonate solution was then added and the organic phase removed. This was washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. This gave the sub-title compound as a pale yellow oil (635 mg, 78%); 1H NMR (400 MHz, d-6 DMSO) δ 0.96-1.15 (6H, m), 1.26-1.84 (16H, m), 2.20-2.50 (2H, m), 3.40-3.81 (5H, m), 4.10-4.28 (2H, m), 4.37 (1H, m), 4.88-5.14 (2H, m), 7.20-7.40 (5H, m), 7.65 (0.5H, d), 7.80 (0.5H, d).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:21])[CH2:18][O:19][CH2:20]3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: [H][H]
Reactant: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)COC1
Product: OC1(c2ccc3c(c2)CNC3)COC1

Procedure:
Prepared in analogy to Example A62(c) from 3-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-oxetan-3-ol and hydrogen. Brown solid. MS (m/e): 192.3 ([M+H]+, 100%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:18])=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[NH2:17])C>C(O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:7]2[C:8](=[CH:9][C:10]=1[O:15][CH3:16])[NH:17][C:4](=[O:3])[C:5]([CH3:18])=[CH:6]2
Reactant: CCOC(=O)C(C)=Cc1cc(OC)c(OC)cc1N
Solvent: CCO
Product: COc1cc2cc(C)c(=O)[nH]c2cc1OC
Yield: 92 %

Procedure:
Into 30 ml of ethyl alcohol, 0.5 g of 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid ethyl ester was dissolved. This solution was irradiated with ultraviolet rays at 365 nm for about 20 hours, and the precipitated crystal was filtered out. This crystal was recrystallized from ethanol, whereby 0.38 g of the aimed compound was obtained (yield: 92%).