Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:42]([CH2:47][CH3:48])=[N:43][CH:44]=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:42]([CH2:47][CH3:48])=[N:43][CH:44]=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CCc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K31) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (373 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)=[CH:4][CH:3]=1.[CH3:22][N:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:24](Cl)=[O:25]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[C:12]([O:18][C:24](=[O:25])[N:23]([CH3:22])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:11]=3)=[CH:20][CH:21]=1
Reactant: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(O)ccc12
Reactant: CN(C(=O)Cl)c1ccccc1
Product: Cc1c(Cc2ccc(F)cc2)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12

Procedure:
The title compound was prepared from 3-(4-fluorobenzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and N-methyl-N-phenylcarbamoyl chloride.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+:10]>O>[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[K+:10].[K+:10]
Reactant: O=C(O)CCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCC(=O)[O-]

Procedure:
Six kg of succinic acid were dissolved in 10 liters of hot water (60-70° C.), and 8 kg of solid potassium hydroxide was added to adjust the pH to 7.5. 19 liters of potassium succinate solution were obtained, with a concentration of 47% w/w.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Product: CC(C)(C)OC(=O)N1CCCC(COCc2ccc(-c3ccc(Cl)cc3)cc2)C1
Yield: 85.5 %

Procedure:
Using 1-(tert-butoxycarbonyl)-piperidin-3-yl methanol (431 mg, 2.00 mmol) and 4′-chloro-4-chloromethylbiphenyl (474 mg, 2.00 mmol), the same procedure was followed as in Step 5a of Example 5 to give 711 mg (86%) of the desired compound as a colorless oil.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][C:56]([F:59])([F:58])[F:57])=[CH:50][CH:49]=3)[CH:41]=2)([O:38][CH3:39])[O:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].O>O1CCCC1>[CH2:15]([O:14][C@H:13]1[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:11]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:10]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][CH2:55][C:56]([F:58])([F:59])[F:57])=[CH:52][CH:53]=3)[CH:41]=2)([O:38][CH3:39])[O:9][C@@H:8]1[CH2:7][OH:6])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]silane 17g (23.7 g, 27.01 mmol) in tetrahydrofuran (100 mL) was added tetrabutylammonium fluoride (54.0 mL, 54.02 mmol, 1 M in tetrahydrofuran) at room temperature. The mixture was stirred at room temperature for 1 hour and then 40° C. for 12 hours. The reaction mixture was cooled to room temperature, and then 50 mL of saturated aqueous sodium bicarbonate and 100 mL of water were added. The resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (80 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 17h as orange-yellow oil (5.5 g, 27.0%, HPLC: 84.7%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ (ppm): 7.39-7.30 (m, 12H), 7.21 (m, 4H), 7.07 (d, 2H), 7.00 (d, 2H), 6.80 (d, 2H), 4.98-4.86 (m, 3H), 4.70 (d, 1H), 4.50 (d, 1H), 4.34-4.24 (m, 2H), 4.11 (m, 2H), 3.95-3.86 (m, 3H), 3.80 (m, 1H), 3.73 (m, 1H), 3.70 (s, 1H), 3.30 (d, 1H), 3.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:39]1([CH2:45][C:46]([NH2:48])=[O:47])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:42]3[CH2:43][CH2:44][N:39]([CH2:45][C:46]([NH2:48])=[O:47])[CH2:40][CH2:41]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:34])[CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Agent: Cl
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(N)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound. HR-MS (ES, m/z) calculated for C34H40N5O4Cl2 [(M+H)+] 652.2452, observed 652.2451.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22]>>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)CN
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and glycine methyl ester hydrochloride according to the procedure of Example 154 as a gum; MS (ES) m/z: 291.3 (MH+).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[N:14]([CH:17]1[CH:20](CCO)[NH:19][C:18]1=[O:24])=[N+:15]=[N-:16].N1C=CC=CC=1>C(Cl)Cl>[N:14]([CH:17]1[CH:20]([CH2:2][CH2:3][O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[NH:19][C:18]1=[O:24])=[N+:15]=[N-:16]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [N-]=[N+]=NC1C(=O)NC1CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: [N-]=[N+]=NC1C(=O)NC1CCOC(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
Trifluoroacetic anhydride (0.2 mol) is added dropwise to an ice-cold, stirred solution of 3-azido-4-(2-hydroxyethyl)-azetidin-2-one (0.2 mol) and pyridine (0.21 mol) in methylene chloride (200 ml). The solution is stirred for 15 more min. at room temperature (25° C.), then washed with water, dried with magnesium sulfate, and filtered. Evaporation of the methylene chloride under vacuum leaves 3-azido-4-(2-trifluoroacetoxyethyl)azetidin-2-one.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH3:14][N:15]1[C@H:19]2[C@H:20]3[N:25]4[C@H:26]([O:27][CH2:28][C@H:24]4[C:23]4[C:29]([O:33][CH3:34])=[CH:30][CH:31]=[CH:32][C:22]=4[CH2:21]3)[C@@H:16]1[CH2:17][C@H:18]2[C:35]([O-:37])=[O:36]>>[CH3:14][N:15]1[CH:19]2[CH:20]3[N:25]4[CH:26]([O:27][CH2:28][CH:24]4[C:23]4[C:29]([O:33][CH3:34])=[CH:30][CH:31]=[CH:32][C:22]=4[CH2:21]3)[CH:16]1[CH2:17][CH:18]2[C:35]([OH:37])=[O:36].[CH2:8]([C:3]([OH:4])([C:5]([OH:7])=[O:6])[CH2:2][C:1]([OH:13])=[O:12])[C:9]([OH:11])=[O:10]
Reactant: COc1cccc2c1[C@@H]1CO[C@@H]3[C@@H]4C[C@@H](C(=O)[O-])[C@H]([C@H](C2)N31)N4C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: COc1cccc2c1C1COC3C4CC(C(=O)O)C(C(C2)N13)N4C

Procedure:
In this example, 10 ml of the DC-52 millipore filtrate obtained in Example 1 is cooled to 5° C., adjusted to pH 3.0 with citric acid, and then freeze-dried to obtain 630 mg of DC-52 citrate powder (equivalent weight ratio: 1.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]#[N:31])[C:9]2[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([C:26]#[N:27])[C:18]([NH:20][C:21](=O)[O:22]CC)=[O:19])=[CH:11][C:10]=2[O:28][CH3:29])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:30]#[N:31])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:21](=[O:22])[NH:20][C:18](=[O:19])[C:17]([C:26]#[N:27])=[N:16]3)=[CH:11][C:10]=2[O:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1ccc(C(C#N)c2ccc(Cl)cc2)c(OC)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1cc(-n2nc(C#N)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 8.3 parts of ethyl [2-[[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]hydrazono]-2-cyanoacetyl]carbamate, 1.77 parts of anhydrous potassium acetate and 100 parts of acetic acid is stirred for 2 hours at reflux temperature. The reaction mixture is evaporated in vacuo. The residue is stirred in water. The product is filtered off and dissolved in trichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo, yielding 2-[4-[(4-chlorophenyl)cyanomethyl]-3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C@@H:9]3[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:29]N1C(=O)CCC1=O>O1CCCC1>[Br:29][C:7]1[N:6]([C@@H:9]2[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(Cl)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)ccc21
Yield: 75.6 %

Procedure:
The title compound was prepared according to General Procedure IV using 5-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.17 g, 0.41 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 2.6 g (7.0 mmol) of N-bromosuccinimide that was added over 2 h. The product from work-up by General Procedure IV was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with dichloromethane containing 1.0% methanol to give 2-Bromo-5-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.15 g, 0.31 mmol, 76%); MS (ES+): m/z (rel. intensity) 511 (0.25, M+23 (Na)) 1H NMR (DMSO-d6) δ8.02-8.00 (d,1H, J=8.7), 7.68 (d, 1H, J=2.1 Hz), 7.30-7.27 (dd, 1H, J=1.9 Hz, J=8.9 Hz), 5.96-5.93 (d, 1H, J=8.9 Hz), 5.67-5.62 (m, 2H), 5.55-5.45 (m,1H), 4.20-3.90 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.73 (s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[N:12]=[C:6]2[CH2:7][CH:8]([NH2:11])[CH2:9][CH2:10][N:5]2[N:4]=1.C(Cl)Cl.[CH3:16][N:17]1[C:21]([C:22](Cl)=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[CH:19]=[N:18]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[Br:2][C:3]1[N:12]=[C:6]2[CH2:7][CH:8]([NH:11][C:22]([C:21]3[N:17]([CH3:16])[N:18]=[CH:19][C:20]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)=[O:23])[CH2:9][CH2:10][N:5]2[N:4]=1
Reactant: Cc1cccc(-c2cnn(C)c2C(=O)Cl)n1
Reactant: NC1CCn2nc(Br)nc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2cnn(C)c2C(=O)NC2CCn3nc(Br)nc3C2)n1
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
The 2-bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (38 mg) obtained in (Example 5.16) <Step 6> was added at 0° C. to a methylene chloride (1 ml) solution of the 1-methyl-4-(6-methylpyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (35 mg) obtained in (Example 5.47) <Step 1> and triethylamine (0.06 ml). The obtained mixture was stirred for 30 minutes. Thereafter, a saturated sodium hydrogen carbonate aqueous solution (2 ml) was added to the reaction solution, and the mixed solution was then purified by LC/MS, so as to obtain the title compound (29 mg) in the form of a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:12](=[O:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:20]([NH:23][CH2:24][CH2:25][C:26](O)=[O:27])(=[O:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:12](=[O:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:27])(=[O:22])[CH3:21]
Reactant: COC(=O)CC(CSCCN)C(=O)c1cccnc1
Reactant: CC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CC(CSCCNC(=O)CCNC(C)=O)C(=O)c1cccnc1
Yield: 75 %

Procedure:
A solution of methyl 3-[(2-aminoethylthio)methyl]-4-oxo-4-(3-pyridyl)butanoate (747 mg), 3-(acetylamino)propanoic acid (302 mg), dicyclohexylcarbodiimide (433 mg), 1-hydroxybenzotriazole (567 mg) and N-methylmorpholine (402 mg) in dichloromethane (10 mL) were stirred at room temperature overnight. The solution was concentrated and purified by flash chromatography (SiO2, chloroform:methanol=9:1) to give the title compound in 75% yield; ESMS (M+1)+353.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[O:19][CH3:20])[CH2:3]1>CCOC(C)=O.[Pd]>[F:21][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[O:19][CH3:20])[CH2:3]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(F)(F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1OCCN1CCC(F)(F)C1
Reaction time: 18 h
Yield: 89.2 %

Procedure:
3,3-Difluoro-1-[2-(2-methoxy-4-nitrophenoxy)ethyl]pyrrolidine (0.173 g, 0.5728 mmol) was dissolved in EtOAc (5 mL). 10% Pd/C (0.017 g) was added. The reaction was stirred under 1 atm of H2. for 18 h. The mix was then filtered through celite and the celite washed with EtOAc (3×10 mL). The organics were concentrated to give 0.1389 g (0.5107 mmol, 89%) of the product as a red oil. 1H NMR (CDCl3) δ 6.73 (d, 1H, J=8.4 Hz), 6.29 (s, 1H), 6.19 (d, 1H, J=8.4 Hz), 4.02 (t, 2H, J=5.8 Hz), 3.80 (s, 3H0, 3.04 (t, 2H, J=13.4 Hz), 2.87 (m, 4H), 2.27 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C.O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(-n2cccc2)cc1

Procedure:
To a stirred solution of methyl 4-aminobenzoate (7.6 g) in acetic acid (25 ml) was added 2,5-dimethoxytetrahydrofuran (6.6 g) dropwise and the reaction mixture was heated under reflux for 1 hour and then diluted with water. The resulting precipitated crystals were purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane afforded the title compound as colorless plates (7.5 g, 74%), m.p. 128°-129° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[O:20]1CCOCC1.[OH-].[Na+]>O>[NH2:3][C:4]1[C:5]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:20])=[O:1]
Reactant: O=C1Cc2cccc(S(=O)(=O)c3ccccc3)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1S(=O)(=O)c1ccccc1

Procedure:
A mixture of 2-oxo-7-phenylsulfonylindoline (6.50 g.), dioxane (100 ml.), sodium hydroxide (3.0 g.) water (50 ml.) was refluxed under heating for 16 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water, washed with diethyl ether, adjusted to pH 4 with 1N sulfuric acid and then extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure. The residue was washed with a mixture of ethanol and diethyl ether and cooled. The precipitates were collected by filtration to give white crystals of 2-(2-amino-3-phenylsulfonylphenyl)acetic acid (3.60 g.). mp 218° to 220° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][CH:5]([N:7]2[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[CH:8]2)[CH2:4]1)[CH3:2].C(=O)(O)[O-].[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([CH:3]1[CH2:4][CH:5]([N:7]2[CH:11]=[C:10]([CH:12]=[O:13])[N:9]=[CH:8]2)[CH2:6]1)[CH3:2]
Reactant: CCC1CC(n2cnc(CO)c2)C1
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1CC(n2cnc(C=O)c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
The compound (119 mg) obtained in Step 2 of this Reference Example was dissolved in toluene (5 mL). To this solution, a solution of sodium bicarbonate (166 mg) in water (4 mL), iodine (305 mg), and 2,2,6,6-tetramethyl-1-piperidinyloxy (11 mg) were added in this order, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, saturated aqueous sodium thiosulfate was added, and organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1-1/2) to obtain the title compound (115 mg, diastereomeric mixture, trans:cis=1:1). 1H-NMR (CDCl3) δ: 0.86 (1.5H, t, J=7.3 Hz), 0.90 (1.5H, t, J=7.3 Hz), 1.44 (9H, s), 1.51 (1H, dq, J=7.4, 7.4 Hz), 1.59 (1H, dq, J=7.4, 7.4 Hz), 1.87-1.97 (1H, m), 2.04-2.13 (0.5H, m), 2.28-2.38 (1.5H, m), 2.42-2.52 (1H, m), 2.66-2.75 (1H, m), 4.48 (0.5H, tt, J=9.0, 7.8 Hz), 4.72 (0.5H, tt, J=7.8, 7.4 Hz), 7.58 (0.5H, s), 7.61 (0.5H, s), 7.69 (0.5H, s), 7.74 (0.5H, s), 9.87 (0.5H, s), 9.88 (0.5H, s).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:27]([C:17]34[CH2:26][CH:21]5[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]5)[CH2:24]3)[CH2:18]4)=[O:28])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: CCC(NC(=O)C12CC3CC(CC(C3)C1)C2)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 150 mg (0.74 mmol) 1-adamantanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)C[OH:10])=CC=C([N+]([O-])=O)C=1.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]>>[NH:21]1[CH2:28][C@H:27]([OH:10])[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
A plasmid (pHuCol(α2)Ec, FIG. 66) containing the gene for Type I (α2) collagen with optimized E. coli codon usage (FIGS. 50A-50E) (SEQ. ID. NO. 31) under control of the tac promoter and containing the gene for chloramphenicol resistance was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F−). Transformation cultures were plated on LB agar containing 20 μg/ml chloramphenicol. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 100 ml of LB media containing 20 μg/ml chloramphenicol. This culture was grown to an OD600 nm of 0.5 and 100 μl aliquots transferred to 1.5 ml tubes. The tubes were stored at −80° C. For expression, a tube was thawed on ice and used to inoculate 25 ml of LB media containing 20 μg/ml chloramphenicol. After overnight growth at 37° C., a four ml aliquot was withdrawn, centrifuged, the cell pellet washed once with 1 ml of 2×YT media containing 20 μg/ml chloramphenicol, and the washed cells used to inoculate 1 L of 2×YT medium containing 20 μg/ml chloramphenicol. This culture was grown at 37° C. to an OD600 nm of 0.8. The culture was centrifuged and the cell pellet washed once with 100 ml of M9 medium (1×M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 20 μg/ml chloramphenicol). The cells were resuspended in 910 ml of M9 medium (1×M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 20 μg/ml chloramphenicol) and allowed to grow at 37° C. for 30 minutes. NaCl (80 ml of 5 M), hydroxyproline (7.5 ml of 2M), and IPTG (500 μl of 1 M) were added and growth continued for 3 hours. Cells were harvested by centrifugation and stored at −20° C.