Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH3:23])[C:7]([N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>C1COCC1.C(O)C>[Cl:31][C:32]1[N:37]=[C:36]([NH:1][C:2]2[CH:25]=[CH:24][C:5]3[N:6]([CH3:23])[C:7]([N:9]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[N:8][C:4]=3[CH:3]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(Nc3ccnc(Cl)n3)ccc21
Temperature: 75 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
To a solution of tert-butyl 5-amino-1-methyl-1H-benzimidazol-2-yl(phenyl)carbamate (1.03 g, 3.0 mmol) in THF (3 ml) and ethanol (9 ml) was added NaHCO3 (0.76 g, 9.0 mmol) and 2,4-dichloropyrimidine (0.89 g, 6.0 mmol) and the reaction was heated to 75° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. The crude material was purified on silica gel to give the title compound as a white foam (0.98 g, 73%). 1H NMR (300 MHz, d6-DMSO) δ 10.00 (s, 1H), 8.10 (d, J=5.7 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.36-7.39 (m, 5H), 7.24-7.34 (m, 1H), 6.70 (d, J=6.0 Hz, 1H), 3.73 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:28])(=[N:22]C(OCC)=O)=[O:21])=[CH:16][CH:15]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH:30]([CH3:32])[CH3:31].[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:28])(=[NH:22])=[O:21])=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH:30]([CH3:32])[CH3:31]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(NC(C)C)c3cc2Br)cc1
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Nc1ncnc2cc(OCc3ccc(S(C)(=N)=O)cc3)c(Br)cc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
(RS)-S-[4-({[6-Bromo-4-(isopropylamino)quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-methylsulphoximide (37 mg, 0.07 mmol) is dissolved in ethanol (5 ml), treated with sodium ethoxide (16 mg, 0.26 mmol), and is stirred at 60° C. for 6 hours and subsequently stirred at room temperature overnight. The batch is added to dilute aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. The desired product is obtained after chromatographic purification (silica gel, dichloro-methane/methanol: 020% methanol) of the residue in 79% yield (25 mg)
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]([CH2:14][C:15](Cl)=[O:16])#[N:13].N1C=CC=CC=1>ClCCCl>[C:12]([CH2:14][C:15]([NH:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:16])#[N:13]
Reactant: CCOC(=O)c1nccn1N
Reactant: N#CCC(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nccn1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
In a 100 ml RB flask was added ethyl 1-amino-1H-imidazole-2-carboxylate (0.4 g, 2.58 mmol) from (1a), DCE (12.0 mL), 2-cyanoacetyl chloride (0.320 g, 3.09 mmol) and pyridine (0.417 mL, 5.16 mmol). The resulting mixture was stirred overnight under nitrogen at room temperature. The reaction was concentrated and diluted with ethyl acetate and washed with water (2×), then the aqueous was back-extracted with ethyl acetate. The organics were collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide ethyl 1-(2-cyanoacetamido)-1H-imidazole-2-carboxylate (0.38 g, 66.3% yield).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)C.[H-].[Na+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](C2C=CC=CC=2)=O)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([CH3:28])=[CH:5][C:4]([OH:3])=[O:14])=[CH:25][CH:26]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)c1ccc(CC(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=CC(=O)O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
The solution of ethyldiethylphosphonoacetate (1.2 eq, 0.25 g) in 4 ml of DMF was put into the flask and then cooled to 0° C. To the solution was added 60% sodium hydride (1.4 eq, 1.27 mmol, 51 mg) and then added 4-t-butylphenylacetophenone (0.16 g, 0.91 mmol) in 3 ml DMF slowly. The mixture solution was stirred for 4 hours. After conforming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, and washed with water. The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was dissolved in MeOH/THF solution and added 1N NaOH solution, and then refluxed overnight. After conforming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, and acidified with 1N HCl solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained solid was purified with column chromatography to yield the title compound (134 mg, 68.1%)
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[OH-].[Na+].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=[O:32].[Na+].[Na+].Cl>C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:32])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: -7 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
A flask equipped with a stirrer is charged with acetonitrile (0.6 L). Under mixing, compound VI (30 g) is added, followed by 18.8% aqueous NaOH (70 ml, 5.0 eq.). The flask is then cooled to −7° C. Aqueous 10.6% active NaOCl (70 ml, d=1.16, 1.4 eq.) is added dropwise over 45 min. The two-phase mixture is stirred at room temperature for 1.5 h. Aqueous Na2S2O5 (120 ml) is added. The pH is then adjusted to 8 with 10% HCl solution (120 ml). The phases are separated. The organic layer is washed with water, and the aqueous phase is washed twice with acetonitrile. The organic phases are combined, dried over MgSO4, and concentrated to one quarter of their original volume. Pantoprazole is precipitated from the concentrate and separated by filtration to yield pantoprazole (20.1 g, 64.8%) containing 0.04% compound VI and free of sulfone within the limit of UV detection.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19].O>C(Cl)Cl>[C:18]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CNc1cccc(N)c1C#N
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNc1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (4.4 g) in methylene chloride (50 ml) is added pyridine (4.9 ml), and thereto is added dropwise acetoxyacetyl chloride (6.5 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (5.1 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16](=[O:19])[NH:17][N:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.[CH:22]1([C:25]2[CH:29]=[C:28]([CH2:30]O)[N:27]([CH3:32])[N:26]=2)[CH2:24][CH2:23]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:22]1([C:25]2[CH:29]=[C:28]([CH2:30][N:17]3[C:16](=[O:19])[N:14]4[CH:15]=[C:10]([C:7]5[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=5)[CH:11]=[CH:12][C:13]4=[N:18]3)[N:27]([CH3:32])[N:26]=2)[CH2:24][CH2:23]1
Reactant: O=c1[nH]nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Reactant: Cn1nc(C2CC2)cc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nc(C2CC2)cc1Cn1nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn2c1=O
Reaction time: 4 h

Procedure:
6-(4-(Trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50.0 mg, 0.169 mmol), (3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)methanol (38.6 mg, 0.2535, 1.5 equiv.) and PPh3 (60.5 mg, 0.2535 mmol, 1.5 equiv.) were placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added THF (3 mL) and diethyl azodicarboxylate (40% in toluene, 110.5 mg, 0.2535 mmol, 1.5 equiv.) at room temperature. The reaction mixture was stirred at the same temperature for 4 h. The reaction mixture was directly loaded onto prep-HPLC to give 2-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as light yellow crystals. FTIR (ATR) 1710 cm−1 (CO).
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[S:9][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=S)N(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(N(c2ccccc2)c2ccccc2)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 20 g of 1,1-diphenylthiourea, 19 g of ethyl bromopyruvate and 200 ml of ethanol, giving the title compound as an orange oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([C:13]([NH:15][CH2:16][C:17]#[CH:18])=O)=[CH:11][C:10]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[O:20])=[CH:9][N:8]=2)[CH2:3]1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([C:13]3[N:40]([CH2:39][C:38]4[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=4)[C:17]([CH3:18])=[CH:16][N:15]=3)=[CH:11][C:10]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:30])[F:32])=[CH:26][CH:27]=3)=[O:20])=[CH:9][N:8]=2)[CH2:3]1
Reactant: C#CCNC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Reactant: COc1ccc(CN)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(C)cnc2-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cc1

Procedure:
A stirred mixture of (R)-2-(3-hydroxypyrrolidin-1-yl)-N3-(prop-2-yn-1-yl)-N5-(4-(trifluoromethoxy)phenyl)pyridine-3,5-dicarboxamide (Stage 72.2, 0.50 g, 1.115 mmol) and 4-methoxybenzylamine (0.175 mL, 1.338 mmol) in toluene (30 mL) was treated with zinc trifluoromethanesulphonate (61 mg, 0.17 mmol) and heated under reflux for 41 h. The solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, EtOAc 100%) to afford the title compound as a foam. HPLC (Condition 4) tR=4.66 min, UPLC-MS (Condition 8) tR=0.93 min, m/z=568.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.72 (br. s, 1H), 2.19 (s, 3H), 2.74-3.09 (m, 2H), 2.85-3.07 (m, 1H), 3.15-3.31 (m, 2H), 3.64 (s, 3H), 4.15 (br. s, 1H), 4.90 (m, 3H), 6.72-6.86 (m, 5H), 7.35 (d, J=8.59 Hz, 2H), 7.85 (d, J=8.42 Hz, 2H), 7.19-8.03 (m, 1H), 8.78 (br. s, 1H), 10.05-10.20 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(C#CCCCO)ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCc2cc(CCCCCO)ccc21
Yield: 52.2 %

Procedure:
850 mg (2.7 mmol) 6-(5-Hydroxy-pent-1-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in 30 ml ethanol were hydrogenated in the presence of 10% Pd/C over night. Purification by column chromatography yielded 450 mg (68%) 6-(5-Hydroxy-pentyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as yellow oil, MS: 319 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[Cl:19])=[CH:4][C:3]=1[N:20]1[C:24](=[O:25])[N:23]([CH:26]([F:28])[F:27])[C:22]([CH3:29])=[N:21]1>C(O)(=O)C.O.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:5]2[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([N:20]3[C:24](=[O:25])[N:23]([CH:26]([F:27])[F:28])[C:22]([CH3:29])=[N:21]3)[CH:4]=2)=[C:11]([Cl:19])[CH:12]=1
Reactant: Cc1nn(-c2cc(Oc3ccc([N+](=O)[O-])cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2cc(Oc3ccc(N)cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To a stirred mixture of 10.0 g (0.021 mole) of 1-[2,4-dichloro-5-(2-chloro-4-nitrophenoxy) phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 100 ml of glacial acetic acid and 5 ml of water was added slowly 10.0 g (0.179 mole) of iron powder. The reaction mixture was heated at 50° C. and then was allowed to cool to room temperature at which it was stirred for 1.5 hours. The mixture was poured into ice-water, and the aqueous mixture was extracted with diethyl ether. The extract was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography to yield 8.5 g of 1-[5-(4-amino-2-chlorophenoxy)-2,4-dichlorophenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid, m.p. 161°-162° C., compound 180 of Table 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:13](=[O:27])[C@@H:12]([CH2:28][C:29]([O:31]CC)=[O:30])[O:11]2)=[C:6]([O:34][CH3:35])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO.O1CCCC1>O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[C:13](=[O:27])[C@@H:12]([CH2:28][C:29]([OH:31])=[O:30])[O:11]2)=[C:6]([O:34][CH3:35])[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1O[C@H](c2ccc(OCC)cc2OC)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc([C@H]2O[C@H](CC(=O)O)C(=O)N(CC(C)(C)C)c3ccc(Cl)cc32)c(OC)c1

Procedure:
A mixture of ethyl trans-5-(4-ethoxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (0.18 g), potassium carbonate (0.10 g), methanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) was refluxed for 1.5 h. The resulting mixture was concentrated in vacuo, acidified with 1N hydrochloric acid (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo to give trans-5-(4-ethoxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid as colorless crystals (mp=230°-232° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[O:17]=[C:18]1[NH:23][CH:22]=[C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH:20]=[CH:19]1>>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:28]([C:27]4[CH:26]=[CH:25][C:24]([C:21]5[CH:20]=[CH:19][C:18](=[O:17])[NH:23][CH:22]=5)=[CH:32][CH:31]=4)=[O:29])[CH2:13][CH2:12]3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]c(C3CCNCC3)cc12
Reactant: O=C(O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Product: O=C(c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CCC(c2cc3c(Cl)nccc3[nH]2)CC1

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part K, but with 4-chloro-2-piperidin-4-yl-1H-pyrrolo[3,2-c]pyridine and 4-(6-oxo-1,6-dihydropyridin-3-yl)benzoic acid as starting materials. Purification was by flash column chromatography on silica gel. 1H NMR (d4-MeOH) δ 7.99 (dd, 1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.66-7.63 (m, 2H), 7.54-7.50 (m, 2H), 7.30 (dd, 1H), 6.65 (d, 1H), 6.41 (s, 1H), 3.96-3.84 (m, 1H), 3.45-3.05 (m, 4H), 2.22-2.01 (m, 2H), 1.92-1.71 (m, 2H). ESI MS (M+1)+: 433, 435 (Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:7]=[C:8]([C:10](=[N:20][NH2:21])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH:9]=1)=[O:4].[N:26]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:7]=[C:8]([C:10]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[F:19])[N:26]=[N:21][N:20]=2)[CH:9]=1)=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(C(=NN)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(-c2nnnn2-c2cccc(F)c2F)cn1S(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution of 4-[N-(2,3-difluoro-phenyl)-N′-amino-carbamimidoyl]-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (250 mg, 0.67 mmol) in 2N HCl (10 mL) was added a solution of NaNO2 (56 mg, 0.81 mmol) in water (2 mL) slowly at 0° C. The reaction mixture was stirred at this temperature for 5 minutes and then neutralized by addition of 6N NaOH. The resulting white precipitate was collected by filtration and washed with water. After drying on the vacuum pump for 6 hours, the crude product was obtained (250 mg, 97%) as white solid. 1H NMR (500 MHz, DMSO-d6) δ7.94 (q, 1H), 7.78 (t, 1H), 7.68 (s, 1H), 7.60 (q, 1H), 7.15 (s, 1H), 3.94 (s, 3H), 3.82 (s, 3H) ppm. MS (ES+): m/e=384.1 (M+H); LC/Method A/3.63 min.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:57][C:58]1[S:59][CH:60]=[CH:61][N:62]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH:20]([OH:22])[CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:57][C:58]2[S:59][CH:60]=[CH:61][N:62]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CC(O)CC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)CC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 53.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-propionic acid (100 mg, 0.30 mmol), benzotriazol-I -yloxytris(dimethylamino)phosphonium hexafluorophosphate (200 mg, 0.45 mmol), triethylamine (0.13 mL, 0.93 mmol) and 2-aminothiazole (52 mg, 0.45 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (61 mg, 47.9%) as a white solid: mp 162-163° C.; EI-HRMS m/e calcd for C22H26N2O2S (M+) 382.1715, found 382.1718.
Reaction SMILES: C(O)CCCCCCCO.BrCC1C=CC(C2C=CC=CC=2)=CC=1.[C:25]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:30]=[CH:29][C:28]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:27][CH:26]=1.C1(C2C=CC=CC=2)C=CC(COCCCCCCCC(O)=O)=CC=1.Cl.Cl.[CH2:74]([O:81][C:82](=[O:90])[CH2:83][C@@H:84]([NH2:89])[CH2:85][N:86]([CH3:88])[CH3:87])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>>[CH2:74]([O:81][C:82](=[O:90])[CH2:83][C@@H:84]([NH:89][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:30][CH:29]=1)[CH2:85][N:86]([CH3:87])[CH3:88])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: OCCCCCCCCOCc1ccc(-c2ccccc2)cc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: BrCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C(O)CCCCCCCOCc1ccc(-c2ccccc2)cc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(-c2ccccc2)cc1

Procedure:
The title compound, m/e=455.3 ([M+H]+), was produced in analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 4-(bromomethyl)-biphenyl, leading to 8-(biphenyl-4-ylmethoxy)-octan-1-ol, which was oxidized in step 2 to 8-(biphenyl-4-ylmethoxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(biphenyl-4-ylmethoxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][NH2:11])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccc(-n2ccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-n2ccnc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
4-(1-imidazolyl)-benzonitrile (1 g, 5.92 mmol) was dissolved in anhydrous THF (10 mL) and added drop-wise to a stirring solution of LAH-THF (1 M in THF, 18 mL) at room temperature. The reaction mixture was refluxed under Ar for 2 h and the progress was monitored by TLC. The mixture was cooled to 0° C. and quenched by drop-wise addition of a saturated Na2SO4—H2O solution. The mixture was stirred for 1 h and filtered to remove lithium salts. The filtrate was dried over anhydrous MgSO4 and concentrated to obtain 4-(1-imidazolyl)-benzylamine (0.8 g, 80%). LCMS: MH+=174.