Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(OCC)C>[CH2:9]([PH:4](=[O:3])[OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CCOP(Cl)OCC
Solvent: CCOCC
Solvent: O
Product: O=[PH](O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Diethylchlorophosphite (15.6 g,0.1 mol) in 100 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and stirred at room temperature overnight. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 mL of water was added followed by 0.5 mL of concentrated hydrlochloric acid. An exothermic reaction was observed and stirring continued for 15 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear liquid was brought up in sodium hydroxide (40 mL, 2.0 M NaOH), stirred for 1 hour and washed once with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give phenethylphosphinic acid (1,R=CH2CH2Ph, R1=H)(9.8 g, 58%) as a clear light yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:25]1[N:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[N:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)n1

Procedure:
Using a procedure similar to that described in Example 86 except starting with 4-amino-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (prepared as described in Example 8b) and 2-chloro-4,6-dimethylpyrimidine the hydrochloride salt of the title compound was obtained as a white solid (55%), mp 205°-207° C.; MS(CI): 411 (M+H); NMR (250 MHz, DMSO-d6): 10.07(br s, 1H), 8.40(br m, 1H), 7.38-7.31(m, 4H), 7.03-6.94(m, 4H), 6.72(s, 1H), 4.46(s, 1H), 4.35-4.33(m, 2H), 4.21-3.97(br m, 1H), 3.60-3.48(m, 4H), 2.74(s, 2H), 2.37(s, 6H), 2.13-1.94(m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(c1cccc(Br)n1)N1CCCC1

Procedure:
Prepared according to the procedure described in Example 121, Step 1, using 6-bromo-pyridine-2-carboxylic acid and pyrrolidine.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:24])[C@H:11]([CH3:23])[NH:12]C(OCC1C=CC=CC=1)=O)[CH3:2].[BrH:26].CCOCC>C(O)(=O)C>[BrH:26].[CH2:1]([NH:3][C:4](=[O:25])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:24])[C@H:11]([CH3:23])[NH2:12])[CH3:2]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Temperature: -60 °C
Yield: 82 %

Procedure:
1.81 g (0.0052 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline ethylamide were stirred for 1 hour in 10 ml of 4-N hydrobromic acid in acetic acid. To the solution were added 150 ml of dry ether and, after stirring for a few minutes, the oil was allowed to settle. The mixture was cooled to -60° C. and the ether decanted from the oil and discarded. The oil was then dissolved in methanol, the product crystallising out on the addition of ethyl acetate. There were obtained 1.25 g (82%) of L-alanyl-L-proline ethylamide hydrobromide of melting point 202°-204° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>[OH-].[Na+]>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=CC(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C=CC(=O)O)ccc1OC(C)=O
Temperature: 0 °C

Procedure:
118 g (0.058 mol) of 3-allyl-4-hydroxy-cinnamic acid are dissolved in 580 ml of 2 N sodium hydroxide solution, 800 g of ice are added and 120 g (1.16 mols) of acetic anhydride are introduced dropwise over the course of 15 minutes at 0°-5°C, whilst stirring. The crystals which have precipitated are then separated off, suction-dried and recrystallised from ethyl acetate. 3-Allyl-4-acetoxy-cinnamic acid of melting point 143°-144°C is thus obtained.
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=O)=C(F)C(F)=C(F)C=1F.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1>>[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH:44][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:24]=[CH:25][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:27][CH:28]=2)=[O:8])=[CH:39][CH:38]=1
Reactant: NCc1ccncc1
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCc4ccncc4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and (4-pyridyl)methylamine according to Procedure K: mp 211–215° C.; Anal. Calcd for C21H18N6O4S.¾H2O: C, 54.36; H, 4.24; N, 18.11. Found: C, 54.41; H, 4.20; N, 18.12.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=1)=[O:5].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[OH:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[O:35][C:2]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=1)=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cn1
Reactant: COc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(NC(=O)c2cc(C(F)(F)F)ccc2Oc2ccc(OC)cc2OC)cn1
Temperature: 100 °C

Procedure:
To methyl 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (51.3 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) was added 2,4-dimethoxyphenol (23.1 mg, 0.45 mmol), cesium carbonate (146.6 mg, 0.45 mmol) and the mixture was heated at 100° C. for 50 minutes to yield methyl 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinate that was taken into the next step without further purification.
Reaction SMILES: [OH-].[Na+].P(=O)(O)(O)O.[O:8]=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>OCC(CO)O>[CH:18]1([OH:19])[CH:9]([OH:8])[CH:10]([OH:11])[CH:12]([OH:13])[CH:14]([OH:15])[CH:16]1[OH:17]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: OC1C(O)C(O)C(O)C(O)C1O
Temperature: 30 °C
Reaction time: 15 h

Procedure:
During growth of cells in the fermentation vessel, the medium was maintained at a temperature of 30° C. pH 6.0 was maintained by addition of NaOH or phosphoric acid as needed. Agitation was begun at 600 r.p.m. and increased as needed to maintain D.O >30%. Aeration was 1 vvm air. Starting at 15 h after inoculation, a mixture of sterile glucose (25% w/v) and glycerol (6.8% w/v) was added to the fermentor at a rate of 0.1 ml/min/L. At 39 hours, the rate of addition of this mixture was decreased to 0.05 ml/min/L. The culture was terminated at 96 hours. Peak expression of TFPI (1 mg/ml) occurred by 72 h post-inoculation.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Cl[CH2:16][CH2:17][CH2:18][OH:19]>C(N(CC)CC)C>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=2)[O:14]1
Reactant: OCCCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 3-chloro-1-propanol according to Method AC (heating to 90° C. for 6 days before addition of further 3-chloro-1-propanol and triethylamine, and heating to 90° C. for a further 3 days) and was isolated as a brown gum (quantitative). LCMS (ES+) 253 (M+H)+, RT 2.53 minutes (Method 1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19].O>N1C=CC=CC=1>[CH3:21][O:20][C:18](=[O:19])[C:17]([NH:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1)=[O:22]
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Amino-6-chloropyridazine (516 mg) was dissolved in pyridine (26 mL), and to the solution were sequentially added triethylamine (665 mL) and methyl chlorooxoacetate (441 μL) under ice cooling, followed by stirring at room temperature for 14 hours. Water was added to the reaction mixture to partition the mixture, and the organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, to thereby give the title compound (748 mg).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][OH:11])[C:4]=1[CH3:12].[Cl-].[Li+].[OH-].[Na+]>CN(C)C=O>[OH:11][CH2:10][C:5]1[C:4]([CH3:12])=[C:3]([OH:2])[C:8]([CH3:9])=[CH:7][N:6]=1
Reactant: COc1c(C)cnc(CO)c1C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc(CO)c(C)c1O

Procedure:
A mixture of (4-methoxy-3,5-dimethylpyridin-2-yl)methanol (1.0 g) and anhydrous lithium chloride (0.76 mg) in dimethylformamide (10 mL) was heated at reflux for 43 hours. Sodium hydroxide solution (10% w/v, 30 mL) was then added and the resulting solution was extracted twice with diethyl ether. The aqueous phase was neutralized with 1N HCl (21 mL) and the volatiles were removed in vacuo. The resulting solid was purified by column chromatography with silica gel (eluted with 10% methanol-methylene chloride). Product-rich fractions were combined, concentrated in vacuo, and triturated with chloroform-acetonitrile (4:1) to afford the product, 2-hydroxymethyl-3,5-dimethylpyridin-4-ol, as a white solid (0.78 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C:35]([O:37]CC(=O)C1C=CC=CC=1)=[O:36])=[O:28])[NH:16][C:17]([C:19]1[N:20]([CH3:26])[C:21]([CH3:25])=[C:22]([CH3:24])[CH:23]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(O)(=O)C>[Zn].C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C:35]([OH:37])=[O:36])=[O:28])[NH:16][C:17]([C:19]1[N:20]([CH3:26])[C:21]([CH3:25])=[C:22]([CH3:24])[CH:23]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)OCC(=O)c2ccccc2)n(C)c1C
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)O)n(C)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.9 %

Procedure:
To a mixture of 2-oxo-2-phenylethyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1,4,5-trimethyl-1H-pyrrol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.30 g) and DMF (3.0 ml) were added zinc (0.61 g) and acetic acid (3.0 ml) under ice-cooling, followed by stirring at room temperature for 6 hours. To the reaction mixture was added ethyl acetate and the insolubles were separated by filtration through Celite. The filtrate was concentrated under reduced pressure, and a 1 M aqueous sodium hydroxide solution was added to the residue, followed by washing with diethyl ether. Citric acid was added thereto under ice-cooling, and the solid precipitated was collected by filtration and washed with water to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1,4,5-trimethyl-1H-pyrrol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylic acid (0.19 g).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH2:26]([O:25][C:23](=[O:24])[C:22]([NH:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:28])[CH3:27]
Reactant: Nc1cccnc1NC1CCCC1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cccnc1NC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a solution of N2-cyclopentylpyridine-2,3-diamine (C5) (1.78 g, 10.0 mmol) and triethylamine (1.52 g, 15.0 mmol) in dichloromethane (100 mL) was added ethyl chloro(oxo)acetate (1.49 g, 10.9 mmol), and the reaction mixture was stirred at room temperature for 18 hours. Removal of volatiles in vacuo afforded the crude product (2 g) as a brown solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([CH2:14][C:15](=[O:17])[CH3:16])(=[O:13])[CH3:12].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:14]([C:15](=[O:17])[CH3:16])[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCCCC1
Solvent: C1CCNCC1
Product: COc1ccc(C=C(C(C)=O)C(C)=O)cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
3-(4-methoxybenzylidene)-2,4-pentanedione was prepared by the condensation of 4-methoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol and yields about 70% 3-(4-methoxybenzylidene)-2,4-pentanedione (hereinafter “Compound 3”) with a purity, as determined by GC, of about 99.6%. Compound 3 is an off-white free-flowing powder having a melting point of 82-84° C. with a λmax at 319 nm.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@@H:51]([C:53]([F:56])([F:55])[F:54])[CH2:52][N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][C@@H:51]([C:53]([F:55])([F:54])[F:56])[CH2:52][N:44]2[C:43]1=[O:57])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CC[C@@H](C(F)(F)F)CN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((4S,8R,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (15 mg, 0.026 mmol) and Intermediate 61 (8.5 mg, 0.032 mmol) to give a white solid (16 mg, 73% yield). Anal. Calcd. for C41H51F3N4O6S2 m/z 816.4. found: 817.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.43 (d, J=7.0 Hz, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.30-7.06 (m, 10H), 5.33 (t, J=4.5 Hz, 1H), 5.26 (t, 1H), 5.12-5.06 (m, 1H), 5.00 (qd, J=10.2, 3.2 Hz, 2H), 4.47 (dd, J=13.4, 4.5 Hz, 1H), 3.68 (s, 3H), 3.17-3.03 (m, 2H), 2.89 (dd, J=15.3, 10.4 Hz, 2H), 2.84-2.70 (m, 5H), 2.55 (ddd, J=14.5, 5.9, 2.9 Hz, 1H), 2.49-2.38 (m, 3H), 2.38-2.24 (m, 1H), 2.16-1.99 (m, 4H), 1.99-1.86 (m, 1H), 1.83-1.45 (m, 11H), 1.22 (td, J=11.0, 8.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:36][CH2:37][CH:38]1[CH2:40][CH2:39]1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:36][CH2:37][CH:38]4[CH2:40][CH2:39]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Reactant: NCC1CC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(NCC3CC3)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=547.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and aminomethylcyclopropane.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26]([NH2:28])[N:25]=[C:24]1[CH3:29])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([O:18][C:19](=[O:30])[NH:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26]([NH:28][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)=[O:11])[N:25]=[C:24]1[CH3:29])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1nc(N)cn1CCNC(=O)OC(C)(C)C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: Cc1nc(NC(=O)Nc2cccc(C(F)(F)F)c2)cn1CCNC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
3-Trifluoromethylphenyl isocyanate (0.23 g, 1.2 mmol) was added to a solution of compound 40.2 (0.30 g, 1.2 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 15 minutes, concentrated and purified by flash column chromatography on silica gel using EtOAc to provide (2-{2-methyl-4-[3-(3-trifluoromethyl-phenyl)-ureido]-imidazol-1-yl}-ethyl)-carbamic acid tert-butyl ester (compound 40.3; 0.11 g, 21%). ES (+) MS m/e=428(M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(Br)nc1C
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of 6-bromo-2-methyl-pyridin-3-ol (4.06 g, 21.59 mmol), methyl iodide (1.61 mL, 25.91 mmol), potassium carbonate (5.97 g, 43.18 mmol) and acetonitrile (183.0 mL) was heated at reflux for 17 hours. The mixture was cooled to room temperature, filtered through a plug of celite and the solvent was evaporated under reduced pressure. Water (50 mL) and ethyl acetate (100 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography utilizing a gradient of 0-20% ethyl acetate in hexane to yield 6-bromo-3-methoxy-2-methyl-pyridine (3.18 g, 73%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.42 (d, J=8.6 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 3.82 (s, 3H), 2.32 (s, 3H). ESI-MS m/z calc. 201.0, found 202.1 (M+1)+; Retention time: 1.19 minutes (3 min run).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([C:17]([NH:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[C:22]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:21]=2)=[O:18])=[CH:9]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([C:17]([NH:19][C:20]2[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[C:22]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[CH:21]=2)=[O:18])=[CH:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)c2csc3ccccc23)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(NC(=O)c2csc3ccccc23)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid 5 mL was added to the obtained tert-butyl 4-(benzothiophene-3-carboxamido)-2-(4-fluoroanilino)benzoate, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 4-(benzothiophene-3-carboxamido)-2-(4-fluoroanilino)benzoic acid 24 mg of white solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:19]1([NH:22][C:23]([C:25]2[S:38][C:28]3=[N:29][C:30](S(C)=O)=[C:31]([Cl:34])[C:32]([CH3:33])=[C:27]3[C:26]=2[NH2:39])=[O:24])[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([NH:22][C:23]([C:25]2[S:38][C:28]3=[N:29][C:30]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:31]([Cl:34])[C:32]([CH3:33])=[C:27]3[C:26]=2[NH2:39])=[O:24])[CH2:21][CH2:20]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCc2ccccc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
To a solution of benzyl alcohol (0.541 g, 5.00 mmol) in THF (2.5 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(2.50 ml, 2.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 80° C. in a sealed tube for 2 hours, cooled to room temperature, and then quenched by the addition of water (15 ml). The mixture is diluted to 100 ml with water and then cooled to 0° C. and stirred. A yellow precipitate is formed. This solid is collected by filtration and purified by flash chromatography (1.5:1 hexane:EtOAc) to give the title compound as a pale yellow solid (0.130 g, 33%). Mass (m/z): 388.2 (M++1), 386.2 (M+−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH3:9][C:10]([CH3:12])=O>CC(O)=O>[CH3:9][C:10]1([CH3:12])[C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)=O
Solvent: CC(=O)O
Product: CC1(C)NCCc2[nH]cnc21
Yield: 79.8 %

Procedure:
A solution of histamine (500 mg, 4.5 mmol) and acetone (3.3 mL, 45 mmol) in AcOH (3 mL) was heated at 100° C. overnight. The crude reaction mixture was concentrated and purified on 16 g SiO2 column with 0-80% NH3/MeOH CH2Cl2 to give the desired compound (543 mg, 80%). MS (ESI): mass calcd. for C8H13N3, 151.1. m/z found, 152.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 3.16 (t, J=5.7 Hz, 2H), 2.61 (t, J=5.7 Hz, 2H), 1.43 (s, 6H).