Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[O:11][C:10](=[O:25])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][NH:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[CH2:1]([C@H:8]1[C@@H:12]([CH2:13][N:34]2[C@H:33]([C:31]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:42][C@H:41]3[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]3)[CH2:35]2)[O:11][C:10](=[O:25])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2OC(=O)N[C@H]2Cc2ccccc2)cc1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@H]1OC(=O)N[C@H]1Cc1ccccc1
Yield: 63.4 %

Procedure:
Analogously to Example 1B), by reacting 7.2 g of p-toluene-sulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester (Example 11) with 4.8 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide there are obtained 5.4 g (45%) of (3S, 4aS ,8aS)-2-[(4S ,5R)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl]-N -tert.-butyl-decahydro-isoquinoline-3-carboxamide p-tolylsuphonate, m.p. 202°-204° C.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:10])[CH2:5][CH:6]([OH:9])[CH2:7]O.CS([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>CCCCCC>[CH2:16]([O:15][CH:5]([N:4]([CH3:10])[CH3:3])[CH:6]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(C)C(OCCCCCCCC/C=C\C/C=C\CCCCC)N(C)C
Reaction time: 3 h

Procedure:
In a nitrogen atmosphere, hexane (30 mL) and potassium hydroxide (6.1 g, 108.7 mmol) were put into a four-necked flask, and 3-(dimethylamino)-1,2-propanediol (0.72 g, 6.04 mmol: DAP) was dropped under agitation. Thereafter, linoleyl methane sulfonate (5.0 g, 14.5 mmol) was added, and agitation was performed at room temperature for 3 hours. The reaction was terminated because remaining linoleyl methane sulfonate became 0.2% (degree of conversion: 59.2%, integrated value of isomer: 0.027).
Reaction SMILES: C1(=O)OCCO1.[F-:7].[K+].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].ClC([O-])=O>>[F:7][C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: [F-]
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])Cl
Agent: [K+]
Solvent: O=C1OCCO1
Product: O=C(F)Oc1ccccc1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
The preparation was carried out as in Example 2 but using 250 g of ethylene carbonate, 89 g (1.53 mol) of potassium fluoride and 156.6 g (1.0 mol) of phenyl chloroformate. After addition of the chloroformate, stirring of the reaction mixture was continued at 45°-50° C. for 2 hours. Evaporation under vacuum was carried out as above. By distillation under reduced pressure, 131 g (93.5% yield) of phenyl fluoroformate with a boiling point of 62°-64° at 40 mm Hg were recovered.
Reaction SMILES: CO.[O:3]1[CH2:5][C@H:4]1[CH2:6][N:7]([CH2:17][C@@H:18]1[CH2:20][O:19]1)[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClC1C=CC=CC=1>[CH2:21]([N:28]1[CH2:5][C@H:4]([OH:3])[CH2:6][N:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:17][C@@H:18]([OH:19])[CH2:20]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(C[C@@H]1CO1)C[C@@H]1CO1
Solvent: Clc1ccccc1
Solvent: CO
Product: O=S(=O)(c1ccccc1)N1C[C@@H](O)CN(Cc2ccccc2)C[C@H](O)C1
Temperature: 65 °C

Procedure:
Methanol (2494 kg, 18 rel. vol.—either fresh or recycled) was charged to a reaction vessel and heated to reflux temperature (approx. 65° C.). Simultaneously, and over approximately 6 hours were charged the chlorobenzene solution (containing chirally enriched N,N-bis(2(R)-oxiranylmethyl)benzenesulfonamide) from step (i), Alternative 2 above and benzylamine (109 kg, 0.91 eq.). The batch was maintained at reflux throughout the addition. The reaction was stirred at approximately 65° C. (reflux temperature) for a further 3 hours. Methanol (1938 kg, 14 rel. vol.) was then removed by distillation at atmospheric pressure before chlorobenzene (775 kg, 4 rel. vol.) was added. The resulting solution was used without further treatment in the next step (see step (iii), Alternative 2 below).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([N+:22]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([NH2:22])[CH:9]=2)=[N:6][NH:5][C:4](=[O:25])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1

Procedure:
A mixture of 6.75 gm of 5-methyl-6-(3-nitro-4-benzylamino-phenyl)-4,5-dihydro-2H-pyridazine-3-one and 0.7 gm of 10% palladium charcoal in a mixture of 100 ml of ethanol and 20 ml of glacial acetic acid was treated for 3.5 hours at room temperature with hydrogen at 5 bar. The catalyst was filtered off, the filtrate was evaporated, and the residue was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=O)[O:28]C(C)(C)C)[CH3:25])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.Cl.[C:35](OCC)(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:28])[CH3:35])[CH3:25])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (1.09 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (640 mg). 1H NMR (300 MHz, CDCl3) δ 0.39-0.49 (2H, m), 0.63-0.75 (2H, m), 1.28-1.43 (4H, m), 2.02 (3H, s), 3.95-4.09 (4H, m), 4.36-4.50 (1H, m), 5.74 (1H, d, J=8.3 Hz), 6.95 (1H, dd, J=8.9, 2.5 Hz), 7.00 (1H, d, J=8.7 Hz), 7.11 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.7 Hz), 8.04 (1H, dd, J=8.7, 1.9 Hz), 8.22 (1H, d, J=1.9 Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:27]=[C:26](F)[C:25]([Cl:29])=[CH:24][C:20]=2[C:21]([OH:23])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].CNC.C[N-]C>C1COCC1.CCCCCC>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:27]=[CH:26][C:25]([Cl:29])=[CH:24][C:20]=2[C:21]([Cl:3])=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:7])([CH3:8])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)O)cc1
Agent: CNC
Agent: C[N-]C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)Cl)cc1

Procedure:
Thionyl chloride (220 mL, 3.02 mol) was introduced to a 1 L round bottom flask fitted with a magnetic stir bar. 2-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-4-fluoro-benzoic acid (22 g, 57.0 mmol) was added under rapid agitation and the mixture was heated at reflux under a nitrogen atmosphere. The reaction progress was monitored by the addition of a few drops of the reaction mixture into ˜1 mL of 2.0 M dimethylamine in THF, followed by LCMS analysis. Complete conversion to the dimethyl amide was observed at 1.25 h. The crude mixture was subsequently concentrated in vacuo to produce an orange oil. Hexane (50 mL) was added to the flask and the mixture concentrated again to afford 2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-benzoyl chloride as an orange crystalline solid which was utilized direction in the next step.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:10])=[NH:9].C[O:12][CH:13]=[C:14]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15](OC)=O.C(N(CC)CC)C>CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:10]=[C:13]([OH:12])[C:14]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][N:9]=1
Reactant: COC=C(C#C[Si](C)(C)C)C(=O)OC
Reactant: N=C(N)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[Si](C)(C)C#Cc1cnc(-c2ccccn2)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of compound 37-b (15 g, 71 mmol), compound 37-h (12.2 g, 77.8 mmol), triethylamine (21.4 g, 212 mmol) in methanol (200 mL) was stirred overnight at room temperature. The residue obtained from removal of the solvent was purified by flash chromatography (DCM) to afford compound 37-i (7.5 g, 39%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.668-8.649 (m, 1H), 8.428-8.395 (m, 1H), 8.257 (s, 1H), 7.937-7.880 (m, 1H), 7.517-7.471 (m, 1H), 0.285 (s, 9H). LC-MS (ESI): 270 [M+H]+
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].C([O:23][C:24](=[O:26])[CH3:25])(=O)C>C(OCC)C>[C:2]([O:1][CH:2]([CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:15][CH2:14][CH2:13][CH2:18][CH2:17][CH2:25][C:24]([OH:23])=[O:26])[S:7]([CH3:10])(=[O:9])=[O:8])(=[O:1])[CH3:3]
Reactant: CS(=O)(=O)NCCCC(O)COc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)OC(CCCN(CCCCCCC(=O)O)S(C)(=O)=O)COc1ccc(F)cc1
Reaction time: 18 h

Procedure:
A mixture of 7-{N-[4-hydroxy-45-(4-fluorophenoxy)- pentyl]methanesulfonamido}heptanoic acid (12.3 g., 0.03 mole) (Example 1, Step E) and acetic anhydride (6.1 g., 0.06 mole) is kept at room temperature for 18 hours. This mixture is taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-{N-[4- acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido}- heptanoic acid as a viscous oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)[CH:16]=[C:15]([CH3:28])[C:13]=2[N:14]=1.O.[ClH:30]>O1CCOCC1>[C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]2[CH:16]=[C:15]([CH3:28])[C:13]3[N:14]=[C:10]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[Cl:30])[NH:11][C:12]=3[CH:18]=2)[CH2:20][CH2:21]1)(=[O:27])[CH3:26]
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(N3CCN(C(C)=O)CC3)cc2[nH]1
Reactant: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of 1-{4-[2-(4-Iodo-2-methoxy-pyridin-3-yl)-7-methyl-3H-benzimidazol-5-yl]-piperazin-1-yl}-ethanone (5.2 g, 10.6 mmol) in 4 M HCl in dioxane (60 mL) was added water (5 mL). The reaction mixture was stirred at room temperature for 14 h. Concentration of the reaction mixture gave the title compound (4.02 g, 100%) which was used for the next step without purification. LCMS (M+H)+ m/z 486 (t=1.55 min.).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[C:6]2[C:15]3[N:14]([CH:16]=1)[N:13]([CH3:17])[CH2:12][CH2:11][C:10]=3[C:9]([CH2:18]C(O)=O)=[C:8]([F:22])[CH:7]=2)([OH:3])=[O:2].C(N(CC)CC)C>C(O)C>[F:22][C:8]1[C:9]([CH3:18])=[C:10]2[C:15]3=[C:6]([C:5](=[O:23])[C:4]([C:1]([OH:3])=[O:2])=[CH:16][N:14]3[N:13]([CH3:17])[CH2:12][CH2:11]2)[CH:7]=1
Reactant: CN1CCc2c(CC(=O)O)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCN3C
Yield: 75.4 %

Procedure:
100 mg of the compound (163) obtained in Example 40 and 1.4 ml of triethylamine were added to 5 ml of ethanol, and the solution was heated at reflux for 15.5 hours. After air-cooling, the solids were filtered and washed successively with ethanol and ether to obtain 65 mg of the subject compound (164).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[C:51]([F:54])([F:53])[F:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[C:51]([F:54])([F:53])[F:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3C(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethyl)benzene and isolated as light-yellow gum (7.8 mg, 43%). MS(m/e): 441.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=O)[CH2:12][CH2:13][C:3]1=2.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[N:16][OH:17])[CH2:12][CH2:13][C:3]1=2
Reactant: NO
Reactant: Cn1c2c(c3ccccc31)C(=O)CC2
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c2c(c3ccccc31)C(=NO)CC2
Yield: 92 %

Procedure:
3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one (1.7 g) and hydroxylamine hydrochloride (1.925 g) in pyridine were heated at 60° for 18 h and cooled. The reaction mixture was evaporated in vacuo to a residue to which was added 8% sodium bicarbonate (150 ml). Extraction with ethyl acetate (300 ml) produced a suspension in the organic layer; this layer and associated solid was separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic extracts (and suspended solid) were evaporated to a residue, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to ca. 50°. The residue was adsorbed from this solution on to FCC silica and applied to an FCC column. Elution with ethyl acetate/3-10% methanol provided the title compound (1.69 g), m.p. 219°-224° (decomp.).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[NH:10][CH:9]=1)=[O:7])C>O.CCO>[CH:14]([C:11]1[NH:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[C:12]=1[CH3:13])=[O:15]
Reactant: CCOC(=O)c1c[nH]c(C=O)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)O)c[nH]c1C=O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
KOH (5 g, 2 eq) was added to a suspension of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (8.13 g, 44.8 mmol) in water (100 mL) and EtOH (50 mL) with stirring. The mixture was heated to reflux for 2.5 hr, cooled to rt, concentrated to about ⅔ volume, diluted with water (300 mL) and acidified to pH=3 using 1N HCl. The white solid was collected by filtration and dried to afford 6 g (87%) of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid as a tan solid.
Reaction SMILES: [CH2:1]([N:4]([C@H:14]1[CH2:19][CH2:18][C@H:17](C2C=CC(CNC)=CC=2)[CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH:2]=[CH2:3].Br[CH2:30][CH2:31][CH2:32][OH:33]>C(Cl)Cl.CO>[CH2:1]([N:4]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:7]2[CH:8]=[CH:9][C:10]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:11][C:6]=2[CH2:5][NH:4][CH3:1])[CH2:18][CH2:19]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: OCCCBr
Reactant: C=CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CNC)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: C=CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CCCO)cc2CNC)CC1

Procedure:
from trans-N-allyl-N-(4-chlorobenzoyl)-4-(4-methylaminomethylphenyl)cyclohexylamine and 3-bromo-1-propanol. Oil. Rf value: 0.56 (alumina, methylene chloride/methanol=50:1, v:v).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:29]([OH:31])=[O:30])[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[C:36]([CH3:39])([CH3:38])[CH3:37])(=O)C.S(=O)(=O)(O)O>ClCCl>[C:36]([O:30][C:29](=[O:31])[C@@H:19]([CH2:20][O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(N[C@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](COCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 77 %

Procedure:
N-[(9H-Fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70 mmole) in dichloromethane (8 mL) was treated with t-butyl acetate (3 mL) and concentrated sulfuric acid (40 μL) in a sealed flask at 0° C. Upon completion (TLC), the reaction was quenched with of dichloromethane (10 mL) and saturated aqueous potassium bicarbonate (15 mL). The organic layer was washed with distilled water, and evaporated. The resulting residue was purified by flash column chromatography (98:2 dichloromethane/methanol) to yield the title compound as a colorless oil (0.292 g, 77%); 1H NMR (CDCl3) δ 1.44 (s, 9H); 3.68 (dd, J=2.9 Hz, J=9.3 Hz, 1H); 3.87 (dd, J=2.9 Hz, J=9.3 Hz, 1H); 4.22 (t, J=7.1 Hz, 1H); 4.30–4.60 (m, 5H); 5.64–5.67 (m, 1H); 7.25–7.39 (m, 9H); 7.58–7.61 (m, 2H); 7.73–7.76 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][C@@H:24]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:30][CH2:29]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.OC1C2N=NNC=2C=CC=1>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([NH:23][C@@H:24]([CH2:42][C:43]3[CH:44]=[C:45]([F:50])[CH:46]=[C:47]([F:49])[CH:48]=3)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]3([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)[CH2:30][CH2:29]3)=[O:20])=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cccc2c1CCN(Cc1ccccc1)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1)c1cccc2c1CCN(Cc1ccccc1)C2=O
Yield: 169.5 %

Procedure:
A solution of 100 mg of 2-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 168 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 7.2 mg of hydroxybenzotriazole, 85 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.243 cm3 of N,N-diisopropylethylamine in 10 cm3 of dichloromethane is stirred at a temperature close to 20° C. for 20 h. Dichloromethane is added to the reaction medium. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 400 mg of product obtained are purified by flash chromatography over silica (column: 50 g; particle size: 15-40 μm; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 103 mg of 2-benzyl-N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][CH:16]=O)[CH:13]=2)[N:8]([CH3:18])[CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=C(S(C)(=O)=O)[N:23]=1.[OH-].[Na+]>C1COCC1.CN(C=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:16]([NH:15][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:18])[CH:7]=[C:6]3[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[N:23]=1
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Reactant: CC(C)C(=O)c1cn(C)c2ccc(NC=O)cc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C(=O)c1cn(C)c2ccc(Nc3nccc(Cl)n3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of N-(3-isobutyryl-1-methyl-1H-indol-5-yl)formamide (450 mg, 1.84 mmol) in anhydrous THF (3 mL) and anhydrous DMF (3 mL) was added 60% NaH (228 mg, 5.52 mmol) at 0° C. After being stirred for 30 min at room temperature, it was cooled to 0° C. To this, was added 4-chloro-2-(methylsulfonyl)pyrimidine (466 mg, 2.43 mmol) and then stirred for 2 hours. Quenching the reaction by addition of ice and 2N solution of sodium hydroxide (2 mL) resulted precipitation of brown solids. Additional 20 mL of water was added to complete of solid formation. The resulted solids were collected by filtration, rinsed with water and the dried in vacuo to provide the desired intermediate 5 as a brown solid (542 mg, 89%); MS (ESI) m/z 329 [M+H]+.
Reaction SMILES: [OH:1][C@H:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][C:4](N1[C@H](C(C)C)CSC1=S)=[O:5].[Li+].[OH-].Cl.CC[O:44]C(C)=O>C1COCC1.O>[OH:1][C@H:2](/[CH:15]=[CH:16]/[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][C:4]([OH:44])=[O:5]
Reactant: CCOC(C)=O
Reactant: CC(C)[C@@H]1CSC(=S)N1C(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
At 0° C. to a solution of (S,E)-3-hydroxy-1-((R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-(tritylthio)hept-4-en-1-one (934 mg, 1.66 mmol, prepared according to the procedure in Yurek-George, A. et al, J. Am. Chem. Soc. 2004, 126, 1030) in THF (30 mL) was added a solution of LiOH (196.1 mg, 8.19 mmol) in H2O (10 mL). The reaction mixture was allowed to warm to rt over 1 h, whereupon 1M HCl was added until the pH reached 2. EtOAc (30 mL) was then added and the layers were separated. The aqueous layer was extracted with EtOAc (20 mL) the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography (eluant 3:7-1:1-1:0 EtOAc/Hexane) gave the 3 as a white solid (600 mg, 1.43 mmol, 86%).