Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:6])[OH:9]
Reactant: CCOP(=O)(CCCN)c1ccccc1
Agent: Cl
Product: NCCCP(=O)(O)c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of 6.83 g of ethyl 3-aminopropyl(phenyl)phosphinate and 30 ml of 20 % hydrochloric acid is refluxed with stirring for 4 hours. The clear solution is evaporated to dryness and the residue is recrystallized from methanol/propylenoxide to give 3-aminopropyl(phenyl)phosphinic acid as a white solid, m.p. 298-300° .
Reaction SMILES: N[C@H:2]1[CH2:15][CH2:14][C@:13]2([O:16][CH3:17])[C@:4]34[CH2:20][CH2:19][N:18]([CH3:21])[C@@H:12]2[CH2:11][C:10]2[CH:9]=[CH:8][C:7]([OH:22])=[C:6]([O:23][C@@H:3]13)[C:5]4=2.[C:24]([O:28][C:29]([NH:31][C:32](=[N:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])SC)=[O:30])([CH3:27])([CH3:26])[CH3:25].C([N:45](C(C)C)C(C)C)C>CN(C)C=O.[N+]([O-])([O-])=O.[Ag+]>[O:23]1[C@@H:3]2[C@@:4]34[CH2:20][CH2:19][N:18]([CH3:21])[C@@H:12]([C@:13]3([O:16][CH3:17])[CH2:14][CH2:15][C@@H:2]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[NH:45])[CH2:11][C:10]2=[C:5]4[C:6]1=[C:7]([OH:22])[CH:8]=[CH:9]2
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CO[C@@]12CC[C@H](N)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Reactant: CCN(C(C)C)C(C)C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CN(C)C=O
Product: CO[C@@]12CC[C@H](N(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Reaction time: 1.5 h
Yield: 104.8 %

Procedure:
A solution of Compound 13 (1.00 g, 3.16 mmol), N,N′-bis-(tert.-butoxycarbonyl)-S-methylisothiourea (1.00 g, 3.44 mmol) and N-ethyldiisopropylamine (0.60 ml, 3.44 mmol) in absolute N,N-dimethylformamide (60 ml) was mixed with silver nitrate (0.55 g, 3.24 mmol) and the mixture stirred for 1.5 h. Then the silver mercaptane was filtered off through Celite and washed afterwards with CH2Cl2 (4×50 ml). The filtrate was washed with H2O (6×200 ml) and saturated NaCl solution (1×200 ml), dried (Na2SO4) and evaporated. In this way 1.85 g of a yellow oil were obtained which was purified through MPLC (p=5 bar, silica gel 60, CH2Cl2/MeOH 10:1). Yield: 0.67 g (38%) of white foam resin: 1H-NMR (CDCl3): δ 11.53 (s, br, NH—COO(CH3)3); 8.81 (d, J=8.0, C(6)-NH—); 6.73 (d, J=8.2,1 arom. H); 6.56 (d, J=8.2, 1 arom. H); 4.66 (dd, 3J=2.6, 4J=1.6, H—C(5)); 3.25 (s, CH3O—C(14)); 2.35 (s, CH3N); 1.50 (s, 2×C(CH3)3).
Reaction SMILES: C([N:4](C(C)C)CC)(C)C.Cl[C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][C:19]2[NH:23][N:22]=[C:21]([CH:24]3[CH2:26][CH2:25]3)[CH:20]=2)[N:12]=1.F[C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([C@:37]2([CH3:42])[CH2:41][CH2:40][CH2:39][NH:38]2)=[O:36])=C[CH:29]=1>C1COCC1>[Cl:17][C:15]1[N:14]=[C:13]([NH:18][C:19]2[NH:23][N:22]=[C:21]([CH:24]3[CH2:26][CH2:25]3)[CH:20]=2)[N:12]=[C:11]([N:38]2[CH2:39][CH2:40][CH2:41][C@@:37]2([CH3:42])[C:35]([NH:34][C:31]2[CH:32]=[N:33][CH:28]=[CH:29][N:4]=2)=[O:36])[N:16]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@]1(C(=O)Nc2cnccn2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
Diisopropylethylamine (0.77 mL, 4.42 mmol) was added to a mixture of 4,6-dichloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine (800 mg, 2.95 mmol) and (S)—N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide (625 mg, 2.8 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature overnight and the product was separated by preparative HPLC. Removal of the solvents furnished 8B (860 mg, 64%) as a TFA salt. LC/MS [M+H]+: 440; Ret time (Method C): 2.33 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13]Br)[CH3:11].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCCCC(CC)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(C=O)cc1

Procedure:
4-Hydroxybenzaldehyde (61 g) and 2-ethylhexylbromide (106 g) were added to 150 ml of dimethylformamide containing 138 g of potassium carbonate. The mixture was refluxed overnight and then poured into a volume of cold water and extracted with ethyl acetate. The extract was dried, evaporated and distilled (0.1 millimeter vacuum) to yield 4-[(2-ethylhexyl)oxy]benzaldehyde, boiling point (b.p.) 118°-121° C.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][CH:12]1[CH2:17][CH:16]=[C:15]([C:18]2[N:19]=[C:20]([SH:23])[S:21][CH:22]=2)[CH2:14][N:13]1[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25].O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:27]([O:26][C:24]([N:13]1[CH:12]([CH3:11])[CH2:17][CH:16]=[C:15]([C:18]2[N:19]=[C:20]([S:23][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:21][CH:22]=2)[CH2:14]1)=[O:25])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CC(c2csc(S)n2)=CCC1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCC(C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 1.24 ml, 1.24 mmol) was added at 0° C. to a solution of allyl 2-methyl-5-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (368 mg, 1.24 mmol) in THF (2.4 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 4.73 g, 2.5 mmol) and the solution was allowed to stand in a refrigerator for 13 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 4/1→3/1) to give allyl (4R,5S,6S)-3-[(4-(1-[(allyloxy)carbonyl]-6-methyl-1,2,5,6-tetrahydro-3-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (544 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 8 h
Yield: 105.4 %

Procedure:
3-Chloro-4-nitrobenzoic acid (Apin; 1 g, 4.96 mmol) was suspended in toluene (10 mL) and thionyl chloride (1.11 mL, 14.88 mmol) added. The mixture was heated to 85° C. for 45 min Further thionyl chloride (1.1 mL) was added and the mixture heated at reflux. 0.5 hr. The reaction mixture was allowed to cool and stand overnight. The mixture was concentrated to give the title compound as a yellow liquid (1.15 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:26](OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([O:14][CH3:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxypiperidine (1.0 g) in N,N-dimethyl formamide (10 ml) was added sodium hydride (0.14 g) under ice cooling. Then the reaction mixture was stirred for 30 minutes at room temperature and for 2 hours at 60° C. To the reaction mixture was added iodomethane (4.0 ml) at 60° C. After stirring for 6 hours at 60° C., the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 1-tert-butoxycarbonyl-4-(4-chlorophenyl)-4-methoxypiperidine (0.75 g).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([CH:15]([F:17])[F:16])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:19][C:20]1[C:25]([CH2:26]O)=[CH:24][CH:23]=[C:22]([CH3:28])[N:21]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[F:16][CH:15]([F:17])[C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:2])=[O:18])=[CH:6][S:7][C:8]=2[CH:13]=[C:12]([O:14][CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([CH3:28])=[CH:23][CH:24]=2)[CH:11]=1
Reactant: Cc1ccc(CO)c(C)n1
Reactant: COC(=O)Cc1csc2cc(O)cc(C(F)F)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(COc2cc(C(F)F)c3c(CC(=O)O)csc3c2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
To a mixture of methyl(4-(difluoromethyl)-6-hydroxy-1-benzothiophen-3-yl)acetate (78 mg) and THF (dry) (2 mL) were added (2,6-dimethylpyridin-3-yl)methanol (43.2 mg), tri-n-butylphosphine (0.212 mL) and ADDP (94 mg) at room temperature. The mixture was stirred at room temperature for 2 h. To the mixture were added ADDP (94 mg) and tri-n-butylphosphine (0.212 mL), and the mixture was stirred at room temperature for 30 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by short pad of silica gel (EtOAc/hexane). To a mixture of the residue and THF (2 mL) was added 1N NaOH (1 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative HPLC (C18, H2O/CH3CN (including 10 mM NH4HCO3)). The fraction was extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (29.1 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li][CH2:8][CH2:9][CH2:10]C.CCCCCC.C[O:19][B:20](OC)[O:21]C.C(O)CCO>C(OCC)C>[CH3:1][C:2]1[CH:6]=[C:5]([B:20]2[O:21][CH2:10][CH2:9][CH2:8][O:19]2)[S:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: COB(OC)OC
Reactant: Cc1ccsc1
Solvent: CCOCC
Solvent: OCCCO
Solvent: CCCCCC
Product: Cc1csc(B2OCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylthiophene (10.0 g, 0.1 mol) in 120 ml of anhydrous diethyl ether was added 2.5 M n-BuLi in hexane(40 ml, 0.1 mol) at room temperature. After stirring at room temperature for 30 min, the resulting solution was refluxed for 1 h. The mixture was cooled down to −76° C. and trimethylborate (16.72 ml, 150 mol) was added slowly. The mixture was allowed to warm to room temperature and stirred for 2 h. After quenching with 10% HCl (150 ml), the organic layer was separated and the aqueous layer was extracted with ether (2×). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was added to 1,3-propanediol (7.3 ml, 0.1 mol) and refluxed for 3 h. The mixture was then placed directly on a silica column and eluted with hexane, then chloroform to give the product, 12.86 g, 71%. 1H NMR (CDCl3-d3, 500 MHz): δ 7.32 ppm (s, 1 H), 7.11 ppm (s, 1 H), 4.14-4.12 ppm (t, 4 H, J=8.6 Hz), 2.40 (s, 3 H), 2.04 ppm (m, 2 H); 13C-NMR (CDCl3, 500 MHz): δ 138.8, 137.8, 127.03 127.02, 62.09, 27.48, 15.23 ppm. EI, MS m/z (%): 182 (100, M+).
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26](O)[CH3:27].C([BH3-])#N.[Na+]>ClCCl>[CH3:27][CH:26]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH:15]2[CH2:16][CH2:17][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:13][CH2:14]2)[C:1](=[O:3])[O:4]1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(O)c1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC1OC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid (1 ml) was added dropwise to a solution of N-tert-butoxycarbonyl-4-piperidone (9.4 g), 1-(2-amino-phenyl)-ethanol (4.3 g) and sodium cyanoborohydride (10 g) in dichloromethane and the mixture stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water, the organics separated and washed with aqueous sodium hydrogencarbonate solution, water, dried, and evaporated under reduced pressure. The crude product was dissolved in tetrahydrofuran (100 ml) and N,N-diisopropylethylamine (23 ml), cooled to 0° C., then triphosgene (4.3 g) added. The mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water, the organics washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 20% ethyl acetate/isohexane. Yield 1.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][C@@:17]([C:28]([OH:31])([CH3:30])[CH3:29])([O:18][C:19]4[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=4)[C:12]3=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.[C:38](O)(=[O:47])[CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40].CCCCCC>C(O)C>[C:38]([O:31][C:28]([C@@:17]1([O:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]2[C:9]([C:7]3[CH:6]=[CH:5][C:4]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:3]([O:2][CH3:1])[N:8]=3)=[N:10][N:11]=[C:12]12)([CH3:30])[CH3:29])(=[O:47])[C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Solvent: CCO
Solvent: CCCCCC
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OC(=O)[C@@H](O)c2ccccc2)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a mixture of 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (0.50 g) in ethanol (2 mL) was added a mixture of (+)-mandelic acid (148 mg) in ethanol (1 mL) at room temperature. To the reaction mixture was added hexane/IPE at room temperature, and the mixture was stirred for 3 hr. The crystals were collected by filtration and dried to give the title compound (0.55 g).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:43])[CH2:4][O:5][C:6]([CH2:8][N:9]([S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[NH:23])=[CH:20][CH:19]=3)=[N:16][C:12]=2[CH:11]=1)=[O:7].Cl[C:45]([O:47][CH3:48])=[O:46]>CC(C)=O.O>[CH3:2][CH:3]([CH3:43])[CH2:4][O:5][C:6]([CH2:8][N:9]([S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)(=[O:32])=[O:31])[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH2:24])=[N:23][C:45]([O:47][CH3:48])=[O:46])=[CH:25][CH:26]=3)=[N:16][C:12]=2[CH:11]=1)=[O:7]
Reactant: COC(=O)Cl
Reactant: CC(C)COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)N=C(N)c1ccc(Cc2nc3cc(N(CC(=O)OCC(C)C)S(=O)(=O)c4cccc5cccnc45)ccc3n2C)cc1

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-(2-methylpropyloxycarbonylmethyl)-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and methyl chloroformate in acetone/water.
Reaction SMILES: [C:1]([NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1O
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 56.8 %

Procedure:
(1S,2S)-2-(N-Oleoylamino)cyclohexanol (3.79 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 3.52 g of the title compound (yield: 57%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][NH2:10])[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1cc(Br)ccn1
Temperature: 70 °C
Yield: 82.6 %

Procedure:
To a solution of 4-bromo-2-fluoropyridine (2.0 g, 11.4 mmol) in pyridine (10 mL) was added hydrazine (5 mL, 159 mmol). The mixture was heated at 70° C. for 2 hours, then cooled to room temperature. The volatile organics were removed under reduced pressure, then water (60 mL) was added to the residue and an off-white solid precipitated. The solid was filtered, washed with water, and dried under reduced pressure at 50° C. to give 1.77 g (84%) of the title compound as an off-white solid. m/z (ES+) 188, 190 (M+H)+.
Reaction SMILES: [Mg].[O:2]=[C:3]([CH3:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[N+:13]([C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])([O-:15])=[O:14].Cl>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18]([CH:4]([C:3](=[O:2])[CH3:12])[C:5]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:6])=[O:19])([O-:15])=[O:14]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of magnesium turnings (4.8 g) and carbon tetrachloride (2 ml) in pure ethanol (30 ml) was stirred and warmed gently to 50° C. until the reaction was initiated (effervescence observed). Ether (100 ml) was added cautiously with stirring. A solution of t-butyl 3-oxobutanoate (31.6 g) in ether (100 ml) was added dropwise at such a rate as to maintain the mixture at reflux. Stirring and heating at reflux was continued for 2 hours. A solution of 2-nitro-4-trifluoromethylbenzoyl chloride (50.7 g) in ether (100 ml) was added dropwise and the resultant solution was stirred and heated at reflux for 2.5 hours. The cooled reaction mixture was treated with hydrochloric acid (2M, 100 ml) with stirring and the two layers were separated. The organic phase was extracted with aqueous sodium hydroxide solution (2M, 2×50 ml) and water (4×50 ml). The combined aqueous layers were acidified to pH 1 and extracted with ether (2×100 ml). The combined organic layers were washed with water (50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness to give t-butyl 2-(2-nitro-4-trifluoromethylbenzoyl)-3-oxobutanoate (62.2 g) as a crude red oil which was not further purified.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:7](=[O:9])[C@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: COC(=O)N[C@@H](C(=O)O)C1CCCCC1
Agent: Cl
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Yield: 50.5 %

Procedure:
Reaction of 1.24 g of (R)-methoxycarbonylamino-cyclohexyl-acetic acid and 1.40 g of (L)-proline benzyl ester hydrochloride using the procedure described for example 91b gave 1.17 g (50%) of the title compound as a colorless oil. (+)-APCI-MS: 403 (MH+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[I:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2.N1CCCCC1>C(O)C>[I:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2cc(I)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(I)cc32)c(C)c1CCC(=O)O
Yield: 71.1 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 130 mg 5-iodo-2-oxindole, and 75 μL of piperidine in 3 mL of ethanol were stirred at 95 ° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 155 mg of the title compound (71%) as an orange solid.