Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:16]([C@@H:17]4[C@H:22]([N:23]=2)[CH2:21][CH2:20][O:19][CH2:18]4)=[CH:15][C:14]([O:24][CH2:25][CH3:26])=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:25]([O:24][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:27][CH3:28])[C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)=[N:23][C@H:22]1[C@@H:17]2[CH2:18][O:19][CH2:20][CH2:21]1)[CH3:26]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)OC)cc1)=N[C@@H]1CCOC[C@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCOC[C@H]21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 7.6 mmol of 4((4aR,10aR)-6-Ethoxy-7-methoxy-1,4,4a,10a-tetrahydro-2H-3-oxa-10-aza-phenanthren-9-yl)-benzoic acid methyl ester in 100 ml of dioxan a solution of 7.5 ml of 2 molar sodium hydroxide in water is added and the mixture is stirred for 15 h at RT. A solution of 7.5 ml of 2 molar HCl in water is added and the mixture is stirred for 30 min. After concentration under reduced pressure the solid residue is treated with 100 ml of dichloromethane. After filtering the filtrate is concentrated under reduced pressure yielding the title compound as a grayish solid residue. The title compound is stirred up with diethylether, filtered off and dried under reduced pressure yielding the title compound as white powdery solid. M.p. 203-205° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@H:11]([NH2:29])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48](O)=[O:49])=[O:41])(=[O:33])[CH3:32].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@H:11]([NH:29][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][NH:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:31](=[O:33])[CH3:32])[C:12](=[O:28])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCNC(=O)[C@@H](N)CC(=O)OCc1ccccc1
Reactant: CC(=O)NCCCCCC(=O)NCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCNC(=O)CCCCCNC(C)=O
Yield: 7.3 %

Procedure:
2.1 g of (S)-3-amino-3-tetradecylcarbamoylpropionic acid benzyl ester and 1.5 g of 6-(6-acetamidohexanamido)hexanoic acid were mingled in 10 ml of methylene chloride and after adding thereto 1.1 g of DCC and treating the mixture in the same manner as in Example 26, the product was subjected to silica gel column chromatography, and was eluted with methanol-chloroform (1:3 by v/v ratio) to provide 250 mg of (s)-3-[6-(6-acetamidohexanamido)hexanamido]-3-tetradecylcarbamoylpropionic acid benzyl ester.
Reaction SMILES: [SH2:1].[C:2]([C:4]1[NH:5][C:6]([CH3:29])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:3].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:3][C:2](=[S:1])[C:4]1[NH:5][C:6]([CH3:29])=[C:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: S
Reactant: CCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)NC(C(N)=S)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Hydrogen sulphide was bubbled through a solution of diethyl 2-cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (1 g, 2.6 mmoles) in triethylamine (0.36 ml, 2.6 mmoles) and pyridine (20 ml) at room temperature for 2 hours. The solution was degassed with nitrogen and poured into water (300 ml). After stirring for 2 hours, the precipitate was filtered off, dissolved in methylene chloride and dried (Na2SO4). The solvent was removed in vacuo and the residue triturated with CCl4 and filtered to give the title compound (0.5 g). M+ 419; (CDCl3) δ 9.3 (s,NH2), 5.2 (s,H).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH3:8][C:9]1[C:14](/[CH:15]=[CH:16]/[N+:17]([O-])=O)=[CH:13][CH:12]=[CH:11][C:10]=1[O:20][CH3:21].CO>C1COCC1>[CH3:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:15][CH2:16][NH2:17]
Reactant: COc1cccc(/C=C/[N+](=O)[O-])c1C
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(CCN)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To lithium borohydride (2M in THF; 2.00 ml; 4.00 mmol) was added dropwise over 0.5 min chlorotrimethylsilane (1.02 ml; 8.00 mmol). A precipitate was formed and after ca. 3 min, 2-methyl-1-(methyloxy)-3-[(E)-2-nitroethenyl]benzene (Preparation 9, 193 mg; 1.00 mmol) in THF (4 ml) was added dropwise via syringe over 5 min, making sure that the temperature remained at ca. 25° C. (using a water cold bath). The solution was stirred at room temperature overnight. The mixture was cooled with an ice bath, methanol was added slowly, and the solvent removed. The residue was partitioned between 25% aqueous sodium hydroxide and dichloromethane (3 extractions), and the solvent evaporated. Purification of the residue by solid phase extraction (SCX column) gave the title compound (80 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=2)[CH:7]=1.[CH3:28]I>C(OCC)C>[CH3:3][O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([O:26][CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=2)[CH:7]=1
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCC(OC)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of sodium hydride (0.5 g.) in ethyl ether at 0° C. was added methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate (1.7 g.) in ether. The mixture was allowed to warm to room temperature. Methyl iodide (0.6 ml) was added and the reaction was stirred at room temperature for three days. The reaction was quenched with saturated aqueous ammonium chloride. Th mixture was extracted with ethyl ether. The organic extract was washed with water, dried (MgSO4) and concentrated to an oil. The oil was purified by HPLC on silica gel using a 1:9 ratio of ethyl acetate/hexanes as an eluent.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCC)cc1OC)n2C)c1ccccn1
Yield: 43 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and ethyl chloroformate. Yield: 43% of theory, C31H35N7O6 (601.7); Rf value: 0.44 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=602; (M+H+Na)++=312.8.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.9 %

Procedure:
4-methyl-3-nitrobenzoic acid (40.0 g, 221 mmol), 4-dimethylaminopyridine (54.5 g, 446 mmol) and WSC (84.4 g, 440 mmol) were dissolved in dichloromethane (450 ml). tert-Butanol (34.4 g, 464 mmol) was added with stirring at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate-hexane=1:1 mixed solvent (500 ml). The organic layer was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (48.7 g, yield 93%) as a pale-yellow solid.
Reaction SMILES: [CH:1]1([C:4](=O)/[CH:5]=[C:6](\O)/[CH:7]([F:9])[F:8])[CH2:3][CH2:2]1.O.[NH2:13][NH2:14].Cl>C(O)C>[CH:1]1([C:4]2[NH:14][N:13]=[C:6]([CH:7]([F:9])[F:8])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(/C=C(\O)C(F)F)C1CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: FC(F)c1cc(C2CC2)[nH]n1
Reaction time: 3 h
Yield: 76.4 %

Procedure:
Intermediate 62 (390 mg, 2.4 mmol) dissolved in ethanol (2 ml), added hydrazine hydrate (0.13 ml, 2.65 mmol) and HCl (0.18 ml). This mixture was refluxed for 3 h. After 3 h, ethanol was removed on rotavapour and work up (H2O/AcOEt) afforded the title compound (290 mg) which was used in the next step without further purification. 1H-NMR (δ ppm, CDCl3, 400 MHz): 12.96 (s, 1H), 6.84 (t, J 54.8, 1H), 6.15 (s, 1H), 1.95-1.87 (m, 1H), 0.99-0.91 (m, 2H), 0.74-0.66 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:31])[CH:14]([NH:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[C:22]([F:30])[CH:23]=[C:24]([F:29])[CH:25]=3)[CH2:20]2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[OH:2][CH2:3][C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:31])[CH:14]([NH:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[C:22]([F:30])[CH:23]=[C:24]([F:29])[CH:25]=3)[CH2:20]2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CO)cn1

Procedure:
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionic acid methyl ester was reduced using LAH to afford the title compound: mixture of diasteromers C13 NMR (100 MHz, CDCl3) 14.1, 14.2, 14.4, 19.4, 19.5, 21.2, 22.7, 24.7, 24.8, 24.9, 28.1, 28.3, 28.8, 28.9, 29.6, 29.7, 36.4, 52.1, 52.7, 59.3, 60.0, 60.6, 60.7, 70.5, 100.8, 101.0, 101.3, 104.6, 110.5, 110.6, 110.7, 110.8, 117.9, 118.1, 118.4, 118.6, 131.2, 131.3, 137.3, 137.4, 139.5, 139.6, 139.7, 139.8, 139.9, 139.9, 159.7, 159.8, 159.9, 162.1, 162.2, 162.3, 172.4, 172.6; MS m/z 421.4 (M+1).
Reaction SMILES: Cl.[CH3:2][N:3]([CH:12]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14][CH2:13]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H][H]>C(O)C.O.[C].[Pd]>[CH3:2][N:3]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(CCc1ccccc1)C1CCNCC1
Yield: 70.1 %

Procedure:
60 ml of concentrated hydrochloric acid and 13.3 g of 10% palladium-carbon were added to a solution of 266 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-benzylpiperidine in 1 liter of ethanol and 500 ml of water. The mixture was stirred at a hydrogen pressure of 1 atm. at 60° C. for 5 hours. 10% palladium-carbon was removed by filtration and then washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The residue was added to ice water. The mixture was made alkaline with a 25% aqueous sodium hydroxide solution and then extracted with methylene chloride. The extract was water-washed and then concentrated under reduced pressure. The residue was subjected to vacuum distillation to obtain 131.9 g of 4-[N-methyl-N-(2-phenylethyl)amino]piperidine as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([O-])=[O:9])[C:4](=[O:11])[CH2:3]1.[NH3:12]>>[OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH2:12])=[O:9])[C:4](=[O:11])[CH2:3]1
Reactant: N
Reactant: O=C([O-])CN1CC(O)CC1=O
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
reacting the 4-hydroxy-2-oxopyrrolidin-1-yl-acetate with ammonia to provide a 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C@@:3]([OH:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[F:16][C:17]1[C:22]([CH2:23][NH2:24])=[CH:21][C:20]([CH3:25])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[F:14][C:2]([F:1])([F:15])[C@@:3]([OH:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH:24][CH2:23][C:22]1[C:17]([F:16])=[N:18][CH:19]=[C:20]([CH3:25])[CH:21]=1)=[O:6]
Reactant: O=C(O)[C@](O)(c1ccccc1)C(F)(F)F
Reactant: Cc1cnc(F)c(CN)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(F)c(CNC(=O)[C@](O)(c2ccccc2)C(F)(F)F)c1
Reaction time: 14 h

Procedure:
A solution of (2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoic acid (6-e with R=CF3 and R′=H, 105 mg, 0.48 mmol), the amine (2-e, 67 mg, 0.48 mmol) and diisopropylethylamine (415 uL, 2.4 mmol) in N,N-dimethylformamide (1 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 274 mg, 0.53 mmol). After 14 h, the reaction mixture was partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the desired product (3-1); HRMS (M+H)=343.1059; 1H NMR (500 MHz, CDCl3) δ 7.89 (bs, 1 H), 7.63 (m, 2H), 7.43 (m, 3 H), 7.39 (d, 1 H, J=7.8 Hz), 6.67 (br, 1 H), 4.72 (m, 1 H), 4.48 (d, 2H, J=6.1 Hz), 2.26 (s, 3 H); compound 3-3 [(2R)-3,3,3-trifluoro-N-(2-fluoro-5-trifluoromethylbenzyl)-2-hydroxy-2-phenylpropanamide] was prepared by the same procedure (2-fluoro-5-trifluoromethylbenzylamine was purchased from Alfa Aesar); HRMS (M+H)=396.0825; 1H NMR (500 MHz, DMSO-6d) δ 8.95 (t, 1 H), 7.95 (s, 1 H), 7.65 (m, 3 H), 7.39 (m, 5 H), 4.40 (dq, 2 H).
Reaction SMILES: [C:1]([N:4]([CH3:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]1)=[O:13])([OH:3])=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O=S(Cl)Cl>[CH3:25][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][C:12](=[O:13])[N:14]([CH2:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([N:35]3[CH2:36][CH2:37][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=4)[CH2:33][CH2:34]3)=[O:24])[CH2:20][CH2:21]2)[C:1]1=[O:3]
Reactant: CN(C(=O)O)c1ccccc1CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: O=S(Cl)Cl
Product: CN1C(=O)N(C[C@H]2CC[C@H](C(=O)N3CCN(c4ccccn4)CC3)CC2)C(=O)Cc2ccccc21
Temperature: 25 °C

Procedure:
A solution of trans-4-({2-[2-(Carboxy-methyl-amino)-phenyl]-acetylamino}-methyl)-cyclohexanecarboxylic acid (0.14 mmol, 0.05 g) in SOCl2 (0.8 mL) was heated under reflux for 1.5 hours. The solvent was removed under reduced pressure and the residue was put under vacuum overnight. Then crude product was diluted with 5 ml of dry DCM. 1 ml of this stock solution was transferred in a glass vial. 39 μL (0.27 mmol) of 1-Pyridin-2-yl-piperazine were added and the reaction mixture was left stirring at room temperature under argon over night. The solvent was removed under vacuum and the crude purified by preparative HPLC (Method d) to give 26 mg of the titled compound (yield 39%).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.N.[F:23][C:24](I)([F:26])[F:25]>O1CCCC1>[F:23][C:24]([F:26])([F:25])[S:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:4][N:3]=1
Reactant: FC(F)(F)I
Reactant: Fc1ccc(-c2cnc(S)nc2-c2ccc(F)cc2)cc1
Agent: N
Solvent: C1CCOC1
Product: Fc1ccc(-c2cnc(SC(F)(F)F)nc2-c2ccc(F)cc2)cc1

Procedure:
2-Mercapto-4,5-bis(4-fluorophenyl)pyrimidine (5.04 g) was placed in a flask into which was condensed ~125 ml liquid ammonia. The resultant slurry was diluted with 30 ml tetrahydrofuran and cooled to -78°. Trifluoromethyl iodide (1.9 ml) was introduced as a gas and the cold bath was then removed. The reaction mixture was irradiated with a General Electric 275 W sun lamp for 2 hours. The ammonia was allowed to evaporate and the tetrahydrofuran removed in vacuo. The residue was dissolved in methylene chloride, washed with water and brine, dried and concentrated on the rotary evaporator. Crystallization from ethanol gave the title compound (2.1 g), m.p. 80°-83°. Infrared and H-NMR were consistent with the assigned structure. MS 368 (M+).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Take up vanillin (1.0 g, 6.57 mmol), 6-chloronicotinonitrile (0.911 g, 6.57 mmol) and K2CO3 (1.36 g, 9.86 mmol) in DMF (16.4 mL). Stir at room temperature overnight, then heat at 100° C. for 3 hours. Cool the reaction mixture to room temperature before quenching with water (75 mL). Extract with dichloromethane (2×150 mL). Wash the organic layer with brine (1×75 mL), dry over MgSO4, filter and concentrate to give the title compound (1.65 g, 98.8%): TOF MS ES+ 255.1 (M+H)+, HRMS calcd for C14H11N2O3 255.0770 (M+H)+, found 255.0776, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=12.2 min, 100% purity.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].C(N(CC)CC)C.Cl.[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>C(#N)C>[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH:27][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NCc1cccc(I)c1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NC(=S)NCc2cccc(I)c2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 4-isothiocyanatobenzenesulfonamide (378 mg, 1.76 mmol) in dry acetonitrile (10 mL) and triethylamine (0.3 mL, 4.0 mmol) was added 3-iodobenzylamine hydrochloride salt (476 mg, 1.76 mmol). The reaction mixture became warm and a clear solution resulted. After stirring for 2 h the reaction was concentrated and the crude solid recrystallized from methanol/water to afford a white solid. The solid was filtered and washed with hexanes to afford the desired product MIP-1139 (715 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br, 1H), 8.48 (br, 1H), 7.74-7.61 (m, 5H), 7.36-7.12 (m, 3H), 4.70 (m, 2H); (M+H)+ (448).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[N:32][CH:33]=[C:34]([Br:39])[CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:39][C:34]1[CH:35]=[C:36]2[C:31](=[N:32][CH:33]=1)[N:30]=[C:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1)[CH:38]=[CH:37]2
Reactant: N[C@@H](Cc1ccc(Oc2ccc3cc(Br)cnc3n2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc3cc(Br)cnc3n2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(6-bromo-[1,8]naphthyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[NH:9][N:8]=2)[N:6]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[N:6]=1
Reactant: COC(=O)c1cc(-c2csc(C)n2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C(=O)O)[nH]n2)cs1
Yield: 123.2 %

Procedure:
A solution of methyl 3-(2-methylthiazol-4-yl)-1H-pyrazole-5-carboxylate (0.586 mmol) in 5 ml of THF and 1 ml of MeOH was treated with 2 ml of 1 M NaOH-solution at RT over three nights. Solvent was evaporated and the residue was taken up in water and washed with DCM. 1 M HCl was added to the water phase until pH was 5. The water phase was washed twice with DCM and neutralized by 1 M sodiumbicarbonate solution. The water phase was evaporated from toluene and the evaporation residual suspended to EtOH. Thus obtained solid was filtered to give 151 mg (123%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.69 (s, 3H), 6.68 (s, 1H), 7.60 (s, 1H), 12.89 (bs, 1H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH:4]2[CH2:3][N:2]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl.C([O-])([O-])=O.[K+].[K+].O>C(OCC)(=O)C>[CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC2CNCC2C1
Yield: 81.2 %

Procedure:
Benzyl tert-butyl tetrahydropyrrolo[3,4-c]pyrrole-2,5(1H, 3H)-dicarboxylate (40 mmol; from step (a) above) was dissolved in ethyl acetate. Ethyl acetate saturated with HCl (g) (500 mL) was added at 0° C. and stirred while reaching room temperature. The solvent was evaporated and the product was dissolved in CH3CN. K2CO3 (4 eq.) and water (2 mL) were added. The mixture was stirred for 2 h, before being filtered and evaporated to give 8 g (82%) of the subtitle compound which was used without further purification in the next step.