Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10]N2[C:4](=NCCC2)[CH2:3][CH2:2]1.C1N=[C:16](N)[C:15]2N=CN(CCOCP(O)(O)=O)[C:14]=2N=1.[C:30]12([C:40]([O:42][CH2:43][Cl:44])=[O:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.[CH3:45]N(C=O)C>>[C:30]12([C:40]([O:42][CH2:43][Cl:44])=[O:41])[CH2:39][CH:34]3[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]3)[CH2:37]1)[CH2:31]2.[C:11]12([C:43]([Cl:44])=[O:42])[CH2:10][CH:4]3[CH2:3][CH:2]([CH2:14][CH:15]([CH2:16]3)[CH2:45]1)[CH2:1]2
Reactant: Nc1ncnc2c1ncn2CCOCP(=O)(O)O
Reactant: C1CCC2=NCCCN2CC1
Reactant: CN(C)C=O
Agent: O=C(OCCl)C12CC3CC(CC(C3)C1)C2
Product: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene; 1.53 g, 10 mmol) was added to a suspension of PMEA (1.365 g, 5 mmol) in DMF (25 mL). Adamantoyl oxymethyl chloride (5.72 g, 25 mmol) in DMF (25 mL) was added to the reaction mixture which was then stirred for four days at room temperature and the volatiles were removed under vacuum. The crude product obtained after removal of the solvent was loaded onto a silica gel column and washed with 3% MeOH/CH2Cl2 to remove nonpolar impurities. 1 g (30%) of bis(adamantoyl oxymethyl)PMEA ester was eluted in 8% MeOH/CH2Cl2. Adamantoyl oxymethyl chloride was obtained by conversion of 1-adamantanecarbonyl chloride (Aldrich No. 11,772-2) with (CH2O)n/ZnCl2 and has been described (Bodor, et al J Med Chem (1980) 23:474-480).
Reaction SMILES: C(OC(=O)C)(=O)C.C(Cl)(=O)C.[F:12][C:13]([F:21])([CH2:17][C:18]([OH:20])=[O:19])[C:14](O)=[O:15]>>[F:12][C:13]1([F:21])[CH2:17][C:18](=[O:20])[O:19][C:14]1=[O:15]
Reactant: O=C(O)CC(F)(F)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: O=C1CC(F)(F)C(=O)O1
Temperature: 50 °C

Procedure:
To a solution of 10.8 mL of acetic anhydride and 10.8 mL of acetyl chloride at 0° C. was added 10.80 g (0.070 mol) of 2,2-difluorosuccinic acid in several portions. The mixture was heated for 1 hr at 50° C. and cooled. The reaction was concentrated under reduced pressure to yield 2,2-difluorosuccinic anhydride. NMR (CDCl3) δ3.56 ppm (triplet, 2, J=15 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([OH:12])=[O:11])[C:3]=1[Cl:13].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].[CH3:23]S(C)=O>O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:10]([O:12][CH3:23])=[O:11])[C:3]=1[Cl:13]
Reactant: CS(C)=O
Reactant: Oc1ccccc1
Reactant: Nc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1nc(Oc2ccccc2)c(Cl)c(N)c1Cl
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A solution of 4-amino-3,5,6-trichloropyridine-2-carboxylic acid (7.2 g, 0.03 mol), phenol (3.0 g, 0.036 mol) and sodium hydroxide (2.7 g 0.068 mol) in DMSO (60 mL) and water (9 mL) was heated to 130° C. for 18 hr. The reaction was diluted with water (250 mL) and a tacky solid collected. This material was dissolved in methanol (100 mL) and treated with TMSCHN2 (25 mL 2M in hexanes). The reaction was stirred 30 min and concentrated. The resulting oil was chromatographed over silica gel (80% hexane and 20% ethyl acetate) to give methyl 4-amino-3,5-dichloro-6-phenoxypyridine-2-carboxylate (1.2, g, 14%); mp 88-90° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>C(#N)C>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 78 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (24.0 g, 1.0 eq) was charged into a 1 L, 3-neck round bottom flask set in a heating mantel with a J-KEM controller. Cesium carbonate (39.2 g, 1.3 eq) was charged into the flask. Acetonitrile (250 mL) was charged into the flask and the reaction mixture was stirred with a magnetic stir bar. 4-(Chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (26.7 g, 1.1 eq) was charged slowly over 20 minutes while heating the reaction mixture. The internal temperature at the beginning of the charge was about 21° C. and the internal temperature at the end of the charge was about 82° C. Reaction temperature was maintained at 78° C. 1PC taken after 2.0 hours indicated 95% conversion to product by HPLC. After 2.5 hours the reaction temperature was reduced from about 78° C. to about 54° C. over 33 minutes. 125 mL of acetonitrile (5 vol) was heated to 50° C. in a 250 mL Ehrlenmeyer flask. Celite® was placed in a glass sintered filter funnel and acetonitrile used to wash and pack the filter aid. The acetonitrile wash was discarded to waste. The packed Celite® was approximately 0.5 inches. The reaction mixture was cooled to about 54° C. and filtered through the Celite® filter aid in the glass sintered filter funnel and washed with the 125 mL acetonitrile heated to about 50° C. The acetonitrile filtrate was stirred under nitrogen at ambient temperature for 1.0 hour. The filtrate was concentrated under reduced pressure at about 24° C. forming a thick slurry; 260 mL of distillate was collected. 375 mL of methanol was used to transfer the slurry into a 1 L round bottom flask. The slurry was stirred under nitrogen at ambient temperature for 15.0 hours. The slurry was placed in an ice/salt bath and stirred under nitrogen for 1.2 hours. 150 mL of methanol was placed in an ice/salt bath. The solids were filtered in a Whatman disposable filter cup at about −11° C. and washed with chilled methanol (125 mL). The off-white solids were placed in a vacuum oven set at about 29° C. for 22.5 hours to afford 35.7 g of ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (Compound of Formula (IIk), wherein R3 is ethyl), 79% yield with 99.57 Area % by HPLC.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:31][CH3:32])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:31][CH3:32])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCCNC(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74.2 %

Procedure:
N-Boc-6-aminocaproic acid (7.58 g) prepared by the method described in a Journal of Medicinal Chemistry (J. Med. Chem., 35, p.272 (1993)) and 7.58 g of 3-amino-9-ethylcarbazole were dissolved in 75 mL of dimethylformamide, and the solution was added with 10.4 g WSC hydrochloride and stirred at room temperature for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with 1 N aqueous sodium hydroxide, 10% aqueous citric acid and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 10.3 g of 3-(N-Boc-6-aminocaproyl)amino-9-ethylcarbazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([N:8]([CH2:12][C:13](O)=[O:14])[CH:9]([CH3:11])[CH3:10])[CH:7]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:16][C:13](=[O:14])[CH2:12][N:8]2[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)N(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)N1CC(=O)Nc2ccc(Br)cc21
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of [(5-bromo-2-nitro-phenyl)-isopropyl-amino]acetic acid (27 g, 85 mmol) in acetic acid (400 ml) was added iron powder (15 g, 0.27 mol) and the mixture was stirred for 2 hrs. at 90° C. The reaction mixture was cooled, filtered, and the acetic acid was evaporated. The remaining slurry was extracted with CH2Cl2 (3×300 ml). The CH2Cl2 extracts were combined, dried (MgSO4) and evaporated to afford the subtitled compound (16.8 g, 73%): 1H-NMR (DMSO-d6) δ 1.13 (d, J=6.54 Hz, 6H), 3.57 (s, 2H), 3.99 (septet, J=6.54 Hz, 1H), 6.82 (dd, J=8.23, 1.88 Hz, 1H), 6.72 (d, J=8.17 Hz, 1H), 6.90 (d, J=1.59 Hz, 1H), 10.50 (s, 1H): MS (EI) 267/269 (M)++1 bromine.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[O:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]([NH2:31])[CH2:23][CH2:22]1>>[O:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]([NH:31][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:23][CH2:22]1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: NC1CCOc2ccccc21
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NC4CCOc5ccccc54)cccc3n2)o1

Procedure:
The title compound, MS: m/e=386.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3,4-dihydro-2H-chromen-4-ylamine.
Reaction SMILES: N([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[N:15]=[C:14]([C:24]([OH:26])=O)[CH:13]=[C:12]([CH3:27])[C:11]=2[C:10](=[O:28])[CH:9]=1)C1C=CC=CC=1.Cl.[CH3:30][NH:31][O:32][CH3:33].[CH:34]1[CH:35]=[CH:36][C:37]2N(O)N=[N:40][C:38]=2[CH:39]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH:17]([C:8]1[N:40]([C:38]2[CH:39]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:16]2[N:15]=[C:14]([C:24]([N:31]([O:32][CH3:33])[CH3:30])=[O:26])[CH:13]=[C:12]([CH3:27])[C:11]=2[C:10](=[O:28])[CH:9]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CNOC
Reactant: Cc1cc(C(=O)O)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Reaction time: 1 h
Yield: 58.6 %

Procedure:
7-anilino-4-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylic acid (50 mg, 0.14 mmol), N,O-dimethylhydroxylamine hydrochloride (39 mg, 0.40 mmol), HOBT (28 mg, 0.21 mmol), EDCI (40 mg, 0.21 mmol) were dissolved in CH2Cl2 (3 mL). To this solution was added TEA (78 uL, 0.56 mmol). The reaction was stirred for 1 h and was diluted with CH2Cl2, washed with 0.5N HCl, saturated NaHCO3, and brine. The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The solid obtained was triturated with Et2O and dried to give 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a light yellow solid (34 mg, 59%): LCMS RT: 2.28 min, MH+: 415.2. This transformation can also be accomplished by coupling the appropriate amine with the corresponding acid chloride.
Reaction SMILES: Br[CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH:6]([OH:14])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[CH:3]1Br.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[CH:18]1[C:4]2[C:3]#[C:2][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][CH:6]([OH:14])[C:5]=2[CH:15]=[CH:16][CH:17]=1
Reactant: OC1Cc2ccccc2C(Br)C(Br)c2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1Cc2ccccc2C#Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a stirred solution of 44 (1.528 g, 4 mmol) in tetrahydrofuran (40 ml) was added dropwise lithium diisopropylamide in tetrahydrofuran (2.0 M) (8 ml, 16 mmol) under an atmosphere of Argon at room temperature. The reaction mixture was stirred for 0.5 hour at room temperature, after which it was quenched by addition of dropwise water (0.5 ml). The solvents were evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (2:1-0:1 v/v hexanes/CH2Cl2) to give the product as white solid (0.503 g, 57%). 1H NMR (300 MHz, CDCl3): δ 7.67 (1H, aromatics), 7.37-7.18 (7H, aromatics), 4.57 (1H, dd, J=2.1, 14.7 Hz, CHOH), 3.04 (1H, dd, J=2.1, 14.7 Hz, CH2), 2.86 (1H, dd, J=2.1, 14.7 Hz, CH2). 13C NMR (75 MHz, CDCl3): δ 154.5, 150.6, 128.6, 127.1, 1127.0, 126.0, 125.8, 125.1, 124.7, 123.0, 122.7, 121.7, 111.9, 109.6, 74.2, 47.7.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][NH2:30])[N:24]=1.O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:12]([CH3:13])=[N:30][N:29]([C:25]3[N:24]=[C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)[CH:28]=[CH:27][N:26]=3)[C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)C(SCc1ccc(Cl)cc1)C(C)=O
Reactant: NNc1nccc(-c2ccccn2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
To a solution of 3-(4-chloro-benzylsulfanyl)-pentane-2,4-dione (1.15 g, 4.48 mmol) in ethanol (60 mL) was added (4-pyridin-2-yl-pyrimidin-2-yl)-hydrazine (0.838 g, 4.48 mmol) and p-toluenesulfonic acid monohydrate (ca. 20 mgs). The solution was heated to reflux and stirred for 5 hours. The reaction mixture was allowed to cool to room temperature, and water (200 mL) was added. The precipitate that formed was isolated by filtration and recrystallized from aqueous methanol to provide 1.36 g (74%) of the product as white needles: 1H NMR (CDCl3) δ 8.94-8.92 (m, 1H), 8.75-8.73 (m, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.28-8.26 (m, 1H), 7.91 (t, J=7.9 Hz, 1H), 7.46-7.43 (m, 1H), 7.20 (d, J=8.0 Hz, 2H), 6.89 (d, J=8.0 Hz, 2H), 3.66 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H) ppm. 13C NMR (CDCl3) δ 164.6, 160.5, 157.4, 155.2, 153.5, 149.8, 147.3, 137.6, 137.2, 133.1, 130.6, 128.7, 126.1, 122.2, 114.7, 111.3, 40.1, 14.2, 12.6 ppm.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[O:26]1[CH2:30]C[C@H:28](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27]1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:21]1[CH2:28][CH2:27][O:26][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: Cl
Product: Clc1ccc2c(c1SC1CCOC1)CCNCC2

Procedure:
Use a method similar to the Example 332, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and (S)-toluene-4-sulfonic acid tetrahydrofuran-3-yl ester to give, after deprotection using a method similar to the General Procedure 1-4, the title compound as an off-white solid. MS (APCI+) m/z: 284 (M+H)+; [α]20D −28.0° (c 0.5, CH3OH). ee=97.8% [Chiral HPLC: Column: YMC ODS-AQ 120 Å 4.6×50 mm [S-3μm]; eluent: gradient from 95:5 to 5:95 AB; solvent A: water, 0.01% HFBA, 1% isopropanol; solvent B: acetonitrile, 0.01% HFBA, 1% isopropanol; flow rate 2 mL/min].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]([C:27]([OH:29])=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16]C(OCC2C=CC=CC=2)=O)=[CH:6][CH:5]=1)([O-])=O.O.[ClH:31]>C(O)C.[Pd]>[ClH:31].[ClH:31].[ClH:31].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@H:11]([C:27]([OH:29])=[O:28])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:9]=1
Reactant: O=C(NCCCC[C@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: NCCCC[C@H](Nc1ccc(N)cc1)C(=O)O
Reaction time: 0.75 h
Yield: 93 %

Procedure:
0.40 g (1 mmol) of Nα-(4-nitrophenyl)-Nε-(benzyloxycarbonyl)-L-lysine is dissolved in 20 ml of ethanol, 5 ml of water and 0.5 ml (3.5 eq) of 5N hydrochloric acid in a 250 ml glass reactor (Paar apparatus). 0.5 g of palladium-on-charcoal (50% moisture and 10% active) is then introduced. The mixture is hydrogenated under a pressure of approximately 2.76×105 Pa for 45 minutes and at a temperature of 12° C. After filtration through celite, the filtrate is evaporated. The purplish oily residue is taken up in ethanol and precipitated from a large volume of acetone with stirring. After filtration, 0.3 g of a white crystalline powder is obtained, i.e. a final yield of 93%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=3[N:8]=2)[CH:2]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=3[N:8]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(-c3cccnc3)nc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(-c3cccnc3)nc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(3-pyridyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[CH:7]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][NH:24][S:33]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:7]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(2-Aminomethyl-4-trifluoromethyl-phenoxy)-phenyl]acetic acid ethyl ester (0.084 g, 0.24 mmol) and 4-chlorobenzenesulfonyl chloride (0.060 g, 0.29 mmol) were combined in CH2Cl2 (3 mL). Triethylamine (0.05 mL, 0.36 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by silica gel chromatography (10-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH:16]=O.O.OOS([O-])=O.[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:16]([C:15]3[C:14]([Cl:13])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:22])[NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,4-diaminobenzoic acid methyl ester (3.32 g, 20 mmol) and 2,6-dichlorobenzaldehyde (3.5 g, 20 mmol) in DMF (20 mL)+water (2 mL) was added oxone (2.46 g, 4 mmol). The mixture was stirred at RT for 18 h then EtOAc was added. The mixture was washed with water and brine then was dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a yellow solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C:14]1[C:22]2[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([NH2:33])[CH3:32])[CH:26]=1>>[CH3:23][C:20]1([CH3:24])[CH2:19][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:13][C:6]3[CH:5]=[CH:4][C:3]4[C:2]([NH:33][CH:31]([C:27]5[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=5)[CH3:32])=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=3)[C:22]=2[O:21]1
Reactant: CC(N)c1cccnc1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: Clc1ccc2c(I)cccc2n1
Product: CC(Nc1cccc2nc(Nc3cccc4c3OC(C)(C)C4)ccc12)c1cccnc1

Procedure:
The title compound, MS: m/e=411.5 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and rac-1-pyridine-3-yl-ethylamine.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]3[C:23]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=3[N:19]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:6])=[O:4].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:31][O:30][C:20]1[C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:32]=[CH:33][C:8]([CH2:7][N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:9][CH:10]=3)[S:16][C:17]=2[C:23]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=1
Reactant: C1CCNC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CCl)cc3)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CN4CCCC4)cc3)nc12

Procedure:
Using 4-[(Chloroacetyl-methyl-amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide and pyrrolidine the title compound was obtained as white crystals (61% yield), mp 114-116° C.). MS: m/e=524 (M+H+).
Reaction SMILES: [OH:1][C:2]12[CH2:11][C:6]3([C:12]([OH:14])=[O:13])[CH2:7][CH:8]([CH2:10][C:4]([C:15]([OH:17])=[O:16])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:18](O)[CH2:19][CH2:20][CH3:21].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]12[CH2:3][C:4]3([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[CH2:10][CH:8]([CH2:7][C:6]([C:12]([O:14][CH2:9][CH2:2][CH2:3][CH3:4])=[O:13])([CH2:5]3)[CH2:11]1)[CH2:9]2.[OH:1][C:2]12[CH2:3][C:4]3([C:15]([OH:17])=[O:16])[CH2:10][CH:8]([CH2:7][C:6]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:11]1)[CH2:9]2
Reactant: CCCCO
Agent: O=C(O)C12CC3CC(O)(C1)CC(C(=O)O)(C3)C2
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C12CC3CC(O)(C1)CC(C(=O)OCCCC)(C3)C2

Procedure:
To 900 ml of toulene were added 300 mmol of the obtained 5-hydroxy-1,3-adamantanedicarboxylic acid, 900 mmol of n-butanol and 30 mmol of sulfuric acid, and the resultant mixture was stirred under reflux of toluene for 5 hours. The reaction mixture was concentrated and subjected to column chromatogrpahy on a silica gel to give di-n-butyl 5-hydroxy-1,3-adamantanedicarboxylate in yield of 85.5% at a conversion rate from 5-hydroxy-1,3-adamantanedicarboxylic acid of 95%.
Reaction SMILES: [NH:1]([C:8]([C:10]1[N:11]([CH2:27][C:28]([OH:30])=[O:29])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[CH3:32].CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl>[NH:1]([C:8]([C:10]1[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:14][CH:13]=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C(=O)Nc2ccccc2)cc2cc(NC(=O)CC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1.50 g (3.68 mmol) of {2-(anilinecarbonyl)-5-[(3,3-dimethylbutanoyl)amino]-1H-indol-1-yl}acetic acid from Example LIV, 225 mg (1.84 mmol) of 4-dimethylamino-pyridine and 203.5 mg (4.42 mmol) of ethanol are initially charged in dichloromethane. The mixture is cooled to 0° C., and 776 mg (4.05 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl are added. The mixture is stirred at RT for 4 hours. For work-up, the mixture is diluted and extracted with water and dichloromethane. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure. The resulting crude product is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate 2:1–1:1).