Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.O.[BH4-].[Na+]>CO.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([OH:12])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: OC1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A mixture of 8-(4-chlorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (2.6 g, 10.25 mmol), concentrated hydrochloric acid (12 ml), water (10 ml), and ethanol (50 ml) was heated under reflux for 5 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue 10% sodium hydroxide aqueous solution was added, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (50 ml), to which sodium borohydride (388 mg, 10.25 mmol) was added while cooling in an ice-bath, and the mixture was stirred for 30 minutes. To the reaction mixture, 10% hydrochloric acid was added, and the mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water and brine, and was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford 1-(4-chlorophenyl)piperidin-4-ol (1.73 g, yield 80%) as a pale yellow crystalline powder.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].NC1C([Cl:13])=CC(C(=O)CCC2CCNCC2)=C(OC)C=1.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34](=[O:43])[CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[C:29]([O:44][CH3:45])[C:28]=1[O:46][CH3:47]>>[ClH:13].[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34](=[O:43])[CH2:35][CH2:36][CH:37]2[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:41][CH2:42]2)=[C:29]([O:44][CH3:45])[C:28]=1[O:46][CH3:47]
Reactant: CCCCI
Reactant: COc1c(C(=O)CCC2CCNCC2)cc(Cl)c(N)c1OC
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Product: CCCCN1CCC(CCC(=O)c2cc(Cl)c(N)c(OC)c2OC)CC1
Product: Cl

Procedure:
Proceeding as in Example 10, but replacing 1-bromopropane with iodobutane and 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)propan-1-one with 1-(4-amino-5-chloro-2,3-dimethoxyphenyl)-3-(piperidin-4-yl)propan-1-one, gave 1-(4-amino-5-chloro-2,3-dimethoxyphenyl)-3-[1-(but-1-yl) piperidin-4-yl]-propan-1-one hydrochloride, m.p. 175°-176° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:19].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:18](=[O:19])[C:17]3[C:16](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:9]2[C:8]2[CH:11]=[C:12]([CH3:13])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH3:14])[CH:7]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: Nc1ccccc1C(=O)Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(F)cc2)cc(C)c1OCCO
Temperature: 155 °C

Procedure:
To a mixture of 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.420 g, 2.17 mmol) and 2-amino-N-(4-fluoro-phenyl)-benzamide (0.500 g, 2.17 mmol) in N,N-dimethylacetamide (5 mL) was added sodium hydrogen sulfite (0.350 g, 3.26 mmol) and p-toluenesulfonic acid (0.21 g, 0.11 mmol). The reaction mixture was heated at 155° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with cold water (20 mL) to produce the precipitate. The yellow solid was filtered, washed with cold water (2×20 mL), methanol, and dried under vacuum to provide crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give the title compound as white solid. Yield: 0.10 g (11%). MP 95-97° C. 1H-NMR (400 MHz, CDCl3): δ 8.35 (d, 1H), 7.81-7.78 (d, 2H), 7.58-7.40 (m, 1H), 7.20-7.15 (m, 2H), 7.15-7.01 (m, 4H), 3.98-3.80 (m, 4H), 2.21 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 405.01 (M+1).
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][CH:17]([CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][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)[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1cccs1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1cccs1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-thiophen-2-yl-propionic acid to provide the title compound in good yield.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51]2[N:54]=[C:55]([NH2:57])[S:56][C:50]=2[CH:49]1[C:58]1[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=1[O:65][CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51]2[N:54]=[C:55]([NH:57][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])[S:56][C:50]=2[CH:49]1[C:58]1[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=1[O:65][CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(N)nc2CCN1C(=O)OCc1ccccc1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(NC(=O)C3CC3)nc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclopropanecarboxylic acid (5 μL, 60 μmol, 1 eq.) in DMF (5 mL), DIPEA (51 μL, 300 μmol, 5 eq.) and TBTU (19 mg, 60 μmol, 1 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 minutes. Then (±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (30 mg, 60 μmol, 1 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:30]([O:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]([NH:49][CH2:50][CH2:51][O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[C:43]([NH2:48])[CH:44]=[N:45]2)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClC(Cl)C.CN(C)C1C=CN=CC=1.C(OCC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:49]([CH2:50][CH2:51][O:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:42]2[C:41]3[CH:40]=[CH:39][C:38]([O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:47][C:46]=3[N:45]=[CH:44][C:43]=2[N:48]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-(tert-butoxycarbonylamino)valeric acid (1.50 g, 6.91 mmol) in dichloroethane (30 mL) was cooled to −25° C. Triethylamine (2.40 mL, 17.2 mmol) and pivaloyl chloride (0.85 mL, 6.91 mmol) were added, and the reaction was stirred for three hours, during which time the temperature rose to −10° C. 7-Benzyloxy-N4-(2-phenoxyethyl)quinoline-3,4-diamine (0.850 g, 2.20 mmol), prepared as described in Parts A-B of Example 46, was added in one portion followed by a small scoop of 4-dimethylaminopyridine. The reaction was allowed to warm to room temperature and stirred overnight and then heated at reflux for three hours. The reaction solution was washed with saturated sodium bicarbonate, water (2×), and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with sequentially with 98:2 and 95:5 chloroform:methanol) to yield a solid. The solid was treated with diethyl ether and concentrated under reduced pressure to provide 1.03 g of tert-butyl{4-[7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate as a white powder.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12](O)=O.C=O>CO>[CH2:1]([N:8]([CH:9]([OH:11])[CH3:10])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: CC(O)NCc1ccccc1
Agent: C=O
Solvent: CO
Product: CC(O)N(C)Cc1ccccc1
Yield: 84 %

Procedure:
A mixture consisting of 151 g (1 mol) of N-benzylaminoethanol, 120 ml of 90% formic acid, 120 ml of a 35% aqueous formaldehyde solution and 1 liter of methanol is heated under reflux for 20 hours. The solvent is evaporated off in vacuo and the residue is treated with an aqueous sodium hydroxide solution and then extracted with methylene chloride. After customary treatment, the product is purified by distillation. 138 g of the desired product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](=[NH:20])[CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>O1CCCC1>[NH2:20][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:13][C:14]([CH2:15][CH3:16])([OH:17])[CH2:18][CH3:19]
Reactant: CCC(O)(CC)CC(=N)C1(c2ccc(Cl)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)(CC)CC(N)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-ethyl-1-iminopentan-3-ol (1.6 g) in dry tetrahydrofuran (20 ml) was treated under nitrogen with boranetetrahydrofuran complex (1M solution in tetrahydrofuran 10 ml) and the mixture was heated under reflux for 24 hours. The mixture was cooled in ice and water and then 2N sodium hydroxide solution were added. The resulting mixture was extracted with ether and the extracts were washed, dried and evaporated to give 1-amino-1-[1-(4-chlorophenyl)cyclobutyl]-3-ethylpentan-3-ol which was then converted into the corresponding dimethylamino compound by heating a mixture of the primary amine (1.5 g), 98% formic acid (4 ml) and 37-40% aqueous formaldehyde (2 ml) at 90°-95° C. for 16 hours. The reaction mixture was cooled and poured into a mixture of 16N sodium hydroxide solution (7 ml) and ice. The mixture was extracted with ether and the extract washed, dried and evaporated to give a residue which was dissolved in ether. Addition of a solution of maleic acid in ether gave 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-3-ethylpentan-3-ol maleate (m.p. 110°-111° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=[O:7])#[N:2].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([O:8][CH3:13])=[O:7])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(C#N)c1
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
To a 100 mL rbf was added 3-cyano-4-fluoro-benzoic acid (2.6 g, 15.9 mmol), potassium carbonate (6.6 g, 47.6 mmol), and DMF (30 mL) and the reaction was allowed to stir for 10 minutes. Iodomethane (1.1 mL, 17.5 mmol) was added dropwise and the reaction was allowed to stir for 1 h. The reaction was complete by 1 cms. The reaction was quenched with brine and extracted with EtOAC. The organic layer was washed with brine 3 times and the organic layer was dried over sodium sulfate and evaporated. Methyl 3-cyano-4-fluoro-benzoate (2.5 g, 62%) was isolated as a white solid. ESI-MS m/z calc. 179.0, found 180.0 (M+1)+; Retention time: 1.15 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]=O.[C:12]1([C:18]2[CH:19]=[C:20]([NH:23][C:24](=[O:30])[C@@H:25]([NH2:29])[CH2:26][CH2:27][CH3:28])[NH:21][N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:12]1([C:18]2[CH:19]=[C:20]([NH:23][C:24](=[O:30])[C@@H:25]([NH:29][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:26][CH2:27][CH3:28])[NH:21][N:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=CCc1cccc(F)c1F
Reactant: CCC[C@H](N)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NCCc1cccc(F)c1F)C(=O)Nc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-amino-5-phenyl pyrazole (31.2 mmol) was combined with (S)-2-tert-butoxycarbonylamino-pentanoic acid (37.5 mmol) and dissolved in 50 mL of anhydrous dichloromethane. Triethylamine (93.6 mmol) was added, followed by TBTU (37.5 mmol) and the reaction mixture was stirred at rt for 2 h. The solution was then diluted with 50 mL of fresh dichloromethane and extracted with 50 mL portions of aqueous saturated bicarbonate solution, water and then brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified through flash chromatography on silica gel. The purified product was then heated neat at 150° C. for 3 h. The reaction mixture (14.4 mmol) was then cooled to rt and dissolved in 40 mL of anhydrous 4.0 N HCl dioxane solution and stirred at rt for 3 h. The reactions were concentrated under reduced pressure and triturated with 20 mL of anhydrous Et2O. The solids were filtered and dried to give the desired amine, (S)-2-Amino-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide. 2-(2,3-Difluoro-phenyl)-acetaldehyde (0.2 mmol) was combined with (S)-2-Amino-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide (0.2 mmol) in 2 mL of anhydrous dichloromethane under N2. Sodium triacetoxyborohydride (0.3 mmol) and two drops of acetic acid were then added and the reaction was stirred at rt for 16 h. The crude solution was then concentrated under reduced pressure and purified through flash chromatography on silica gel to give 2-(S)-[2-(2,3-Difluoro-phenyl)-ethylamino]-pentanoic acid (5-phenyl-2H-pyrazol-3-yl)-amide, LC-MS 2.7 min, 398 [M+1].
Reaction SMILES: C([O:4][C@H:5]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=O)C>CO.N.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:4][C@H:5]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CC(=O)O[C@H](CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: N
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](O)CCc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 86.2 %

Procedure:
8.0 g of tert.butyl 2(R)-acetoxy-4-(4-nitrophenyl)butanoate were dissolved in 200 ml of methanol saturated with ammonia at 0° C. and the mixture was stirred for 16 hours. Evaporation of the mixture in vacuo gave 7 g of an almost colorless oil which was dissolved in an equal volume of diethyl ether/n-hexane (1;1) and eluted through a silica gel column with the same solvent mixture to give 6 g of tert.butyl 2(R)-hydroxy-4-(4-nitrophenyl)butanoate as a colorless crystalline solid having a melting point of 41°-42° C.
Reaction SMILES: C([C@H](NC(=O)C1C=CC=C(S(C)(=O)=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:36][S:37]([C:40]1[CH:41]=[C:42]([CH:46]=[C:47]([N:49]2[CH2:53][CH2:52][CH2:51][C:50]2=[O:54])[CH:48]=1)[C:43]([OH:45])=O)(=[O:39])=[O:38].[CH:55]12[CH2:61][CH:58]([CH2:59][CH2:60]1)[CH2:57][CH:56]2[NH:62][C:63](=[O:78])[C@H:64]([CH3:77])[CH2:65][C@H:66]([OH:76])[C@@H:67]([NH2:75])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[CH2:68]([C@H:67]([NH:75][C:43](=[O:45])[C:42]1[CH:46]=[C:47]([N:49]2[CH2:53][CH2:52][CH2:51][C:50]2=[O:54])[CH:48]=[C:40]([S:37]([CH3:36])(=[O:38])=[O:39])[CH:41]=1)[C@@H:66]([OH:76])[CH2:65][C@H:64]([C:63](=[O:78])[NH:62][CH:56]1[CH2:57][CH:58]2[CH2:61][CH:55]1[CH2:60][CH2:59]2)[CH3:77])[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(S(C)(=O)=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(S(C)(=O)=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E1, from 3-methylsulfonyl-5-(2-oxopyrrolidin-1-yl)-benzoic acid (D19) and (2R,4S,5S)-5-Amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CN1CCNCC1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccnc3ccc(Br)cc23)CC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 485 mg 6-bromo-4-chloroquinoline, 1.1 mL N-methyl piperazine, 415 mg potassium carbonate and 10 mL N,N-dimethylformamide was stirred at 130° C. for 8 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and brine and dried over an hydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 502 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH:26][S:27]([C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:29])=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][S:27]([C:30]1[NH:31][C:32]2[C:37]([C:38]=1[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:12]1[CH:21]=[CH:22][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:29])=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Reactant: OC(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Product: CC(C)NS(=O)(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 84.3 %

Procedure:
Substantially the same procedure as in Example 266 was repeated using 4-benzyloxybenzhydrol (1.31 g, 4.50 mmol) and N-isopropylindole-2-sulfonamide (1.00 g, 4.46 mmol) to give 1.92 g (yield: 84%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([CH3:17])([CH3:16])[N+:13]([O-])=O.O.NN>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([NH2:13])([CH3:16])[CH3:17]
Reactant: CC(C)(Cc1c[nH]c2ccc(Cl)cc12)[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
5-Chloro-3-(2,2-dimethyl-2-nitroethyl)-1H-indole (13.5 g, 53.1 mmol), prepared as in Example 2, Step (b), was dissolved in ethanol (≈100 mL). An aqueous suspension of RANEY NICKEL® catalyst (5.0 mL) was added to the solution and the mixture was heated to 80° C. Hydrazine hydrate (10 mL, 321.1 mmol) in ethanol (≈30 mL) was added dropwise to the mixture which was then stirred for an additional 30 minutes. The mixture was filtered through celite and the filter cake was washed with methanol. The filtrate was concentrated by rotary evaporation to ≈75 mL. Crystallization upon addition of water gave [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine (9.17 g, 40.9 mmol), m.p. 156°-158° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(S(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-methanesulfonyl-piperazine (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C34H42Cl2N5O4S [(M+H)+] 686.2329, observed 686.2329.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([C:21]#[N:22])(C)C>C(N(CC)CC)C>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:21]#[N:22])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(C#N)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 20.9 %

Procedure:
Under a nitrogen atmosphere, 4-(tert-butyldimethylsilyloxymethyl)pyridine-1-oxide (1.2 g, 5 mmol) synthesized in Production Example 85 was dissolved in triethylamine, and trimethylsilylcyanide (744 μL, 6 mmol) was added thereto. The mixture was stirred at 90° C. for 3 hours. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature. The solvent was distilled off. The resulting residue was dissolved in ethyl acetate and washed with water 3 times and with a saturated saline solution once. Thereafter, the organic layer was dried over magnesium sulfate. The solvent was distilled off, and thus the title compound (260 mg, 20.9%) was obtained as an oily substance.
Reaction SMILES: [N+](=C)=[N-].[C:4]([CH:7]([CH2:17][CH2:18][CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:6])[CH3:5].[C:31](O)(=O)C>CCOCC>[C:4]([CH:7]([CH2:17][CH2:18][CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:31])=[O:15])(=[O:6])[CH3:5]
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCCCCCC(CCCC(O)COc1ccc(F)cc1)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)tridecanoic acid (11.5 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields the title ester as a yellow viscous oil.