Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20](SC)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=2)[CH:28]=[N:27]1>>[CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([C:14]3[N:22]4[C:17]([CH:18]=[N:19][C:20]([NH:35][C:32]5[CH:33]=[C:34]6[C:29]([CH:28]=[N:27][N:26]6[CH3:25])=[CH:30][CH:31]=5)=[N:21]4)=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: Cn1ncc2ccc(N)cc21
Reactant: CSc1ncc2ccc(-c3cccc(S(=O)(=O)CC4CC4)c3)n2n1
Product: Cn1ncc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)CC6CC6)c5)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 7-(3-cyclopropylmethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.20 mmol) was coupled with 1-methyl-1H-indazol-6-ylamine (50.0 mg, 0.340 mmol) at 105° C. for 168 h to afford the titled compound. Yield of TFA salt: 11 mg (10%) of brown powder; LC/MS: 459 (M+H); HPLC: 97% pure, RT=3.29 min; 1H NMR: (DMSO, δ) 9.74 (s, 1H), 9.10 (s, 1H), 8.58 (d, J=7.7, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.84 (d, J=7.9, 1H), 7.82 (s, 1H), 7.78 (t, J=7.9, 1H), 7.56 (d, J=8.7, 1H), 7.23 (d, J=8.7, 1H), 7.20 (d, J=4.9, 1H), 6.95 (d, J=4.9, 1H), 3.69 (s, 3H), 3.22 (d, J=7.3, 2H), 0.78 (m, 1H), 0.33 (m, 2H), −0.01 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(-c2cc(-c3ccccc3)c3nc(C(=O)O)cn3c2)s1
Yield: 98.2 %

Procedure:
A solution of ethyl 6-(2-(tert-butoxycarbonyl-(isopropyl)amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylate (1.00 g, 2.0 mmol) in THF/MeOH (2:1, 15 mL) was treated with 1 N NaOH (5 mL, 5 mmol) at room temperature for 5 hours. The organic solvents were removed under vacuum and the aqueous residue was acidified with 1 N HCl and the solids extracted into CH2Cl2. The extracts were washed with water and concentrated to give 940 mg of 6-(2-(tert-butoxycarbonyl(isopropyl)-amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylic acid as a yellow solid. LCMS (Conditions C): 3.98 min (RT); (M+H)+=479.43 (100%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:11]1[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[C:7](=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)Cn1c(C)cccc1=O
Solvent: CCO
Solvent: O
Product: Cc1cccc(=O)n1CC(=O)NN
Yield: 88 %

Procedure:
As described for example 112a, (6-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (Petride, Horia; Raileanu, Dan. Revue Roumaine de Chimie (1988), 33(7), 729-39.) in ethanol was reacted with hydrazine hydrate (1.8 equivalents) at rt for 96 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 88%). MS: m/e=204.2 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Br.[OH:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH2:50][NH:49][CH2:48][CH2:47]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C.C(Cl)Cl>[OH:43][C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[CH2:50][N:49]([C:7]([C:6]1[S:5][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:3][C:2]=1[CH3:1])=[O:9])[CH2:48][CH2:47]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)N1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
4-Methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolecarboxylic acid (450 mg, 1.6 mmol), 1-hydroxybenzotriazole (260 mg, 1.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (370 mg, 1.9 mmol) were added to 6-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (300 mg, 1.3 mmol) in 2 ml of triethylamine and 6 ml of methylene chloride. The reaction was stirred under N2 at RT for 18 hrs. The reaction was diluted with 100 ml CH2Cl2 and made acidic with 10% citric acid. The organic layer was separated and the aqueous phase was extracted with 2×100 ml CH2Cl2. The organic phases were combined, washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (40% EtOAc/Hexanes) to yield 229 mg (42%) of the title product of this preparation as a white solid.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.[NH2:94][C:95]1[C:96]([C:112]([NH:114][CH3:115])=[O:113])=[N:97][C:98]([C:101]2[CH:102]=[N:103][N:104]([CH2:106][C:107]([F:111])([F:110])[CH2:108][OH:109])[CH:105]=2)=[CH:99][CH:100]=1>>[F:110][C:107]([F:111])([CH2:108][OH:109])[CH2:106][N:104]1[CH:105]=[C:101]([C:98]2[N:97]=[C:96]([C:112](=[O:113])[NH:114][CH3:115])[C:95]([NH:94][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:100][CH:99]=2)[CH:102]=[N:103]1
Reactant: CNC(=O)c1nc(-c2cnn(CC(F)(F)CO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(F)(F)CO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 84 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 275 mg, 0.606 mmol) and 3-amino-6-[1-(2,2-difluoro-3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 59C, 198 mg, 0.636 mmol) to afford 388 mg of the title compound (84%). MS (ESI): m/z=729.68 [M+H]+. UPLC: tR=1.33 min (UPLC-TOF: polar—2 min).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:11]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9](=[O:38])(=[O:37])[N:8]([CH3:39])[C:7]=2[CH:40]=1.S([O-])(=O)(=O)C.[NH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][C:13]([NH:12][CH:11]1[CH2:10][S:9](=[O:37])(=[O:38])[N:8]([CH3:39])[C:7]2[CH:40]=[C:3]([CH2:2][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH:4]=[CH:5][C:6]1=2)=[O:36])(=[O:25])=[O:24]
Reactant: C1CCNCC1
Reactant: CN1c2cc(CO)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O
Agent: CS(=O)(=O)[O-]
Product: CN1c2cc(CN3CCCCC3)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O

Procedure:
The title compound was prepared from N-(7-hydroxymethyl-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazin-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 12, Step D) via its mesylate and addition of piperidine by a method similar to that described in Example 12, Step E. MS (+ESI, m/z): 647 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH:27]([CH2:42]Br)[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH:27]([CH2:42][N:3]([CH3:4])[CH3:2])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CBr)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)CC(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h
Yield: 59.7 %

Procedure:
Dimethylamine hydrochloride (638 mg; 7.8 mmol), potassium carbonate (1.2 g; 8.7 mmol) and potassium iodide (144 mg; 0.87 mmol) were added to a solution in dimethylformamide (10 ml) of 1,3-bis(1-tert-butoxycarbonyl-4-piperidinyl)-2-(bromomethyl)propane (437 mg; 0.87 mmol) synthesized by the above process, and the mixture was stirred for 4 hours in a bath controlled at 60° C. A 0.1N aqueous solution of sodium hydroxide was added to the reaction mixture to conduct extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 243 mg (yield: 60%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH2:22]([C@H:25]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)[CH2:26]1)[CH2:23][CH3:24]>C1(C)C=CC=CC=1>[CH2:22]([C@H:25]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=3)=[O:35])=[CH:32][CH:31]=2)[CH2:26]1)[CH2:23][CH3:24]
Reactant: CCCCCCCCc1ccc(O)cc1
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)C1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(OC(=O)c2ccc([C@H]3CC[C@H](CCC)C3)cc2)cc1

Procedure:
4.1 g of 4-n-octylphenol and 1.6 g of pyridine are dissolved in 10 ml of toluene, the solution is warmed to 100°, 5.0 g of 4-(trans-3-n-propylcyclopentyl)benzoyl chloride (cf. Example 2) are added dropwise, and the mixture is left to react for 3 hours. The pyridine hydrochloride is subsequently filtered off under suction, and the filtrate is washed with water, dried and freed from solvent in vacuo. After crystallization of the residue from petroleum ether, 4-octylphenyl 4-(trans-3-propylcyclopentyl)-benzoate is obtained; m.p. 36°, c.p. 40.7°.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
An aqueous solution (2 ml) of 700 mg of NaOH was added to 15 ml of a methanol solution of 1.0 g of ethyl 4-(1-t-butyloxycarbonyl-4-piperidyl)butanoate and stirred for 1 hour at room temperature. The methanol was removed by distillation under a reduced pressure, and the residue was made acidic with 1N HCl and then extracted with ethyl acetate. This was washed with brine, dried with magnesium sulfate, and the solvent was removed by distillation under a reduced pressure. Thus, 0.91 g of 4-(1-t-butyloxycarbonyl-4-piperidyl)butanoic acid was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C(O)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(F)c(Br)c1
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Br)c1

Procedure:
A mixture of 3.8 g (16.33 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile and 3.7 g (20 mmol) of 3-bromo-4-fluoroaniline in 200 mL of ethanol was refluxed for 3 hr. After the solvent was removed, the residue as dissolved in ethyl acetate and washed with sodium bicarbonate. The product was collected as a pale yellow solid, 6.5 g (71%); ESMS m/z 387.3, 389.2, mp 269-270° C. (dec).
Reaction SMILES: Cl.C([O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:18]=1[C:19]([NH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:33])[N:29]2[CH3:32])=[CH:24][CH:23]=1)=[O:20])C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[C].[Pd].C(O)C>[OH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]1[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:18]=1[C:19]([NH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:33])[N:29]2[CH3:32])=[CH:24][CH:23]=1)=[O:20]
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3N[C@H]3CCCC[C@@H]3OCc3ccccc3)cc21
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3N[C@H]3CCCC[C@@H]3O)cc21
Reaction time: 24 h
Yield: 56.3 %

Procedure:
At room temperature, 1 M hydrochloric acid (0.38 mL) was added to an ethanol (20 mL) solution of 2-{[(1S,2S)-2-(benzyloxy)cyclohexyl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide (140 mg), 10% palladium-carbon (240 mg) was added, followed by stirring for 1 day under an atmosphere of hydrogen. After neutralizing with a saturated sodium bicarbonate aqueous solution extracting with chloroform, the organic layer was concentrated under a reduced pressure. By purifying the residue by silica gel column chromatography (hexane:ethyl acetate, 1:0 to 1:1), 2-{[(1S,2S)-2-hydroxycyclohexyl]amino}-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide (66 mg) was obtained as an amorphous.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:32][C:31]3[CH2:30][CH2:29][NH:28][CH2:27][C:26]=3[CH:25]=1)=[O:23])=[O:13])=[CH:6]2.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.Cl.O.C(O)(=O)C.C(N(CC)CC)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:32][C:31]3[CH2:30][CH2:29][N:28]([CH3:35])[CH2:27][C:26]=3[CH:25]=1)=[O:23])=[O:13])=[CH:6]2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(N[C@H]1CCCC[C@H]1NC(=O)c1cc2c(s1)CCNC2)c1cc2cc(Cl)ccc2[nH]1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCc2sc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
The compound (171 mg) obtained in Example 17 was suspended in methylene chloride (10 mL), and triethylamine (0.104 mL) was added, followed by stirring at room temperature for 10 minutes. After acetic acid (0.059 mL) was added to the reaction mixture, a 35% formalin (0.070 mL) and sodium triacetoxyborohydride (118 mg) were added, and the mixture was stirred at room temperature for 30 minutes. After 1N aqueous sodium hydroxide (3 mL) was added to the reaction mixture, water was added for partitioning the mixture. After the resultant organic layer was dried over sodium sulfate anhydrate, the solvent was then distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=50:3) to give a colorless foamy substance. This substance was suspended in 1N hydrochloric acid, and the suspension was concentrated under reduced pressure to give the title compound (85 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:56])[C@H:21]([NH:33][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[C:46]5[CH:47]=[N:48][C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=6[C:45]=5[NH:44][C:43]4=[O:55])[CH2:38][CH2:37]3)=[O:35])[CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[O:56]=[C:20]([N:17]1[CH2:16][CH2:15][CH:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][CH2:18]1)[C@H:21]([NH:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]2[C:46]3[CH:47]=[N:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=4[C:45]=3[NH:44][C:43]2=[O:55])[CH2:38][CH2:37]1)=[O:35])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=1
Reactant: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)CC1)N1CCC(n2c(=O)[nH]c3c4ccccc4ncc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)N1CCC(N2CCNCC2)CC1)N1CCC(n2c(=O)[nH]c3c4ccccc4ncc32)CC1

Procedure:
A solution of 300 mg (0.40 mmol) 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylic acid [(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-1-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-ethyl]-amide in 10 mL MeOH was hydrogenated in the presence of 30 mg Pd/C (10%) at 50° C. and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the solvent eliminated under reduced pressure and the residue purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure and dried.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH2:14]([C@@H:21]1[CH2:26][CH2:25][NH:24][CH2:23][C@@H:22]1[OH:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@@H:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][S:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:23][C@@H:22]1[OH:27])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O[C@H]1CNCC[C@H]1Cc1ccccc1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Product: O=S(=O)(CCN1CC[C@@H](Cc2ccccc2)[C@@H](O)C1)c1ccc(O)cc1
Yield: 50 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and (3R,4R)-4-benzyl-piperidine-3-ol in 50% yield as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[Cl-].[Na+]>CN(C)C=O.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:25][CH:24]=2)=[CH:17][CH:18]=1
Reactant: N#CCCCBr
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN(CCCC#N)Cc2ccc(OC)cc2)cc1
Temperature: 110 °C
Yield: 110.8 %

Procedure:
A solution of 4-bromobutyronitrile (14.80g) in dry dimethylformamide (100 ml) was added dropwise over 15 minutes to a stirred solution of bis-(4-methoxybenzyl )amine (25.73g) and N,N-diisopropylethylamine (35 ml, 26 g) in dry dimethylformamide (100 ml ). The yellow solution was heated under nitrogen at 110° C. for 4 hours and was allowed to cool. The solution was poured onto a mixture of water (400 ml) and saturated aqueous sodium chloride (400 ml ) and then extracted with ether (2×200 ml). The extracts were dried (Na2SO4) and concentrated in vacuo to give an oil (35.93 g). The product was chromatographed on silica with eluant diisopropyl ether, and was triturated with cyclohexane to give the title compound (26.00g), m.p. 56°-58° C.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([NH:28][NH2:29])=[O:27]>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:30]=[CH:31][CH:32]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:8])([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: COc1cccc(C(=O)NN)c1
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NNC(=O)C2C(C(=O)O)C2C(N)C(=O)O)c1
Reaction time: 8 h
Yield: 133.3 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (150 mg, 0.44 mmol) in dry THF (3 mL) under argon was added 3-methoxybenzoic hydrazide (438 mg, 2.64 mmol) and potassium cyanide (1.43 mg, 0.02 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1/1) to give 206 mg of the desired compound (92% yield).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7].[CH3:16]O>>[OH:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:16])=[O:11])=[O:7]
Reactant: CO
Reactant: O=C(O)CCC(=O)c1cccc(O)c1
Agent: Cl
Product: COC(=O)CCC(=O)c1cccc(O)c1
Temperature: 0 °C

Procedure:
i. Hydrogen chloride was bubbled into a gently boiling solution of 3-(3-hydroxybenzoyl)propionic acid (40 g, 0.21 mole) in dry methanol (80 ml) until esterification was complete. The solution was poured into ice-water (700 ml) and the product extracted into ether. The combined ethereal solutions were washed in turn with water and sodium bicarbonate solution, dried, and finally evaporated under reduced pressure to give methyl 3-(3-hydroxybenzoyl)propionate (41g, 96 m.p. 101.5°-103° C). On recrystallisation from toluene, the pure ester had m.p. 102°-103.5° C.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:28]([C:30]4[O:34][N:33]=[C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:31]=4)[CH3:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)C.CCO.[OH-].[Na+]>C1COCC1>[CH3:26][C:23]1[C:22]([NH:27][CH:28]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:31]=2)[CH3:29])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([CH2:5][C:4]([OH:41])=[O:3])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4cc(-c5ccccc5)no4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(-c2ccc(-c3ccc(C4(CC(=O)O)CC4)cc3)cc2)c1NC(C)c1cc(-c2ccccc2)no1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
[1-(4′-{3-Methyl-4-[1-(3-phenyl-isoxazol-5-yl)-ethylamino]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropyl]-acetic acid ethyl ester (0.0861 g, 0.157 mmol) was dissolved in THF (2 mL) then EtOH (1 mL) and NaOH (3N aq., 0.157 mL, 0.472 mmol) was added and the reaction stirred at 60° C. overnight. The reaction was submitted to standard workup procedure and purified via preparatory HPLC (0.1% TFA/H2O/ACN) to afford the title compound.