Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[C:21](O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][NH2:25]>CS(C)=O.CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[CH:21]=[N:24][NH:25]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(F)cccc1N1CCN(Cc2ccccc2)CC1
Reactant: NN
Solvent: CCOCC
Solvent: CS(C)=O
Product: c1ccc(CN2CCN(c3cccc4[nH]ncc34)CC2)cc1
Reaction time: 8 h
Yield: 53 %

Procedure:
A stirred solution of 4-benzyl-1-(3-fluoro-2-carboxyphenyl)-piperazine (5.96 g, 20.0 mmol) in dimethylsulfoxide (10 mL) and hydrazine (10 mL) is heated at 95° C. under nitrogen for 4 days. The cooled reaction is diluted with ether and washed with a mixture of water and saturated aqueous sodium bicarbonate. The organic layer is further washed sequentially with water and brine dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using ethyl acetate as the eluant. The resulting oil is reconcentrated from ether to give a white foam which is stirred under hexanes/ether overnight. The resulting white powder is isolated by suction filtration and washed with hexane to give the title compound 3.11 g, (53% yield), identified by HNMR.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([O:39]C)=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([OH:39])=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CCC[C@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@@H]2CCC[C@@H]2C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
To a mixture of methyl (1S,2R)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.25 g), THF (2.0 ml), and methanol (2.0 ml) was added a 1 M aqueous sodium hydroxide solution (2.0 ml) under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction mixture was added 1 M hydrochloric acid (2.0 ml) under ice-cooling, followed by stirring at room temperature. The solid precipitated was collected by filtration and washed with water to obtain (1S,2R)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylic acid (0.22 g).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:24]O>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.083 mL (2.1 mmol) of methanol. MS (m/z, ES+): 339.34 (M+1, 100%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])=[NH:11])[CH2:2]2.[CH2:24]([Br:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)C>C(#N)C>[Br-:31].[CH2:24]([N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH2:11])=[N:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])[CH2:2]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CN2CCC1CC2
Reactant: BrCc1ccccc1
Solvent: CCOCC
Solvent: CC#N
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NC1C[N+]2(Cc3ccccc3)CCC1CC2
Product: [Br-]
Yield: 57.3 %

Procedure:
N-1-Aza-bicyclo[2.2.2]oct-3-yl-N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine (Intermediate 4, 30 mg, 0.089 mmol) and benzyl bromide (Acros, 17 mg, 0.097 mmol) are stirred for 4 h at 70° C. in acetonitrile (2 mL). To the suspension is added diethyl ether (2 mL), the solid collected by filtration, washed with diethyl ether and dried under vacuum to yield the title compound (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:42](=[O:48])[O:43][C:44](Cl)(Cl)Cl)Cl.[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][CH2:55]CO>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:43][CH2:44][CH2:55][CH2:54][O:53][C:52]1[CH:58]=[CH:59][CH:60]=[CH:61][C:51]=1[Cl:50]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCOc1ccccc1Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4ccccc4Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 53.1 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (70 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (94 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-chlorophenoxy)-1-propanol (59 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1I.C([Sn](CCCC)(CCCC)[C:22]1[N:23]=[CH:24][S:25][CH:26]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[C:22]1[N:23]=[CH:24][S:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cscn2)c(F)c1
Reaction time: 34 h
Yield: 62 %

Procedure:
A solution of tert-butyl 3-fluoro-4-iodophenylcarbamate (500 mg, 1.48 mmol) and 4-(tributylstannyl)thiazole (0.578 mL, 1.80 mmol) in dioxane (6 mL) was degassed with Ar before being charged with Pd(Ph3P)4 (170 mg, 0.147 mmol). It was stirred at 100 C for 34 h, then concentrated in vacuo. The residue was loaded to a flash column, eluted with 0-25% EtOAc in hexane to give tert-butyl 3-fluoro-4-(thiazol-4-yl)phenylcarbamate (270 mg). MS 295.3 (M+H)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[I:58][C:59]1[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][S:65]([C:62]3[CH:63]=[CH:64][C:59]([I:58])=[CH:60][CH:61]=3)(=[O:67])=[O:66])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccc(I)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of the FR-900506 substance (100.7 mg) in pyridine (3 ml) was added p-iodobenzenesulfonyl chloride (500 mg), and the mixture was stirred at room temperature for 36 hours. The solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (developing solvent: diethyl ether and hexane, 3:1 v/v) to give 17-allyl-1,14-dihydroxy-12-[2-[4-(p-iodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16tetraone (61 mg) and 17-allyl-1-hydroxy-12-[2-[4-(p-iodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 octacosa-14,18-diene-2,3,10,16-tetraone (12 mg), respectively.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:35][CH:31]3[CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: NC1CCC1
Product: Fc1cc2c(c(-c3c(Cl)cccc3Cl)c1)OC(CNC1CCC1)C2

Procedure:
The title compound was prepared (0.074 g, 61%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.14 g, 0.30 mmol) and cyclobutylamine (0.21 g, 3.0 mmol). mp 128-130° C.
Reaction SMILES: [NH2:1][C:2]1C=C[CH:5]=[CH:4][CH:3]=1.C(N)CCC.[CH2:13]([N:15]([CH2:18]C)[CH2:16]C)C.C1C=[C:24]([NH:26][C:27]2NC3N=CNC=3C(=O)N=2)C=C(C(F)(F)F)C=1>>[CH2:2]([N:1]=[C:13]([N:26]([CH3:27])[CH3:24])[N:15]([CH3:18])[CH3:16])[CH2:3][CH2:4][CH3:5]
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1
Reactant: O=c1nc(Nc2cccc(C(F)(F)F)c2)[nH]c2nc[nH]c12
Solvent: CCCCN
Product: CCCCN=C(N(C)C)N(C)C
Yield: 84 %

Procedure:
The procedure of Example 4 was repeated, except that the solution of aniline in TMPG was replaced with a solution of n-butylamine (36.6 g, 0.5 mole) in triethylamine (51 g, 0.5 mole). Workup and distillation, as indicated, yielded 72.0 g (0.42 mole) of N"-butyl-N,N,N',N'-tetramethyl guanidine, bp. 31°-32° C. at 0.03 mm, nD22.3 1.4600, which corresponded to 84% yield of the theory.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[CH:7]=1)(=[O:3])[CH3:2].CC(O)=O.[Br:16]N1C(=O)CCC1=O.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>>[C:1]([O:4][CH2:5][C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[Br:16])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCc1cc(C)no1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1onc(C)c1Br
Temperature: 110 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of (3-methylisoxazol-5-yl)methyl acetate (0.979 g, 6.31 mmol) in AcOH (10 mL, 175 mmol) was added N-bromosuccinimide (1.30 g, 7.30 mmol) and H2SO4 (0.65 mL, 12.19 mmol). The reaction was heated to 110° C. After 1 h, the reaction mixture was cooled to room temperature and carefully poured into a beaker containing ice and saturated NaHCO3. The bi-phasic was vigorously stirred and basic solution (pH ˜8-9) was extracted with EtOAc (2×15 mL). The organic layer was washed with 2% sodium thiosulfate, washed with brine (20 mL), dried over Na2SO4, and concentrated to give a light yellow oil. The oil was purified on Biotage system (isocratic elution 10% EtOAc:90% Hexanes) to give the titled compound (1.30 g, 5.55 mmol, 88% Yield) as a colorless yellow oil. LC/MS m/z 234 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[N:10]1[CH2:26][CH2:25][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][CH:14]2[OH:24])[CH2:12][CH2:11]1.[C:27]([O-:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([O-:32])=[O:31].C(O)(=O)/C=C/C(O)=O>C(OCC)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[N:10]1[CH2:26][CH2:25][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][C:14]2=[O:24])[CH2:12][CH2:11]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: OC1CCN(c2ccccc2)C12CCN(C1CC3CCCCC3C1)CC2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CCN(c2ccccc2)C12CCN(C1CC3CCCCC3C1)CC2

Procedure:
Oxidation of 8-(octahydro-inden-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture of diastereoisomers) according to the general method of example 20 and formation of the fumarate with fumaric acid in diethyl ether yielded the title compound, pale brown solid, m.p. 225° C. and MS: m/e=353.4 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)=[CH:36][N:35]=3)=[CH:26][CH:25]=2)[CH3:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([C:37]2[CH:38]=[CH:39][C:34]([C:33]#[C:32][CH2:31][CH2:30][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:21]([CH3:22])[CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)=[CH:29][CH:28]=3)=[N:35][CH:36]=2)=[CH:41][CH:42]=1
Reactant: CN(Cc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 mL trifluoroacetic acid are added to a solution of 35 mg (0.06 mmol) tert-butyl-4-[(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-amino]-piperidin-1-carboxylate in 3 mL DCM and the reaction mixture is stirred for 3 h at RT. The mixture is evaporated down i.vac., the residue is combined with 10 mL NaHCO3 solution, extracted with 20 mL DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the desired product is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].[NH2:12][C:13]1[C:18]([C:19]#[N:20])=[C:17](F)[CH:16]=[CH:15][CH:14]=1.O>CN1C(=O)CCC1>[NH2:12][C:13]1[C:18]([C:19]#[N:20])=[C:17]([O:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: OCCN1CCOCC1
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1c(N)cccc1OCCN1CCOCC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
4-(Hydroxyethyl)morpholine (1.02 equivalents) was added to NaH (1.2 equivalents) in NMP. After 10 minutes, 6-amino-2-fluorobenzenecarbonitrile (1.0 equivalent) was added in NMP. The resulting mixture was heated at 100° C. for 1 hour. The mixture was then cooled and poured into H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yield a brown gum. The crude material was purified by silica gel chromatography (5:1:95 MeOH:Et3N:EtOAc) to give the desired product. LC/MS m/z 248.3 (MH+), Rt 1.26 minutes.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=CC(OC)=[CH:26][C:25]=2[O:32][CH3:33])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-:35].CO[CH2:38][CH2:39][O:40][CH3:41]>O.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:35])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:38][C:39]([O:40][CH3:41])=[CH:26][C:25]=1[O:32][CH3:33])[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c(OC)c1
Reactant: COCCOC
Reactant: [OH-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1
Reaction time: 1.75 h

Procedure:
A solution of 1.58 g (3.47 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(2,4-dimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 56 ml of ethylene glycol dimethyl ether and 28.2 ml of water is treated, at RT, with 13.87 ml of a 1M solution of LiOH in water, and this mixture is stirred for 1.75 h. After that, the reaction mixture is diluted with ethyl acetate and a little THF and the whole is washed firstly with a mixture consisting of 170.6 ml of sat. ammonium chloride solution and 14.25 ml of 10% citric acid solution (both being cold) and then with saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated on a RE at about 30° C. The residue, which is the title compound, is triturated with hexane and filtered off with suction. M.p.: 144°-145° C. TLC Rf (D)=at the start. FAB-MS (M+H)+ =474. HPLC TRet =14.34 min (gradient II). IR(KBr)=u.a. 3420, 3350, 2818, 1686, 1518 and 1508 cm-1. 1H-NMR(CD3OD)=inter alia 7.30-7.09/m (5H); 6.94/d (1H); 6.47/d (1H); 6.37/dxd (1H); 3,78 and 3.75/each s (each 3H); 1.33/s (9H).
Reaction SMILES: [N+:1]([C:4]1[C:62]([CH3:63])=[CH:61][CH:60]=[CH:59][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][N:9]([C@@H:12]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:13]([NH:15][C@@H:16]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:17]([OH:46])[CH2:18][C@@H:19]([NH:33][C:34]([C@@H:36]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][CH:22]=2)=[O:14])[C:8]1=[O:58])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:62]([CH3:63])=[CH:61][CH:60]=[CH:59][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][N:9]([C@@H:12]([C:54]([CH3:55])([CH3:56])[CH3:57])[C:13]([NH:15][C@@H:16]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:17]([OH:46])[CH2:18][C@@H:19]([NH:33][C:34]([C@@H:36]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][CH:22]=2)=[O:14])[C:8]1=[O:58]
Reactant: [H][H]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2[N+](=O)[O-])C1=O)C(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2N)C1=O)C(C)(C)C)C(C)(C)C
Yield: 82.6 %

Procedure:
A solution of Example 141E (64 mg, 0.074 mmol) in ethanol (2 mL) was treated with 10% Pd/C (23.6 mg, 0.022 mmol) with a hydrogen balloon at 25° C. for 16 h. The catalyst was filtered through Celite®, rinsed with ethanol, and the solvents were evaporated. The crude residue was purified using reverse phase chromatography eluting with a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.051 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(s, 9H), 0.87(s, 9H), 1.58-1.49(m, 2H), 2.12(s, 3H), 2.23-2.12(m, 1H), 2.61-2.54(m, 1H), 2.66-2.64(d, J=7.35 Hz, 2H), 2.88-2.81(m, 2H), 3.02-2.93(q, J=8.58 Hz, 1H), 3.18-3.12(m, 1H), 3.48(s, 3H), 3.69-3.65(m, 1H), 3.86-3.82(d, J=9.93 Hz, 1H), 4.05(s, 1H), 4.33-4.13(m, 4H), 6.65-6.58(m, 2H), 6.99-6.90(m, 4H), 7.08-7.05(d, J=7.72 Hz, 2H), 7.28-7.25(d, J=8.46 Hz, 2H), 7.37-7.33(d, J=9.93 H, 1H), 7.46-7.42(m, 1H), 7.90-7.83(m, 2H), 8.03-7.90(m, 2H), 8.69-8.67(d, J=4.78 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9].C(N(CC)CC)C>CS(C)=O>[CH:2]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=[O:1]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(CO)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reaction time: 5 h
Yield: 75 %

Procedure:
The product from Example 76D (2.3 g, 4.6 mmol) and triethylamine (4.48 mL, 32.1 mmol) in DMSO (25 mL) was treated with sulfur trioxide pyridine complex (2.92 g, 18.4 mmol). After 5 hours, the mixture was partitioned between ethyl acetate and 1N HCl. The separated organic phase was washed with 1N HCl, brine, and concentrated under reduced pressure. The residue was dissolved in THF (30 mL) and saturated aqueous Na2CO3 solution (30 mL) was added. After stirring vigorously for 1 hour, the separated aqueous layer was acidified and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound as a pale yellow solid (1.73 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=[C:9]([CH3:23])[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[CH2:30](O)[C:31]#[C:32][CH3:33]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=[C:9]([CH3:23])[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:30][C:31]#[C:32][CH3:33])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[CH3:12])=[O:4]
Reactant: CC#CCO
Reactant: COC(=O)c1cc(-c2ccccc2)cc(C)c1N(C)S(=O)(=O)c1ccc(O)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(C)cc(-c3ccccc3)cc2C(=O)OC)cc1
Yield: 88.9 %

Procedure:
According to the procedure of Example 5 242 mg (0.58 mmol) of the product of Example 42 and 0.049 ml (0.65 mmol) of 2-butyn-1-ol provides 0.239 g (98%) of 4-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-5-methyl-biphenyl-3-carboxylic acid methyl ester. Electrospray Mass Spec: 464.2 (M+H)+.