Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8](I)=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: OB(O)C1CC1
Reactant: COc1cc(Cl)c(I)cc1N
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(C2CC2)cc1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxyaniline (5.0 g, 17.6 mmol), cyclopropylboronic acid (1.8 g, 21.1 mmol), Pd(OAc)2 (314 mg, 1.4 mmol), tricyclohexylphosphine (500 mg, 17.6 mmol), K3PO4.3H2O (16.4 g, 61.6 mmol) in toluene (62.5 mL) and H2O (3 mL) was stirred at 80° C. under argon for 16 h. The mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product (3.1 g, 88.5% yield). ESI-MS m/z: 198.2[M+H]+.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1.[Cu]I>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:14]([OH:15])[CH2:16][CH:17]=[CH2:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CO2)cc1
Reactant: C=C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC[C@H](O)C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
(2R)-2-benzhydryl-oxirane (0.5 g, 2.38 mmol) 23a was dissolved in dry THF (5 ml) and was added into a dry THF solution at −78° C. containing CuI (0.045 g, 0.24 mmol) and vinylmagnesium bromide (5.95 ml of 1.0M solution in THF, 5.95 mmol). The reaction mixture was stirred and allowed to reach room temperature over a period of 2 h, and then quenched with saturated NH4Cl solution. The aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel (Hexane/Ethyl Ether=4:1) to give 0.4 g (2S)-1,1-diphenyl-pent-4-ene-2-ol (70%, [α]D=(−)25, c=1, MeOH).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](NC2CCCCCC2)C1

Procedure:
tert-butyl (3S)-3-(cycloheptylamino)pyrrolidine-1-carboxylate was prepared by a method similar to that described in preparation 14 using tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate and cycloheptanone to yield the desired product, 4.54 g (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.O=[C:23]1[C:32]2[N:31]=[CH:30][C:29]([C:33]#[N:34])=[CH:28][C:27]=2[CH2:26][CH2:25][CH2:24]1>>[F:15][C:14]1([F:16])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9][C@@:8]1([C:6]1[CH:7]=[C:2]([NH:1][CH:23]2[C:32]3[N:31]=[CH:30][C:29]([C:33]#[N:34])=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[CH:3]=[CH:4][C:5]=1[F:21])[CH3:20]
Reactant: N#Cc1cnc2c(c1)CCCC2=O
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC3CCCc4cc(C#N)cnc43)ccc2F)C1(F)F
Yield: 63.2 %

Procedure:
Prepared in an analogous manner as described for intermediate A22A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (intermediate A19B) (102 mg, 320 μmol) and 8-oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile (66.2 mg, 384 μmol). The 8-(3-((R)-6,6-difluoro-5,7,7-trimethyl-3-thioxo-1,4-oxazepan-5-yl)-4-fluorophenylamino)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (96 mg, 63.1%) was obtained as a white foam. MS (ISN): m/z=473.1 [(M−H)−].
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH2:14])[CH:11]=2)[CH2:6][CH2:5]1.[CH3:15][CH2:16][N:17](CC)CC>CCO>[NH2:14][CH2:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][CH:4]2[NH:3][C:16](=[NH:17])[CH3:15])=[CH:8][CH:9]=1
Reactant: NCc1ccc2c(c1)C(N)CC2
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CC(=N)NC1CCc2ccc(CN)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
6-Cyanoindan-1-one (prepared using the procedure of Allinger and Jones, JOC 1962, p70. vol 27 for the tetralone analogue) (3.86 g, 24.5 mmol) was converted to the 1-oxime-O-benzyl ether and reduced with BH3 -THF by the methods described in example 59 to give 1-amino-6-(aminomethyl)indane. The diamine was isolated in 31% yield as the 2 HCl salt by treatment of an ether solution with 4.0N HCl in dioxane. 1-Amino-6-aminomethylindane 2HCl (0.5 g, 2.1 mmol) was stirred in EtOH (20 ml), cooled to 0° C. and treated with NEt3 (0.59 ml, 4.2 mmol). Intermediate A (0.43 g, 2.1 mmol) was added and the mixture was allowed to warm to 20° C. and stir overnight. The white crystaline product was collected and washed with a small volume of ether and dried in vacuo to give N-(6-(Aminomethyl)-1-indanyl)acetamidine (0.27 g, 35%) as the 2 HCl salt. NMR (D2 0) 7.45-7.25 (m, 3H), 4.8 (m, 1H), 4.45 (s, 2H), 3.2-2.85 (m, 2H), 2.6)m, 1H), 2.2 (s, 3H, CH3), 2.1 (m, 1H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10])(C)C.[CH3:15][O-:16].[Na+].[CH3:18][OH:19]>>[CH3:15][O:16][CH:5]([O:19][CH3:18])[CH2:6][C:7]1[N:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: C[O-]
Reactant: CO
Reactant: C[Si](C)(C)C#Cc1ncccc1C#N
Agent: [Na+]
Product: COC(Cc1ncccc1C#N)OC
Temperature: 80 °C
Yield: 75 %

Procedure:
To a solution of 2-((trimethylsilyl)ethynyl)nicotinonitrile (19.14 g, 95.7 mmol) in MeOH (200 mL) was added sodium methanolate (16.5 g, 306.2 mmol). The reaction mixture was refluxed at 80° C. for 14 h under N2. After removal of the MeOH, the residue was diluted with H2O and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluting with DCM) to yield 2-(2,2-dimethoxyethyl)nicotinonitrile as a yellow oil (13.76 g, yield 75%). ESI MS: m/z 193 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:27]([CH:24]3[CH2:26][CH2:25]3)(=[O:29])=[O:28])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(NC1CCCC(Nc2cc(I)cc(Cl)n2)C1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of Example 260a (0.320 g, 0.910 mmol) in DMF (6 mL) were added triethylamine (0.165 mL, 1.183 mmol) and cyclopropanesulfonyl chloride (0.102 mL, 1.001 mmol). The reaction mixture was stirred at room temperature overnight, quenched with brine and NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with hexane/EtOAc (7:3 to 1:1) to give 0.092 g of the title compound.
Reaction SMILES: C([C@H]1CN(C2COC2)CCN1C1C=CC(NC2C(=O)N(C)C=C(C3C=CN=C(N4CCN5C6CCCCC=6C=C5C4=O)C=3CO)C=2)=NC=1)C.C([O:53][CH2:54][C:55]1[C:56]([N:79]2[CH2:91][CH2:90][N:82]3[C:83]4[CH2:84][CH2:85][CH2:86][CH2:87][C:88]=4[CH:89]=[C:81]3[C:80]2=[O:92])=[N:57][CH:58]=[CH:59][C:60]=1[C:61]1[CH:66]=[C:65]([NH:67][C:68]2[CH:76]=[C:71]3[CH2:72][O:73][CH2:74][CH2:75][N:70]3[N:69]=2)[C:64](=[O:77])[N:63]([CH3:78])[N:62]=1)(=O)C.[OH-].[Li+]>>[N:69]1[N:70]2[C:71]([CH2:72][O:73][CH2:74][CH2:75]2)=[CH:76][C:68]=1[NH:67][C:65]1[C:64](=[O:77])[N:63]([CH3:78])[N:62]=[C:61]([C:60]2[CH:59]=[CH:58][N:57]=[C:56]([N:79]3[CH2:91][CH2:90][N:82]4[C:83]5[CH2:84][CH2:85][CH2:86][CH2:87][C:88]=5[CH:89]=[C:81]4[C:80]3=[O:92])[C:55]=2[CH2:54][OH:53])[CH:66]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc3n(n2)CCOC3)c1=O
Yield: 64.7 %

Procedure:
Following the procedures as described for compound 131, hydrolysis of 132b (100 mg 0.171 mmol) with lithium hydroxide afforded 132 as a white solid (60 mg, 65%). LCMS: [M+H]+ 543. 1H NMR (500 MHz, CDCl3) δ 8.55 (d, J=5.0, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.43 (d, J=5.5, 1H), 6.87 (s, 1H), 5.97 (s, 1H), 4.80 (s, 2H), 4.58 (s, 3H), 4.47 (s, 1H), 4.15-1.14 (m, 2H), 4.11 (s, 4H), 3.90 (s, 4H), 2.61-2.60 (m, 2H), 2.57 (t, J=6.5, 2H), 1.89-1.91 (m, 2H), 1.79-1.80 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8](CC2C=CC=CC=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH:10]([OH:15])[C:11]([F:13])([F:12])[F:14])[CH:5]=[CH:6][CH:7]=1
Reactant: OC(CN(Cc1ccccc1)c1cccc(F)c1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: OC(CNc1cccc(F)c1)C(F)(F)F
Yield: 98.4 %

Procedure:
Ex-662A) 3-[(3-fluorophenyl)[phenylmethyl]amino]-1,1,1-trifluoro-2-propanol (2.56 g, 8.2 mmol) was dissolved in methanol (30 mL) and hydrogenated over 5% palladium on charcoal for 3 h. The mixture was filtered through celite, and the solvent was removed in vacuo to give 1.8 g (98%) of the desired 3-[(3-fluorophenyl)amino]-1,1,1-trifluoro-2-propanol product as an oil, 99% pure by HPLC analysis. MS m/z=224 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl[(tert-butoxycarbonyl)amino]acetate (1.01 g, 4.37 mmol) was dissolved in THF (10 mL) and cooled to −78° C. LiHMDS (6.5 mL, 1M solution in THF) was slowly added and allowed to stir for 30 minutes. Methyl 4-(bromomethyl)benzoate (1.98 g, 8.64 mmol) in THF (6 mL) was added to the mixture and allowed to stir overnight, slowly warming to room temperature. The reaction was diluted with ethyl acetate and quenched with saturated ammonium chloride. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography. MS: cal'd 379 (MH+), exp 402 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:11])[NH:4][N:3]=1.Br.Br[CH2:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl.O>[CH2:18]([N:17]([CH2:20][CH3:21])[CH2:16][CH2:15][CH2:14][NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:11])[NH:4][N:3]=1)[CH3:19]
Reactant: CCN(CC)CCCBr
Reactant: Nc1n[nH]c2cccc(Cl)c12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1n[nH]c2cccc(Cl)c12
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
A mixture consisting of 5.04 g of 3-amino-4-chloroindazole, 8.30 g of 3-bromopropyldiethylamine hydrobromide, 8.3 g of anhydrous potassium carbonate and 80 ml of anhydrous N,N-dimethylformamide was stirred for 24 hours at 80° C. The reaction mixture was condensed under reduced pressure, the condensed residue was added with 100 ml of chloroform and 50 ml of water. The chloroform layer was separated and dried over anhydrous sodium sulfate, and then chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 5.16 g of 3-(3-diethylaminopropylamino)-4-chloroindazole having the following analytical values in a yield of 61%.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14](=[O:20])[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:6][C:5]=1[Cl:21].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:7]([CH:14]([OH:20])[CH2:15][NH:16][CH:17]([CH3:18])[CH3:19])=[CH:6][C:5]=1[Cl:21]
Reactant: CC(C)NCC(=O)c1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCC(O)c1cc(Cl)c(N)c(C(F)(F)F)c1

Procedure:
m.p. 104°-106° C., m.p. of the hydrochloride: 185°-187° C., was prepared from 4'-amino-3'-chloro-2-isopropylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:23]2C=CC=CC=2)=[CH:4][CH2:3]1.CC1C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C(C)(C)CC=1>>[CH3:23][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:10][C:11]=2[C:2]([CH3:1])([CH3:29])[CH2:3][CH:4]=1
Reactant: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C)cc1
Product: CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 37 mg (0.11 mmol) of ethyl 4-[(7,8-dihydro-5,8,8-trimethylnaphth-2-yl)ethynyl]benzoate (Compound 95) was converted to the title compound (white solid) using 23 mg (1.1 ml, 0.54 mmol) of LiOH (0.5M aqueous solution).
Reaction SMILES: [NH:1]([C:8]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C>Cl>[NH:1]([C:8]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)Nc3ccccc3)ccc21
Agent: Cl
Solvent: CC#N
Product: O=C(O)CC(c1ccccc1)n1cnc2cc(C(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of ethyl 3-[5-(anilinocarbonyl)-1H-benzimidazol-1-yl]-3-phenylpropanoate (27 mg, 65 μmol) in a mixture of hydrochloric acid (20 mL of a 5N solution) and acetonitrile (15 mL) was stirred at room temperature for 96 hours. The resulting suspension was then concentrated and filtered, and the resulting solid dried in vacuo over P2O5 to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.54 min, MH+ 386].
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[C:19]([NH:21][C:22](=[O:33])[C:23]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:20])C1C=CC=CC=1.Cl.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[C:19]([NH:21][C:22](=[O:33])[C:23]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:20]
Reactant: O=C1NC(=O)C(c2c[nH]c3ccc(OCc4ccccc4)cc23)=C1c1c[nH]c2ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2c[nH]c3ccc(O)cc23)=C1c1c[nH]c2ccccc12
Temperature: 0 °C

Procedure:
0.15 g (0.34 mmol) 2-(5-benzyloxy-1H-indol-3-yl)-3-(1H-indol-3-yl)-maleinimide and 4.0 g (34 mmol) pyridinium hydrochloride are heated under an atmosphere of nitrogen for 1 hour at 150° C. After cooling, the reaction mixture is diluted with ice water and extracted with ethyl acetate. The organic phase is washed out with water and evaporated to dryness. The solid residue is triturated with a little water, filtered off with suction and dried in a vacuum at 0.1 Torr and 80° C. There are obtained 85 mg (73% of theory) of dark red product; m.p. 200°-205° C.; RF=0.29 (toluene/ethanol 10:2 v/v).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33]2[N:34]=[C:17]([C:16]3[CH:20]=[CH:21][C:13]([N:7]4[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]4)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=3)[O:19][N:35]=2)[CH:32]=1
Reactant: O=C(O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 42 (137 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from n-pentane afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2](=[N:44][OH:45])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][O:7][NH:8][C:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:12]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:10].C(#N)C.[C:49](N1C=CN=C1)(N1C=CN=C1)=[S:50].C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[CH:12]1[CH:11]([C:9]([NH:8][O:7][CH2:6][C:5]2[CH:41]=[CH:42][CH:43]=[C:3]([C:2]3[NH:1][C:49](=[S:50])[O:45][N:44]=3)[CH:4]=2)=[O:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(N)=NO)c2)C1c1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(-c3noc(=S)[nH]3)c2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a mixed liquid of 300 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 30 ml of acetonitrile were added 132 mg of 1,1′-carbonothioyl bis(1H-imidazole) and 0.27 ml of DBU under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated and then added with 50 ml of water, and 1 M hydrochloric acid was added thereto until the pH reached 4 to 5. After extracting with ethyl acetate, washing with a saturated aqueous sodium chloride solution and drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol). The crude purified product thus obtained was added with ethyl acetate and collected by filtration to obtain 61 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39]>C1COCC1>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[CH2:31][CH:15]1[CH2:16][CH2:17][CH2:18][N:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:21])[CH3:20])[CH2:12][CH2:11]2)[C:14]1=[O:19]
Reactant: Fc1cccc(Cl)c1CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCCC2=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCC(Cc3c(F)cccc3Cl)C2=O)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Dissolve trans-1-(4-[tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one (0.3 g, 0.96 mmol) in anhydrous THF (6 mL) under nitrogen, cool to −78° C. and add LDA (2M solution in THF) (0.72 mL, 1.44 mmol) dropwise. Stir the reaction mixture for 5 minutes and add 2-bromomethyl-1-chloro-3-fluoro-benzene (0.3 g, 1.44 mmol) in anhydrous THF (2 mL) dropwise. Stir the reaction mixture at −78° C. for 3 hours, slowly warm to room temperature, quench with saturated aqueous NH4Cl (5 mL) and extract with DCM (3×10 mL). Dry the organic layer over Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 20% EtOAc in hexane) to obtain trans-3-(-2-chloro-6-fluoro-benzyl)-1-(4-[tert-butyl-dimethyl-silanyloxy]-cyclohexyl)-piperidin-2-one as a white solid (0.2 g). Dissolve the trans-3-(-2-chloro-6-fluoro-benzyl)-1-(4-[tert-butyl-dimethyl-silanyloxy]-cyclohexyl)-piperedin-2-one in methanol containing concentrated hydrochloric acid (5% v/v) and heat at 40° C. for 1 hour. Evaporate the solvent, dissolve the residue in DCM (10 mL) and wash with saturated aqueous NaHCO3 (5 mL). Dry the organic layer over anhydrous Na2SO4, remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 50% EtOAc in hexane) to obtain the title compound as a clear oil (110 mg, 34%): MS (ES+) m/z=340 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[CH:4]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18]C(=O)OC(C)(C)C)[CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].NC(=O)C(N1CCC[C@@H](NC(=O)OC(C)(C)C)C1)C1C=CC=CC=1F.[ClH:53]>CO>[ClH:53].[NH2:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[F:11])[C:3]([N:2]([CH3:27])[CH3:1])=[O:26])[CH2:13]1
Reactant: CN(C)C(=O)C(c1ccccc1F)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(C(N)=O)c2ccccc2F)C1
Agent: Cl
Solvent: CO
Product: CN(C)C(=O)C(c1ccccc1F)N1CCC[C@@H](N)C1

Procedure:
tert-Butyl (3R)-1-(2-(dimethylamino)-1-(2-fluorophenyl)-2-oxoethyl)piperidin-3-ylcarbamate (302 mg, 0.796 mmol), prepared according to the procedures described for tert-butyl (3R)-1-(2-amino-1-(2-fluorophenyl)-2-oxoethyl)piperidin-3-ylcarbamate, was stirred in 3 M HCl in MeOH (8 mL) at 50° C. for 5 hours. The solvent was removed in vacuo to give the bis HCl salt of 2-((R)-3-aminopiperidin-1-yl)-2-(2-fluorophenyl)-N,N-dimethylacetamide as a ˜1:1 mixture of diastereoisomers.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)=[O:10]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccn1
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccccn2)cc1)c1ccccc1

Procedure:
The title product was prepared from pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (41%,). HPLC-MS: m/z=348.1 (M+1); Rt: 4.00 min.