Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH3:20][CH:21]1[NH:26][CH:25]([CH3:27])[CH2:24][N:23]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22]1.C(N(CC)CC)C>C(#N)C>[CH3:20][C@H:21]1[CH2:22][N:23]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][C@@H:25]([CH3:27])[N:26]1[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: CC1CN(S(C)(=O)=O)CC(C)N1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1Cc1nnnn1-c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 103 %

Procedure:
4-[5-(Chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 24, 86 mg, 0.3 mmol) and 3,5-dimethyl-1-(methylsulfonyl)piperazine (Intermediate 36, 78 mg, 0.41 mmol) were weighed into a vial and suspended in acetonitrile (1.2 mL). Triethylamine (84 μL, 0.60 mmol) was added, and the mixture was heated at 140° C. in a microwave with stirring for 3 h. The reaction mixture was applied to a 10 g SCX cartridge, pre-washed with MeOH (50 mL). This was eluted with MeOH (100 mL) and 10% aq NH3 in MeOH (100 mL). The basic fractions were concentrated to give an off-white solid (137 mg). This was purified by MDAP to give the title compound as a colourless solid (38 mg), confirmed by NMR to be the pure cis-isomer.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=2)=[O:13])[CH2:8]1>>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH2:11][CH:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: CS(=O)(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from methanesulfonyl chloride and (3-amino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 360/362 (MH+); HPLC Rf: 3.22 min.; HPLC purity 98%.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[N:3]=[C:4]([CH3:6])[CH3:5].C([N-]C(C)C)(C)C.[Li+].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:35]=[CH:34][C:21]([O:22][C:23]2[CH:33]=[CH:32][C:26]([O:27][CH:28]([CH3:31])[CH:29]=[O:30])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.O.C(Cl)Cl>O1CCCC1>[CH3:1][N:2]([CH3:7])[N:3]=[C:4]([CH2:6][CH:29]([OH:30])[CH:28]([O:27][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]2[CH:34]=[CH:35][C:18]([C:17]([F:37])([F:16])[F:36])=[CH:19][CH:20]=2)=[CH:33][CH:32]=1)[CH3:31])[CH3:5]
Reactant: CC(C=O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)=NN(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)=NN(C)C
Reaction time: 1 h

Procedure:
To a solution of acetone N,N-dimethylhydrazone (6.5 mmol) in tetrahydrofuran (THF; 15 ml) under nitrogen is added lithium diisopropylamide (LDA; 7.2 mmol) in THF (15 ml) at 0° for 5 hours. The resulting solution is cooled to -78°, and to it is added 2-[4-(4-trifluoromethylphenoxy)phenoxy]propanal (7.2 mmol). After 1 hour at -78°, the reaction mixture is allowed to warm to 0° and is poured into water/methylene chloride (3:1). The organic phase is separated (3X), and the combined organic extracts are dried over sodium sulfate and concentrated to give 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)-phenoxy]-2-hexanone N,N-dimethylhydrazone (cpd. 1, Table A).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 3.7 %

Procedure:
The title compound (10.9 mg, 3.2%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (270 mg, 0.803 mmol, prepared in example 1), 4-chlorobenzeneboronic acid (151 mg, 0.966 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol), 2 M sodium carbonate (295 mg in 1.4 mL water) and 1,4-dioxane (5.5 mL) in a manner analogous to the procedure described in Example 2. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 115 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1.[N:25]1[CH:30]=[CH:29][C:28]([Li])=[CH:27][CH:26]=1>>[OH:1][C:2]1([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:23][CH2:24]1
Reactant: [Li]c1ccncc1
Reactant: O=C1CCCCC1N1CCC2(CC1)C(=O)NCN2c1ccccc1
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCCC1(O)c1ccncc1)CC2

Procedure:
The title compound was prepared from rac-8-(2-oxo-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 4-pyridyl-lithium in analogy of the procedure described for the synthesis of (rac,cis)-8-(2-hydroxy-2-phenyl-cyclohexyl)-1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one (Example 73e). (rac,cis) 8-(2-Hydroxy-2-pyridin-4-yl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as colorless solid, MS (ISP): 407.4 MH+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17].[C:32]([O:36][C:37]([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42](O)=[O:43])=[O:38])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:41]2[CH:40]=[C:39]([CH:47]=[CH:46][CH:45]=2)[C:37]([O:36][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:38])=[O:43])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][C@@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][CH2:20]3)[CH:29]=[CH:30][N:31]=2)[CH:4]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a mixture of (S)-2-(2-amino-5-(diethylamino)phenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide (7.1 mmol, 2.94 g), 3-(tert-butoxycarbonyl)benzoic acid (8.52 mmol, 1.89 g) and DIEA (35.5 mmol, 4.59 g) in DMF (16 mL) was added HATU (8.52 mmol, 3.24 g). The mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried and concentrated. The residue was purified by column to give a yellow solid (4.31 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:17])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(Cl)Cl.C(O)(=O)C>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=3)[C:7](=[O:17])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1C(=O)N(c2ccccc2)c2cc(O)ccc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccc(O)cc2N1c1ccccc1
Temperature: 140 °C
Yield: 17 %

Procedure:
A mixture of 6-hydroxy-1-phenyl-1H-indole-2,3-dione (13 mg, 0.054 mmol) and 3-(trifluoromethyl)aniline (160 mg, 1 mmol) in CH2Cl2 (1 mL) and acetic acid (1 drop) was heated at 140° C. The crude product was purified preparative TLC [Eluent: EtOAc/hexane (2:3)], giving the desired product (3.5 mg, 17%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[C:23]1(B(O)O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:31]1([C:2]2[CH:7]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:3]=2)[C:32]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: OB(O)c1cccc2ccccc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccc(S(=O)(=O)c2cc(-c3cccc4ccccc34)nc(N3CCCC3)c2)cc1
Yield: 20.5 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 106 mg (0.55 mmole) 1-naphthylboronic acid, 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 20 hours in 7 ml toluene and 2 ml 2N aqueous potassium carbonate. The solvents are removed in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 44 mg (20%) pure 4-(2-naphthalen-1-yl-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine as an amorphous solid with corresponding NMR- and mass spectra.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)o2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 66 h
Yield: 74.4 %

Procedure:
To a solution of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid methyl ester prepared in Example 144 (80 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was added an aqueous solution (2 mL) of LiOH (32 mg, 1.35 mmol). The reaction mixture was stirred at room temperature for 66 h, and the “pH” of the solution was adjusted to 5-6 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid as a yellow solid (60 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[F:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[F:32])[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-bromomethyl-3-fluoro-benzonitrile analogous to Example 1 to afford 4-chloro-N-(4-cyano-2-fluoro-benzyl)-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide:MS: m/e=472.2 (MH+).
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=CC=CC=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[F:34][C:16]([F:33])([F:15])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH:29][C:12]([CH:7]3[CH2:1][CH2:6][CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:27][CH2:28][C@H:23]2[CH2:22]1
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C1CCCCCC1

Procedure:
The title compound was prepared by substituting cycloheptanecarboxylic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.79 (d, J=6.9, 1H), 7.71 (s, 1H), 7.62 (d, J=7.7, 1H), 7.56 (s, 1H), 7.47 (t, J=7.7, 1H), 4.48-4.40 (m, 1H), 3.54 (d, J=13.2, 1H), 3.46 (d, J=13.2, 1H), 2.86 (ddd, J=3.0, 7.8, 16.6, 1H), 2.76 (dd, J=3.0, 9.5, 1H), 2.51-2.39 (m, 2H), 2.37-2.30 (m, 2H), 2.26 (dd, J=7.5, 9.4, 1H), 2.00-1.80 (m, 5H), 1.75-1.60 (m, 4H), 1.49-1.41 (m, 4H), 1.33 (ddt, J=7.2, 8.9, 12.1, 3H); MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:28]([OH:30])=O)[CH2:12]1)(=[O:10])=[O:9].[CH2:31]([NH:35][C:36](=[O:43])[C:37](=[O:42])[C@@H:38]([NH2:41])[CH2:39][CH3:40])[CH:32]([CH3:34])[CH3:33]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2([C:16]([N:14]3[CH2:15][C@H:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]3[C:28]([NH:41][C@@H:38]([CH2:39][CH3:40])[C:37](=[O:42])[C:36]([NH:35][CH2:31][CH:32]([CH3:33])[CH3:34])=[O:43])=[O:30])=[O:17])[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CC[C@H](N)C(=O)C(=O)NCC(C)C
Product: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Cl)cc2)CC1)C(=O)C(=O)NCC(C)C

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-Amino-2-oxo-pentanoic acid isobutyl-amide in step 1. MS (m/e)=636.17 [M+H+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1/C(=C/c2n[nH]c3ccccc23)Oc2c1ccc(OCc1ccccc1)c2CN1CCNCC1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0720 g, 0.127 mmol) in methylene chloride (2 mL) was added with trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was added with water (6 mL) and saturated aqueous sodium hydrogencarbonate (6 mL), and thereby adjusted to pH 8, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and then the resulting solid was washed with water to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-(benzyloxy)-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0490 g, 82%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>[Cu]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(I)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cu]
Product: CS(=O)(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 120 °C

Procedure:
A mixture of 4-methanesulphonyliodobenzene (18 g), 2-bromonitrobenzene (12.7 g) and copper powder (12 g) was heated at 120° C. for 30 hours to yield a residue which was purified by chromatography on a silica column eluted successively with 5:95 mixture, a 10:90 mixture, a 25:75 mixture and then a 40:60 mixture of ethylacetate and hexane to give 4'-methanesulphonyl-2-nitrobiphenyl (m.p. 178° C.). 4'-methanesulphonyl-2-nitrobiphenyl (5 g) was heated at 90°-95° C. for 6 hours with hydrated sodium sulphide (17.3 g) and ethanol (100 ml) to give 2-amino-4'-methanesulphonylbiphenyl (m.p. 164°-165° C.).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CC(C)=O.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[N:13]1([CH2:12][CH2:11][O:4][C:1](=[S:3])[CH3:2])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC([O-])=S
Reactant: ClCCN1CCCCC1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=S)OCCN1CCCCC1
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
Potassium thioacetate (1.8 g, 16.35 mmol) was added to acetone (50 ml) and then stirred for 10 minutes under argon atmosphere. 1-(2-Chloroethyl)piperidine (1.61 g, 10.40 mmol) was added dropwise thereto and stirred for 18 hours under argon atmosphere at room temperature. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with flash column chromatography (dichloromethane:ethyl acetate=19:1) to obtain 0.71 g (yield: 35%) of the title compound as a red oil.
Reaction SMILES: Cl.[C:2]1(/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:24]=[CH:23][C:13]3[N:14](C4CCCCO4)[N:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C>[NH:14]1[C:13]2[CH:23]=[CH:24][C:10](/[C:9](/[C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=3)=[C:8](/[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)\[CH2:38][CH3:39])=[CH:11][C:12]=2[N:16]=[N:15]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3c(c2)nnn3C2CCCCO2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]nnc3c2)cc1
Temperature: 70 °C

Procedure:
Hydrochloric acid (2.7 mL, 2M in diethyl ether) was added to a solution of (E)-ethyl 3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d][1,2,3]triazol-5-yl)but-1-en-1-yl)phenyl)acrylate (0.28 g, 0.55 mmol) in ethyl alcohol (27 mL) at room temperature, and the resulting mixture was heated at 70° C. for 2 h. The reaction was monitored by TLC. Upon completion, the mixture was cooled down to room temperature and concentrated to give a pale yellow solid. This solid was dissolved in ethyl acetate (100 mL), washed with saturated NaHCO3 (50 mL), water (100 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a silica gel column eluted with 0-50% ethyl acetate in hexanes affording the title compound. LCMS: 424 (M+H)+.
Reaction SMILES: O.[C:2]([NH:12][NH2:13])(=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][NH2:10])=[O:8]>CC(=O)C>[CH:2](=[N:10][NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH:12][N:13]=[CH:5][CH2:6][CH3:7])=[O:11])[CH2:3][CH3:4]
Reactant: NNC(=O)CCCCC(=O)NN
Solvent: O
Solvent: CC(C)=O
Product: CCC=NNC(=O)CCCCC(=O)NN=CCC

Procedure:
In a stainless steel flask equipped with an agitator, 58.6 grams of water were added, the agitator was turned on, then 25 grams of adipic acid dihydrazide were added. The mixture was agitated for at least 10 minutes until a stable dispersion was formed. 16.4 grams of 2-propanone were then added under mixing. A clear solution formed after a few minutes. Mixing was continued for at least another hour until reaction product precipitated and formed a stable dispersion.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[N:2].C[O-].[Na+].[C:13](O)(=[O:15])C>CO>[CH3:9][C:5]1[N:4]=[C:3]([C:1](=[NH:2])[O:15][CH3:13])[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(C#N)n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccc(C)n1
Reaction time: 3 h

Procedure:
To the solution of 2-cyano-6-methylpyridine (30 g) and methanol (300 ml) was added 28% sodium methoxide solution in methanol (14.7 g). After the solution was left to stand for 3 hours, acetic acid (4.6 g) was added thereto, followed by concentration under reduced pressure. The resultant residue was dissolved in ether (300 ml) and washed with water (100 ml). After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain methyl 6-methyl-2-picoline imidate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO.[C:16]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[OH:1]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1O
Reaction time: 1.25 h
Yield: 100 %

Procedure:
916 mg (5 mmol) of 2-hydroxy-4-nitro-benzoic acid is dissolved in a mixture that consists of 8 ml of methanol and 32 ml of toluene, and it is slowly mixed with a solution of trimethylsilyldiazomethane in hexane (2 molar). After the addition is completed, stirring is continued for 1.25 hours at room temperature. After the reaction mixture is concentrated by evaporation, 1 g (about 100% of theory) of 2-hydroxy-4-nitro-benzoic acid methyl ester is obtained.